Intra-arterial Selective Hypothermic Magnesium Sulfate Infusion in Combination With Endovascular Thrombectomy in Acute Ischemic Stroke (ICE-MAG)

Selective Intra-arterial Hypothermic Magnesium Sulfate Infusion in Combination With Endovascular Thrombectomy in Acute Ischemic Stroke: A Phase 1/2 Randomized Clinical Trial

The primary objective of this study is to estimate the safety and effectiveness of selective intra-arterial hypothermic magnesium sulfate infusion after endovascular thrombectomy in patients with acute ischemic stroke.

Addendum regarding phase 1 dosing implementation and planned phase 2 design:

This integrated phase 1/2 trial originally planned weight-individualized magnesium perfusate calculated as Target Mg (μmol/mL) = 0.6 × patient body weight. During phase 1 recruitment, no dedicated emergency pharmacy fast-track compound workflow existed for urgent EVT procedures, which would cause reperfusion delay if individualized mixing was performed intraoperatively. Therefore, a uniform fixed magnesium concentration of 20.29 mmol/L was adopted as a temporary operational solution for all 9 phase 1 participants, with dose escalation only performed by increasing total infusion volume (350/500/650 mL). For the upcoming phase 2 cohort, we will retain the fully safe 650 mL maximum infusion volume and conduct independent magnesium concentration escalation across six ascending tiers: 20.29, 22.54, 25.36, 28.98, 33.81, and 40.57 mmol/L. These concentrations are prepared by diluting the standard 5 g magnesium stock into 1000 mL, 900 mL, 800 mL, 700 mL, 600 mL, and 500 mL pre-cooled normal saline respectively. After defining the maximum tolerated magnesium concentration tier, the original weight-tailored compounding formula will be fully implemented for subsequent efficacy cohorts. All protocol adjustments have received institutional review board amendment approval.

Study Overview

• Status: Enrolling by invitation
• Conditions: Acute Ischemic Stroke
• Intervention / Treatment: Procedure: Endovascular thrombectomy; Procedure: Endovascular thrombectomy combination with selective intra-arterial hypothermic magnesium sulfate infusion (350 ml).; Procedure: Endovascular thrombectomy combination with selective intra-arterial hypothermic magnesium sulfate infusion (500 ml).; Procedure: Endovascular thrombectomy combination with selective intra-arterial hypothermic magnesium sulfate infusion (650 ml).; Procedure: Phase 2 Fixed-Volume Concentration-Escalation Cohort

Detailed Description

Protocol Deviation & Planned Phase 2 Adjustment Statement The pre-specified weight-based magnesium dilution strategy could not be executed during phase 1 due to lack of on-demand intraoperative pharmacy preparation capacity for hyperacute stroke patients. All 9 phase 1 subjects received standardized cold perfusate with a fixed magnesium concentration of 20.29 mmol/L (5g MgSO₄·7H₂O diluted into 1000 mL 4℃ saline), with volumetric escalation (350/500/650 mL) only, without varying magnesium concentration. This temporary fixed-concentration regimen was a pragmatic emergency workflow compromise, not the permanent trial dosing design.

In phase 2 of this integrated registered trial, the validated safe upper limit of 650 mL total infusion volume will be fixed to avoid intracranial fluid overload. We will first conduct single-variable magnesium concentration escalation across six sequential ascending tiers:

20.29 mmol/L (5 g stock diluted in 1000 mL 0.9% saline) 22.54 mmol/L (5 g stock diluted in 900 mL 0.9% saline) 25.36 mmol/L (5 g stock diluted in 800 mL 0.9% saline) 28.98 mmol/L (5 g stock diluted in 700 mL 0.9% saline) 33.81 mmol/L (5 g stock diluted in 600 mL 0.9% saline) 40.57 mmol/L (5 g stock diluted in 500 mL 0.9% saline) After establishing a tolerable magnesium concentration threshold and identifying the maximum tolerated dose, the original registry-specified weight-individualized compounding method (Target Mg = 0.6 μmol/mL × patient body weight) will be fully applied for efficacy evaluation cohorts. This amendment was reviewed and formally approved by the institutional review board (Amendment No.XYFY2025-KL360-02).

