Neuroprotective Agents for Ischemic Stroke

Recruiting in Palo Alto (17 mi)

Overseen by Thomas W Link, MD, MS

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Northwell Health

Must not be taking: Anticoagulants

Disqualifiers: Pregnancy, Heart block, Renal insufficiency, others

No Placebo Group

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

Ischemic stroke is the leading cause of long-term disability in the United States. Endovascular intervention with mechanical thrombectomy has become the standard of care for acute large vessel occlusion (LVO) stroke since multiple clinical trials demonstrated improved long-term clinical outcomes with treatment. However, despite high rates of successful vessel recanalization and thus reperfusion of ischemic brain tissue in current practice, many patients continue to suffer debilitating strokes and poor long-term functional outcome. Pharmacologic neuroprotection could potentially present a means of addressing this mismatch in radiologic vs. clinical outcomes by protecting and salvaging damaged brain tissue. Intra-arterial delivery of a cocktail of neuroprotective therapy at the time of endovascular reperfusion would provide immediate, targeted therapy directly to the damaged brain territory. Hypothermia, minocycline and magnesium can target multiple facets of the complex ischemic injury cascade, and have each demonstrated neuroprotection in multiple preclinical models. This is a phase I trial that aims to demonstrate safety and feasibility of administering cold saline, minocycline, and magnesium sulfate intra-arterially immediately after thrombectomy in stroke interventions.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop your current medications. However, if you are on therapeutic anticoagulation, you cannot participate in the trial.

What data supports the idea that Neuroprotective Agents for Ischemic Stroke is an effective treatment?

The available research shows mixed results for the effectiveness of Neuroprotective Agents for Ischemic Stroke. In rats, a combination of cold saline and magnesium sulfate reduced brain damage significantly. However, in humans, magnesium sulfate alone did not generally improve outcomes after a stroke, except in a small group of ischemic stroke patients. Minocycline showed promise in improving outcomes and reducing disability scores in stroke patients. Overall, while some studies show potential benefits, the effectiveness of these treatments varies, and more research is needed to confirm their benefits. ^{1 2 3 4 5}

What safety data exists for neuroprotective agents in ischemic stroke treatment?

The safety data for neuroprotective agents such as intra-arterial cold saline, minocycline, and magnesium sulfate in ischemic stroke treatment is varied. Minocycline has shown a good safety profile in early phase clinical trials and animal models, demonstrating neuroprotective effects and improved outcomes. Magnesium sulfate, however, did not show significant improvement in functional outcomes or mortality in a meta-analysis of clinical trials, although some benefits were noted in specific subgroups like ischemic stroke patients. Overall, minocycline appears to have a more favorable safety and efficacy profile compared to magnesium sulfate. ^{1 2 5 6 7}

Is the treatment of cold saline, minocycline, and magnesium promising for ischemic stroke?

Yes, the treatment is promising because cold saline and magnesium can reduce brain injury, and minocycline has shown to improve outcomes in ischemic stroke. ^{1 2 4 5 8}

Eligibility Criteria

This trial is for adults aged 18-90 with acute ischemic stroke due to large vessel occlusion, who are eligible for intra-arterial thrombectomy. Excluded are pregnant or lactating women, those with certain heart conditions, renal insufficiency, severe liver issues, systemic lupus erythematosus, idiopathic intracranial hypertension, prior therapeutic anticoagulation or known allergies to contrast dye or trial drugs.

Inclusion Criteria

Signed and dated informed consent and IRB form by the patient or legally authorized health care proxy

My brain scan shows a complete blockage in a major brain artery.

I am eligible for a clot removal procedure as confirmed by specialists.

Exclusion Criteria

I have been on blood thinners before coming here.

I have had a heart attack or been diagnosed with heart block.

My blood flow restoration is rated TICI 0-2A.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Intra-arterial administration of cold saline, minocycline, and magnesium sulfate immediately after thrombectomy

Immediate post-thrombectomy

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including CT or MRI within 24 hours, and neurologic exams at discharge and 90 days

90 days

3 visits (in-person)

Treatment Details

Interventions

• Intra-arterial cold saline, minocycline, and magnesium (Neuroprotective Agent)

Trial Overview The study tests the safety and feasibility of delivering a mix of neuroprotective agents (cold saline, minocycline and magnesium sulfate) directly into the artery immediately after mechanical clot removal in stroke patients. It's an early-phase trial focusing on targeted therapy to damaged brain areas.

