Selective Intra-arterial Hypothermic Magnesium Sulfate Infusion in Combination With Endovascular Thrombectomy in Acute Ischemic Stroke: A Phase 1/2 Randomized Clinical Trial
试验速览
- 阶段
- 1 期
- 状态
- Enrolling By Invitation
- 发起方
- 入组人数
- 42
- 试验地点
- 1
- 主要终点
- Mortality at 90 days
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age range of 18-80 years old (including critical value);
- •No gender restrictions;
- •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;
- •The symptoms and signs are consistent with acute anterior circulation ischemic stroke, NIHSS≥6;
- •The time from onset to endovascular thrombectomy of acute ischemic stroke is within 24 hours;
- •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)
- •The mRS score before stroke is 0-1 points;
- •Written informed consent provided by the patients or their legal relatives.
排除标准
- •General exclusion criteria:
- •Clinical manifestations suggest the presence of intracranial cerebral parenchymal hemorrhage or subarachnoid hemorrhage (even if imaging results are normal);
- •During a stroke, accompanied by epilepsy, an accurate NIHSS score cannot be obtained;
- •Accompanied by coma or mental disorders, it may interfere with the assessment of neurological function;
- •History of allergy to iodinated contrast agents or history of anaphylactic shock;
- •Baseline blood glucose<50mg/dL (2.78mmol) or>400mg/dL (22.20mmol);
- •*Acceptable fingertip blood glucose results
- •Baseline platelet count<50 × 10^9/L;
- •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);
- •During a stroke, there may be fever or active infections that require systemic treatment (such as active pulmonary tuberculosis);
- •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;
- •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;
- •Severe liver and kidney dysfunction, including but not limited to: cirrhosis, hepatic encephalopathy, ascites, renal failure or uremia (Ccr<25ml/min), hepatorenal syndrome, etc;
- •Pregnant or lactating women;
- •Patients with acute stroke within 48 hours after percutaneous cardiovascular and cerebrovascular intervention and major surgery;
- •Currently participating in interventional clinical trials and using research drugs or medical devices;
- •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:
- •CTA/MRA/DSA shows excessive vessel curvature, which may hinder the delivery of interventional instruments;
- •Suspected cerebral vasculitis based on medical history and CTA/MRA/DSA;
- •Suspected aortic dissection based on medical history and CTA/MRA/DSA;
- •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;
- •CTA/MRA/DSA confirms moyamoya disease or moyamoya syndrome;
- •CT/MRI confirms significant effect of midline shift;
- •CT/MRI confirms the presence of intracranial tumors (excluding small meningiomas);
- •CT/MRI confirms the presence of intracranial hemorrhage.
研究组 & 干预措施
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.
干预措施: Endovascular thrombectomy combination with selective intra-arterial hypothermic magnesium sulfate infusion (350 ml). (Procedure)
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.
干预措施: Endovascular thrombectomy combination with selective intra-arterial hypothermic magnesium sulfate infusion (500 ml). (Procedure)
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.
干预措施: Phase 2 Fixed-Volume Concentration-Escalation Cohort (Procedure)
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.
干预措施: Endovascular thrombectomy combination with selective intra-arterial hypothermic magnesium sulfate infusion (650 ml). (Procedure)
Control
Endovascular thrombectomy alone
干预措施: Endovascular thrombectomy (Procedure)
结局指标
主要结局
Mortality at 90 days
时间窗: 90 days after intra-arterial hypothermic magnesium sulfate infusion
Effectiveness evaluation indicators:
时间窗: 90 days after intra-arterial hypothermic magnesium sulfate infusion
Percentage of subjects with 90 days of functional independence (defined as mRS 0-2) (%) Evaluation time: 90 d (±14 d) after surgery
次要结局
- Grade 3-5 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) 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(24 hours (±6 hours) after surgery)
- Cerebrospinal fluid parameters(24 hours-7 day)
研究者
Ji Xunming,MD,PhD
Professor of Neurology, Xuanwu Hospital, Capital Medical University
Capital Medical University