• Study Type: Interventional
• Enrollment (Estimated): 42
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Jiangsu
    • Xuzhou, Jiangsu, China, 221000
      • 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 range of 18-80 years old (including critical value);
2. No gender restrictions;
3. The clinical diagnosis is acute ischemic stroke of the anterior circulation, and the site of acute occlusion of the responsible vessel is located in the intracranial segment of the internal carotid artery and the M1 or M2 segment of the middle cerebral artery;
4. The symptoms and signs are consistent with acute anterior circulation ischemic stroke, NIHSS≥6;
5. The time from onset to endovascular thrombectomy of acute ischemic stroke is within 24 hours;
6. Indications for endovascular thrombectomy of acute ischemic stroke: ① ASPECTS score ≥ 6 points, within 6 hours of onset; ② 6-16 hours after onset, meeting DEFUSE-3 criteria (infarct core volume < 70 mL, mismatch rate ≥ 1.8 and mismatch volume > 15 mL) or DAWN criteria (NIHSS ≥ 10 and infarct core volume < 31 mL); Or NIHSS ≥ 20 and infarct volume 31-51 mL); ③ Within 16-24 hours of onset, meet DAWN criteria (NIHSS ≥ 10 points and infarct core volume < 31mL); Or NIHSS ≥ 20 points and infarct volume 31-51 mL)
7. The mRS score before stroke is 0-1 points;
8. Written informed consent provided by the patients or their legal relatives.

Exclusion Criteria:

General exclusion criteria:

1. Clinical manifestations suggest the presence of intracranial cerebral parenchymal hemorrhage or subarachnoid hemorrhage (even if imaging results are normal);
2. During a stroke, accompanied by epilepsy, an accurate NIHSS score cannot be obtained;
3. Accompanied by coma or mental disorders, it may interfere with the assessment of neurological function;
4. History of allergy to iodinated contrast agents or history of anaphylactic shock;

5. Baseline blood glucose<50mg/dL (2.78mmol) or>400mg/dL (22.20mmol);

   *Acceptable fingertip blood glucose results

6. Baseline platelet count<50 × 10^9/L;
7. Recently (i.e. within 30 days prior to inclusion in the study), there has been a history of significant gastrointestinal or other clinically significant bleeding; Active bleeding, abnormal coagulation factors, or bleeding tendency (taking anticoagulant drugs with INR ≥ 3 or PT ≥ 3 × ULN; if the researcher believes that the subject has no coagulation dysfunction, there is no need to wait for coagulation test results to determine whether to enroll);
8. During a stroke, there may be fever or active infections that require systemic treatment (such as active pulmonary tuberculosis);
9. History of chronic heart failure with NYHA criteria>1; Uncontrolled hypertension (systolic blood pressure>180mmHg or diastolic blood pressure>105mmHg after standardized treatment), hypotension (systolic blood pressure ≤ 100mmHg after standardized treatment), unstable angina, myocardial infarction, or bypass or stent surgery within 6 months;
10. Accompanied by pulmonary diseases such as chronic obstructive pulmonary disease, tuberculosis, pneumonia, pneumothorax, atelectasis, pulmonary fibrosis, bronchopulmonary dysplasia, pleural effusion, acute respiratory distress syndrome, irregular breathing, etc;
11. Severe liver and kidney dysfunction, including but not limited to: cirrhosis, hepatic encephalopathy, ascites, renal failure or uremia (Ccr<25ml/min), hepatorenal syndrome, etc;
12. Pregnant or lactating women;
13. Patients with acute stroke within 48 hours after percutaneous cardiovascular and cerebrovascular intervention and major surgery;
14. Currently participating in interventional clinical trials and using research drugs or medical devices;
15. Participants may not be able to complete this study due to other reasons or may not be considered eligible for inclusion by the researchers;

Image exclusion criteria:

