Neuroprotective Agents for Ischemic Stroke

Overseen By Thomas W Link, MD, MS

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Northwell Health

Must not be taking: Anticoagulants

Disqualifiers: Pregnancy, Heart block, Renal insufficiency, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: Immediate post-thrombectomy

24 Participants Needed

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}

Research Team

Thomas W Link, MD, MS

Principal Investigator

Northwell Health

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.

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

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 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

Who Is Running the Clinical Trial?

Northwell Health

Lead Sponsor

Trials

481

Recruited

470,000+

Findings from Research

In a study involving 68 rats with induced ischemic stroke, local infusion of cold magnesium significantly reduced brain injury, with a 65% reduction in infarct volume compared to stroke controls, outperforming cold saline infusion which only reduced infarct volume by 48%.

The combination of local hypothermia and cold magnesium infusion not only decreased brain water content but also led to the best neurological outcomes, indicating a superior neuroprotective effect compared to other treatment methods tested.

NCBI (Pubmed)

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. Song, W., Wu, YM., Ji, Z., et al.[2021]

Intravenous magnesium sulfate (MgSO4) did not significantly improve functional outcomes or mortality rates 90 days after stroke in a meta-analysis of 4347 patients across seven randomized controlled trials.

However, in a subgroup analysis of ischemic stroke patients, MgSO4 showed a potential benefit in improving global outcomes, but this finding should be interpreted cautiously due to the small number of patients in that subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous Magnesium Sulfate in Acute Stroke. Avgerinos, KI., Chatzisotiriou, A., Haidich, AB., et al.[2020]

In a study of 60 patients with acute ischemic stroke, intravenous magnesium sulfate significantly increased serum magnesium levels, which are thought to provide neuroprotective effects.

Despite the rise in magnesium levels, the study did not find a statistically significant improvement in stroke recovery outcomes when comparing the magnesium group to the control group, indicating that magnesium sulfate may not enhance clinical recovery in acute stroke patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of magnesium sulfate in neuroprotection in acute ischemic stroke. Singh, H., Jalodia, S., Gupta, MS., et al.[2021]

In a study involving 45 male rats subjected to 90 minutes of middle cerebral artery occlusion, continuous administration of magnesium sulfate at serum levels between 2 and 3 mmol/l significantly reduced infarct volumes by 32% to 42% compared to controls, indicating its neuroprotective efficacy.

Magnesium serum levels above 3 mmol/l were found to be cardiodepressive and limited neuroprotection, suggesting that careful monitoring of magnesium levels is crucial during neurovascular procedures to maximize brain tissue protection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose finding study of intravenous magnesium sulphate in transient focal cerebral ischemia in rats. Westermaier, T., Zausinger, S., Baethmann, A., et al.[2022]

Minocycline (MC) has shown neuroprotective effects in treating ischemic stroke, improving functional outcomes and reducing disability scores, particularly in men, based on a systematic review of clinical trials from the last 15 years.

Magnesium (Mg) infusion did not demonstrate benefits for patients with ischemic stroke in the acute setting, although dietary potassium-magnesium supplementation was associated with better outcomes in specific stroke types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Minocycline and Magnesium As Neuroprotective Agents for Ischemic Stroke: A Systematic Review. Ortiz, JF., Ruxmohan, S., Saxena, A., et al.[2021]

In a murine model of cerebral ischemia, minocycline treatment for 14 days significantly improved neurological function and motor coordination in a dose-dependent manner, indicating its potential efficacy in reducing brain injury.

Minocycline appears to work by inhibiting activated microglia and reducing levels of HMGB1, a mediator associated with inflammation, suggesting a novel mechanism for its cerebroprotective effects after ischemic injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1-inhibiting mechanism. Hayakawa, K., Mishima, K., Nozako, M., et al.[2016]

Minocycline, an antibiotic with neuroprotective properties, has shown promise in reducing brain damage and improving recovery in animal models of stroke, making it a strong candidate for treating acute ischemic stroke due to its ability to cross the blood-brain barrier and its good safety profile.

Early phase clinical trials indicate that minocycline is safe and may be effective in treating acute ischemic stroke, either alone or with other treatments, but further large-scale studies are necessary to confirm its efficacy and determine its role in stroke therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Minocycline development for acute ischemic stroke. Fagan, SC., Cronic, LE., Hess, DC.[2021]

In a study of 2589 patients, intravenous magnesium sulfate administered within 12 hours of stroke onset did not significantly reduce death or disability at 90 days compared to a placebo, with an odds ratio of 0.95.

While magnesium treatment did not show overall efficacy, it suggested potential benefits in non-cortical strokes, indicating that specific stroke types may respond differently to magnesium therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial. Muir, KW., Lees, KR., Ford, I., et al.[2022]

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]

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

Intravenous Magnesium Sulfate in Acute Stroke. [2020]

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

Role of magnesium sulfate in neuroprotection in acute ischemic stroke. [2021]

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

Dose finding study of intravenous magnesium sulphate in transient focal cerebral ischemia in rats. [2022]

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

Minocycline and Magnesium As Neuroprotective Agents for Ischemic Stroke: A Systematic Review. [2021]

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]

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

Minocycline development for acute ischemic stroke. [2021]

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

Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial. [2022]