Participant Groups

Group I: Intra-arterial neuroprotective substances Experimental Treatment 1 Intervention

Cold saline, minocycline, and magnesium sulfate to be infused intra-arterially immediately after thrombectomy via the internal carotid artery. A dose escalation design will be used, as described above in "Study Description."

Intra-arterial cold saline, minocycline, and magnesium is already approved in China, United States, United States for the following indications:

🇨🇳 Approved in China as Minocycline Hydrochloride for:

• Ischemic stroke

🇺🇸 Approved in United States as Magnesium Sulfate for:

• Pre-eclampsia
• Seizures
• Arrhythmias

🇺🇸 Approved in United States as Minocycline Hydrochloride for:

• Acne
• Rosacea
• Periodontitis

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

North Shore University Hospital Manhasset, NY

Who Is Running the Clinical Trial?

Northwell Health Lead Sponsor

References

1. Italy pubmed.ncbi.nlm.nih.gov

Intra-carotid cold magnesium sulfate infusion induces selective cerebral hypothermia and neuroprotection in rats with transient middle cerebral artery occlusion. [2021] Local hypothermia induced by intra-arterial infusion of cold saline reduces brain injury in ischemic stroke. Administration of magnesium sulfate through the internal carotid artery is also known to reduce ischemic brain damage. The neuroprotective effects of combination therapy with local endovascular hypothermia and intra-carotid magnesium sulfate infusion has not been evaluated. The aim of the study was to determine whether infusion of intra-carotid cold magnesium offers neuroprotective efficacy superior to cold saline infusion alone. Sixty-eight Sprague-Dawley rats were subjected to 3 h of middle cerebral artery occlusion and were randomly divided into six groups: sham-operated group; stroke control group; local cold magnesium infusion group; local cold saline infusion group; local normothermic magnesium infusion group; and local normothermic saline infusion group. Before reperfusion, ischemic rats received local infusion or no treatment. Infarct volume, neurological deficit, and brain water content were evaluated at 48 h after reperfusion. Selective brain hypothermia (33-34 °C) was successfully induced by intra-carotid cold infusion. Local cold saline infusion and local cold magnesium infusion reduced the infarct volumes by 48 % (p

2. United States pubmed.ncbi.nlm.nih.gov

Intravenous Magnesium Sulfate in Acute Stroke. [2020] Background and Purpose- Acute stroke treatment is challenging, and stroke remains a major cause of death and disability. The purpose of this meta-analysis is to investigate the effects of postacute stroke intravenous administration of the neuroprotectant magnesium sulfate (MgSO4) on global outcome, functional outcome, and mortality 90 days poststroke (ischemic and nonischemic). Methods- We searched in Pubmed, Science Direct, CENTRAL, and ClinicalTrials.gov, up to November 11, 2017, and we conducted a systematic review and meta-analysis of randomized controlled trials. We synthesized results by using random-effects model, weighted mean differences, standardized mean differences, and odds ratios. Results- Seven randomized controlled trials (4347 patients) met our criteria. Compared with placebo, treatment did not improve functional outcome defined as Barthel Index >60 (odds ratio =1.05; 95% CI, 0.92-1.19) and >95 (odds ratio =0.95; 95% CI, 0.76-1.20), 90 days poststroke. It also did not improve global outcome measured with modified Rankin Scale (standardized mean difference =-0.01; 95% CI, -0.12 to 0.10), 90 days poststroke. In an additional subgroup meta-analysis that exclusively included ischemic stroke patients, intravenous MgSO4 resulted in lower modified Rankin Scale score (improved global outcome; weighted mean difference =-0.96; 95% CI, -1.34 to -0.58; I2=0%], 90 days poststroke. Finally, mortality stayed unaltered (odds ratio =1.10; 95% CI, 0.94-1.29). Conclusions- The findings of our meta-analysis showed that intravenous MgSO4 generally did not improve global/functional outcomes and mortality at 90 days after stroke (combined ischemic stroke and nonischemic stroke). The finding of favorable neurological outcome, selectively in ischemic stroke patients, should be viewed with extreme caution given the limited number of patients included in this subgroup meta-analysis.