1. CTA/MRA/DSA shows excessive vessel curvature, which may hinder the delivery of interventional instruments;
2. Suspected cerebral vasculitis based on medical history and CTA/MRA/DSA;
3. Suspected aortic dissection based on medical history and CTA/MRA/DSA;
4. CTA/MRA/DSA confirmed multi vessel regional occlusion (such as bilateral anterior circulation or anterior/posterior circulation, extracranial carotid artery with intracranial tandem lesions), or clinical evidence of bilateral infarction or multi regional infarction;
5. CTA/MRA/DSA confirms moyamoya disease or moyamoya syndrome;
6. CT/MRI confirms significant effect of midline shift;
7. CT/MRI confirms the presence of intracranial tumors (excluding small meningiomas);
8. CT/MRI confirms the presence of intracranial hemorrhage.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Control; Endovascular thrombectomy alone	Procedure: Endovascular thrombectomy; Endovascular thrombectomy
Experimental: Selective intra-arterial hypothermic magnesium sulfate infusion of low volume; Endovascular thrombectomy combination with selective intra-arterial hypothermic magnesium sulfate infusion (350 ml). Note: In phase 1, all participants in these three volume-escalation arms received a uniform fixed-concentration perfusate of 20.29 mmol/L (5 g magnesium sulfate stock diluted into 1000 mL pre-cooled saline). Weight-tailored perfusate originally specified in registry could not be implemented due to absence of emergency pharmacy fast-track compounding workflow.	Procedure: Endovascular thrombectomy combination with selective intra-arterial hypothermic magnesium sulfate infusion (350 ml).; According to patient's weight, magnesium sulfate (MgSO4) will be diluted to 350 ml 4°C saline solution (0.6μmol/kg/ml). During the thrombectomy procedure, a micro-catheter will be advanced until it reaches beyond the clot responsible for the ischemic symptoms, then cold 50 ml MgSO4 solution will be infused into the ischemic territory at 10 ml/min through the micro-catheter. After that, thrombectomy with a stent retriever will be performed to recanalize the occluded vessel as soon as possible. Immediately after successful thrombectomy, cold MgSO4 solution will be re-infused into the ischemic brain tissue through the catheter at a rate of 30 ml/min for 10 min. Note: The pre-planned weight-tailored magnesium solution could not be prepared intraoperatively in phase 1 due to unavailable emergency pharmacy workflow. All 9 patients received uniform 20.29 mmol/L perfusate, with only infusion volume escalated.
Experimental: Selective intra-arterial hypothermic magnesium sulfate infusion of moderate volume; Endovascular thrombectomy combination with selective intra-arterial hypothermic magnesium sulfate infusion (500 ml). Note: In phase 1, all participants in these three volume-escalation arms received a uniform fixed-concentration perfusate of 20.29 mmol/L (5 g magnesium sulfate stock diluted into 1000 mL pre-cooled saline). Weight-tailored perfusate originally specified in registry could not be implemented due to absence of emergency pharmacy fast-track compounding workflow.	Procedure: Endovascular thrombectomy combination with selective intra-arterial hypothermic magnesium sulfate infusion (500 ml).; According to patient's weight, magnesium sulfate (MgSO4) will be diluted to 500 ml 4°C saline solution (0.6μmol/kg/ml). During the thrombectomy procedure, a micro-catheter will be advanced until it reaches beyond the clot responsible for the ischemic symptoms, then cold 50 ml MgSO4 solution will be infused into the ischemic territory at 10 ml/min through the micro-catheter. After that, thrombectomy with a stent retriever will be performed to recanalize the occluded vessel as soon as possible. Immediately after successful thrombectomy, cold MgSO4 solution will be re-infused into the ischemic brain tissue through the catheter at a rate of 30 ml/min for 10 min. Then pause for 5 min, followed by another 5 min of infusion at the original rate.Note: The pre-planned weight-tailored magnesium solution could not be prepared intraoperatively in phase 1 due to unavailable emergency pharmacy workflow. All 9 patients received uniform 20.29 mmol/L perfusate, with only infusion volume escalated.
Experimental: Selective intra-arterial hypothermic magnesium sulfate infusion of high volumn; Endovascular thrombectomy combination with selective intra-arterial hypothermic magnesium sulfate infusion (650 ml). Note: In phase 1, all participants in these three volume-escalation arms received a uniform fixed-concentration perfusate of 20.29 mmol/L (5 g magnesium sulfate stock diluted into 1000 mL pre-cooled saline). Weight-tailored perfusate originally specified in registry could not be implemented due to absence of emergency pharmacy fast-track compounding workflow.	Procedure: Endovascular thrombectomy combination with selective intra-arterial hypothermic magnesium sulfate infusion (650 ml).; According to patient's weight, magnesium sulfate (MgSO4) will be diluted to 650 ml 4°C saline solution (0.6μmol/kg/ml). During the thrombectomy procedure, a micro-catheter will be advanced until it reaches beyond the clot responsible for the ischemic symptoms, then cold 50 ml MgSO4 solution will be infused into the ischemic territory at 10 ml/min through the micro-catheter. After that, thrombectomy with a stent retriever will be performed to recanalize the occluded vessel as soon as possible. Immediately after successful thrombectomy, cold MgSO4 solution will be re-infused into the ischemic brain tissue through the catheter at a rate of 30 ml/min for 10 min. Then pause for 5 min, followed by intermittent infusion at the original rate for another 5 min twice. The interval between two times is also 5 min.Note: The pre-planned weight-tailored magnesium solution could not be prepared intraoperatively in phase 1.All 9 patients received uniform 20.29 mmol/L perfusate.
Experimental: Phase 2 Fixed-Volume Concentration-Escalation Cohort; Intra-arterial selective cooling magnesium sulfate perfusate. All subjects receive a fixed maximum total infusion volume of 650 mL. Six ascending magnesium concentration tiers will be tested sequentially: 20.29 mmol/L, 22.54 mmol/L, 25.36 mmol/L, 28.98 mmol/L, 33.81 mmol/L, and 40.57 mmol/L. Each concentration is prepared by diluting one 5 g/10 mL magnesium sulfate heptahydrate stock vial into 1000 mL, 900 mL, 800 mL, 700 mL, 600 mL, or 500 mL pre-cooled 4 °C normal saline, respectively. After identifying the maximum tolerated magnesium concentration, the original registry-specified weight-individualized compounding formula will be implemented for subsequent efficacy-focused cohorts. This phase is not yet enrolling participants.	Procedure: Phase 2 Fixed-Volume Concentration-Escalation Cohort; This unenrolled phase 2 cohort uses a fixed 650 mL maximum infusion volume with six ascending magnesium concentrations: 20.29, 22.54, 25.36, 28.98, 33.81, 40.57 mmol/L. Each tier is mixed by diluting one 5 g magnesium stock into 1000/900/800/700/600/500 mL pre-cooled saline. After confirming safe magnesium levels, we will adopt the registry's weight-based formulation. Infusion protocols match phase 1, and this two-stage design is approved under IRB amendment No.XYFY2025-KL360-02

