Acute Ischemic Stroke
Conditions
Keywords
thrombectomy, magnesium sulfate, intra-arterial hypothermic
Brief summary
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.
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).
Interventions
PROCEDUREEndovascular 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.
PROCEDUREEndovascular 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.
PROCEDUREEndovascular 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.
PROCEDUREEndovascular thrombectomy
Endovascular thrombectomy
PROCEDUREPhase 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
Sponsors
Capital Medical University
The Affiliated Hospital of Xuzhou Medical University
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Intervention model description
This study was divided into two parts. The first part was a dose escalation study (non-randomized) using a "3+3" design. The second part was a randomized, parallel, open-label, endpoint-blinded study conducted at the maximum tolerated dose (MTD)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mortality at 90 days | 90 days after intra-arterial hypothermic magnesium sulfate infusion | — |
| Effectiveness evaluation indicators: | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | TEAE includes but not limited to cardiovascular system response, abnormal electrocardiogram, water-electrolyte imbalance, core temperature decreasing, vascular spasm, shiver, infect, disturbance of consciousness. |
| 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 | 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 (%) |
| Cerebrospinal fluid parameters | 24 hours-7 day | 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 |
Countries
China
Outcome results
None listed