3. India pubmed.ncbi.nlm.nih.gov

Role of magnesium sulfate in neuroprotection in acute ischemic stroke. [2021] To study the effect of intravenous magnesium sulfate infusion on clinical outcome of patients of acute stroke.

4. Austria pubmed.ncbi.nlm.nih.gov

Dose finding study of intravenous magnesium sulphate in transient focal cerebral ischemia in rats. [2022] During many neurovascular procedures temporary occlusion of cerebral arteries is inevitable. Neuroprotective drugs may reduce the risk of cerebral infarction in this situation. Increasing evidence indicates neuroprotective properties of magnesium in cerebral ischemia. Previous experimental studies on the neuroprotective efficacy of magnesium-treatment in transient focal ischemia provide widely differing results using different magnesium doses and treatment-regimens. The present study was conducted to find the maximum protective dose of intravenous magnesium sulphate in a rat model of transient focal ischemia.

5. United States pubmed.ncbi.nlm.nih.gov

Minocycline and Magnesium As Neuroprotective Agents for Ischemic Stroke: A Systematic Review. [2021] Stroke is a leading cause of death, disability, and dementia worldwide. Strokes can be divided into ischemic strokes and hemorrhagic strokes. At the moment, tissue plasminogen activator (tPA) is the only FDA-approved drug for ischemic stroke. Minocycline (MC) and Magnesium (Mg) are promising therapies for ischemic stroke, especially in the pre-hospital setting. These drugs are readily available, inexpensive, and generally safe. We decided to investigate these drugs' neuroprotective effects in treating ischemic stroke in the acute and chronic setting. We conducted a systematic review of the published literature on MC and Mg's functional outcome in ischemic stroke. This paper's methodology included only clinical trials published in the last 15 years, using PubMed as a database. The systematic review demonstrated that MC infusion in the pre-hospital and hospital setting improved functional outcomes and disability scores. Furthermore, MC also decreased matrix metalloproteinase 9 (MMP-9) levels. MC might have a more significant effect on men than women because different molecular pathways of cerebral ischemia seem to be involved between both genders. The systematic review showed that patients with ischemic stroke did not benefit from magnesium sulfate infusion in the pre-hospital and hospital setting. Nevertheless, patients with lacunar strokes and patients who supplemented their meals with potassium-magnesium salt in the diet had better functional outcomes. Future studies would need a more significant sample of participants and a better selection to increase the study's power and avoid selection bias, respectively. Further publications could benefit from subcategorizing strokes and investigating the gender role in stroke treatment. These directives could give a more robust conclusion regarding the neuroprotective effects of these drugs.

6. United States pubmed.ncbi.nlm.nih.gov

Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1-inhibiting mechanism. [2016] Minocycline, a semisynthetic tetracycline antibiotic, has been reported to ameliorate brain injury and inhibit microglial activation after focal cerebral ischemia. However, the cerebroprotective mechanism of minocycline remains unclear. In the present study, we investigated that mechanism of minocycline in a murine model of 4-hour middle cerebral artery (MCA) occlusion.

7. United States pubmed.ncbi.nlm.nih.gov

Minocycline development for acute ischemic stroke. [2021] Minocycline, a tetracycline antibiotic, has shown anti-inflammatory, anti-apoptotic, and neuroprotective effects in many models of cerebral ischemia and neurodegenerative disease. Its high penetration of the blood-brain barrier, good safety profile, and delayed therapeutic window make it an ideal candidate for use in stroke. In animal models, minocycline reduced infarct size and improved neurologic outcome when administered acutely, with similar neuroprotective benefits seen following delayed administration. To date, two early phase clinical trials have shown minocycline to be safe and potentially effective in acute ischemic stroke, alone or in combination with tissue plasminogen activator. A large efficacy clinical trial is now needed to confirm previous studies, allow for subgroup analysis, and pinpoint the potential place for minocycline in acute stroke therapy.

8. England pubmed.ncbi.nlm.nih.gov

Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial. [2022] Magnesium is neuroprotective in animal models of stroke, and findings of small clinical pilot trials suggest potential benefit in people. We aimed to test whether intravenous magnesium sulphate, given within 12 h of stroke onset, reduces death or disability at 90 days.