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality at 90 days		90 days after intra-arterial hypothermic magnesium sulfate infusion
Effectiveness evaluation indicators:	Percentage of subjects with 90 days of functional independence (defined as mRS 0-2) (%) Evaluation time: 90 d (±14 d) after surgery	90 days after intra-arterial hypothermic magnesium sulfate infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Grade 3-5 Treatment Emergent Adverse Event (TEAE) related to intervention occurring during treatment period	TEAE includes but not limited to cardiovascular system response, abnormal electrocardiogram, water-electrolyte imbalance, core temperature decreasing, vascular spasm, shiver, infect, disturbance of consciousness.	Within 72 hours after intra-arterial hypothermic magnesium sulfate infusion
All Treatment Emergent Adverse Event (TEAE) related to intervention occurring during treatment period		Within 72 hours after intra-arterial hypothermic magnesium sulfate infusion
All Treatment Emergent Adverse Event (TEAE) occurring during treatment period		Within 72 hours after intra-arterial hypothermic magnesium sulfate infusion
The proportion of symptomatic/asymptomatic intracranial hemorrhage within 24 hours		Within 24 hours after intra-arterial hypothermic magnesium sulfate infusion
No reflow rate	No reflow rate, defined as the percentage of subjects with a decrease in CBV or CBF by more than 15% compared to the contralateral side at 24 hours after treatment (%)	24 hours (±6 hours) after surgery
Cerebrospinal fluid parameters	The levels of Mg²⁺, glutamate, NFL, MMP-9, inflammatory factors, as well as the metabolomics/proteomics of cerebrospinal fluid, are used to verify the central nervous system protection mechanism	24 hours-7 day

Collaborators and Investigators

• Sponsor: Capital Medical University
• Collaborators: The Affiliated Hospital of Xuzhou Medical University

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2025
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): March 30, 2027

Study Registration Dates

• First Submitted: August 27, 2025
• First Submitted That Met QC Criteria: September 1, 2025
• First Posted (Actual): September 9, 2025

Study Record Updates

• Last Update Posted (Actual): August 13, 2026
• Last Update Submitted That Met QC Criteria: August 11, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: magnesium sulfate; thrombectomy; intra-arterial hypothermic
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Stroke; Ischemic Stroke
• Other Study ID Numbers: ICE-MAG

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No