Intra-Arterial Neuroprotective Agents and Cold Saline in Ischemic Stroke Intervention

This is a phase I, single center, single arm clinical trial with dose escalation design.

Location: North Shore University Hospital in Manhasset, NY

Study population: Subjects aged 18-90 years undergoing mechanical thrombectomy for acute ischemic stroke due to large vessel occlusion at North Shore University Hospital

Primary Objective: To demonstrate the safety and feasibility of intra-arterial administration of a cocktail of neuroprotective agents at the time of reperfusion in endovascular stroke intervention for acute ischemic stroke due to large vessel occlusion.

Secondary Objectives:

1. To describe the feasibility of delivering a combination of neuroprotective agents directly into the affected internal carotid artery immediately after recanalization of an occluded vessel in ischemic stroke intervention.
2. To describe the maximum tolerated dose of a combination of 4C saline at 30 ml/min for 10 minutes, minocycline, and magnesium sulfate directly into the affected internal carotid artery immediately after recanalization of an occluded vessel in ischemic stroke intervention.
3. To describe the clinical outcomes of the patients undergoing the experimental procedure and compare to historical controls.

Primary Endpoint: Presence of symptomatic intracranial hemorrhage within 24 hours of treatment; presence of serious adverse event related to the administration of intra-arterial cold saline, minocycline or MgSO4; and technical feasibility of the proposed experimental treatment.

Secondary Endpoints: Total volume of infarct on MRI 24 hours after procedure, clinical outcome as measured by the NIHSS prior to discharge and MRS at 90 day follow up.

Study design:

Based on the available literature, the target dose of Minocycline and MgSO4 is 6 mg/kg and 2g, respectively. For targeted hypothermia, 4C normal saline will be infused at a rate of 30 ml/min to achieve an estimated drop in temperature in the ipsilateral hemisphere to 33-34C within 10 minutes.

To ensure adequate safety measures, a dose escalation design is employed to carefully evaluate for adverse events throughout the study. The standard "3+3" dose escalation design will be used in the 3 groups described below. Within each group, at each dosage, if none of the first 3 patients experience a related adverse event, the study proceeds to the next group or dose level. If one of the 3 patients experiences an adverse event, then an additional 3 patients will be treated at that dose level before proceeding. Escalation will continue only if a maximum of 1 out of 6 patients experience an adverse event. If 2 or more patients at a given dose level experience an adverse event, then the maximum tolerated dose (MTD) will be determined as the preceding dose level.

Group 1: IA cold saline alone 3-6 patients receive 4C at 30 ml/min over 10 min

Group 2: IA cold saline + Minocycline 3-6 patients receive IA cold saline + 2 mg/kg Minocycline; 3-6 patients receive IA cold saline + 4 mg/kg Minocycline; 3-6 patients receive IA cold saline + 6 mg/kg Minocycline

Group 3: IA cold saline + Minocycline + Magnesium sulfate 3-6 patients receive IA cold saline + MTD Minocycline + 2g MgSO4; 3-6 patients receive IA cold saline + MTD Minocycline + 4g MgSO4

Both the Minocycline and MgSO4 will be reconstituted within the 300 ml of cold saline to be administered together.

Follow up:

Post-stroke intervention care will proceed as standard of care with the addition of screening for adverse events related to the IA administration of cold saline, minocycline and/or magnesium sulfate.

Day 1: CT or MRI within 24h of intervention, neurologic exam, routine labs, NIHSS.

Day of discharge: neurologic exam, routine labs, NIHSS, mRS. Day 90: neurologic exam, NIHSS, mRS.