Deferoxamine for Subarachnoid Hemorrhage

(DISH Trial)

Recruiting at 1 trial location

Overseen By Aditya Pandey, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Aditya S. Pandey, MD

Must not be taking: Antiplatelets, Anticoagulants, Iron supplements

Disqualifiers: Giant aneurysm, Severe anemia, others

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: Unknown

Duration: 3 days

120 Participants Needed

Trial Summary

What is the purpose of this trial?

Aneurysmal subarachnoid hemorrhage (aSAH) has a high incidence of mortality and significant morbidity, with mortality exceeding 30% in the first two days.The initial injury is related to increasing intracranial pressure, cerebral edema, and neuronal injuries associated with the release of iron. Iron has been shown to increase the incidence of cerebral edema, ischemia, and formation of hydrocephalus. Deferoxamine mesylate (DFO), a hydrophilic chelator, creates a stable complex with free iron thus preventing the formation of iron related free radicals. This trial will evaluate the safety and efficacy of clinical deferoxamine for the treatment of aSAH for patients that are admitted to the hospital at the University of Michigan or Peking University Health Science Center. Eligible participants will be enrolled and randomized to 1 of 2 doses of Deferoxamine or placebo (saline). Information regarding the patients will be collected and followed for up to 6 months post discharge.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are using anti-platelet or anticoagulant drugs or taking iron supplements with more than 325 mg of ferrous iron.

What data supports the effectiveness of the drug Deferoxamine for treating subarachnoid hemorrhage?

Research shows that Deferoxamine, an iron-chelating drug, has neuroprotective effects in animal models of intracerebral hemorrhage and ischemic stroke, reducing brain damage and improving recovery. These findings suggest potential benefits for similar conditions like subarachnoid hemorrhage. ^{1 2 3 4 5}

Is deferoxamine safe for humans?

Deferoxamine has been tested in humans for various conditions, and studies show it is generally well-tolerated. In patients with intracerebral hemorrhage, doses up to 62 mg/kg/day were well-tolerated without increasing serious side effects or death. However, there have been reports of eye-related side effects in some patients, so regular eye check-ups are recommended for those on long-term treatment. ^{1 5 6 7 8}

How is the drug Deferoxamine unique for treating subarachnoid hemorrhage?

Deferoxamine is unique because it acts as an iron chelator, which means it binds to excess iron that can cause damage after a brain bleed, and it can be administered intranasally to directly target the brain, potentially offering a more effective and less invasive treatment option. ^{1 3 4 5 9}

Research Team

Aditya Pandey, MD

Principal Investigator

University of Michigan

Eligibility Criteria

This trial is for patients with a recent brain aneurysm bleed who were independent before the event, can start treatment within 24 hours, and have had their aneurysm secured. They must be able to give consent and not have severe kidney issues, hearing loss, low blood counts, or allergies to deferoxamine.

Inclusion Criteria

You have been diagnosed with a brain aneurysm using special imaging tests.

You need to have a Glasgow Coma Scale score of 7 or higher after having an External Ventricular Drain placed if it is needed.

Informed consent obtained by patient or legal authorized representative (LAR)

Exclusion Criteria

I have a significant disability, with difficulty in daily activities.

I have a serious lung condition or need home oxygen.

I have severe anemia or need blood transfusions often.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants are randomized to receive either Deferoxamine at one of two doses or placebo for the treatment of aSAH

3 days

Daily in-hospital visits

Follow-up

Participants are monitored for safety and effectiveness after treatment, including cognitive assessments and monitoring for delayed cerebral ischemia

6 months

Regular follow-up visits post-discharge

Treatment Details

Interventions

• Deferoxamine
• Placebo

Trial Overview The study tests if Deferoxamine (DFO), which binds iron in the body to prevent damage from free radicals, is safe and effective for treating bleeding from a brain aneurysm. Participants will receive either DFO at two different doses or a placebo.

Participant Groups

Group I: Deferoxamine lower dose Experimental Treatment 1 Intervention

Deferoxamine 32 Milligram Per Kilogram (mg/kg)

Group II: Deferoxamine higher dose Experimental Treatment 1 Intervention

Deferoxamine 48 mg/kg

Group III: Placebo Placebo Group 1 Intervention

normal saline

Deferoxamine is already approved in United States, European Union for the following indications:

Approved in United States as Desferal for:

• Acute Iron Poisoning
• Chronic Iron Overload

Approved in European Union as Desferal for:

• Iron overload
• Aluminum toxicity

Who Is Running the Clinical Trial?

Aditya S. Pandey, MD

Lead Sponsor

Trials

1

Recruited

120+

Michigan Medicine PKUHSC Joint Institute for Translational & Clinical Research

Collaborator

Trials

1

Recruited

120+

Findings from Research

A Phase I study found that the iron chelator Deferoxamine Mesylate (DFO) is well-tolerated in patients with intracerebral hemorrhage (ICH) at doses up to 62 mg/kg/day, showing no increase in serious adverse events or mortality.

The ongoing Phase II trial will assess the efficacy of DFO in improving clinical outcomes in 324 ICH patients over 3 months, providing critical data on whether to proceed to a larger Phase III trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High dose deferoxamine in intracerebral hemorrhage (HI-DEF) trial: rationale, design, and methods. Yeatts, SD., Palesch, YY., Moy, CS., et al.[2021]

Desferrioxamine mesylate (DFO) significantly reduced perihematomal edema and hematoma volume in patients with intracerebral hematoma (ICH) within 7 days of treatment, based on a meta-analysis of 5 randomized controlled trials involving 239 patients.

At 30 days post-treatment, DFO also led to a significant improvement in neurological function, as measured by the reduction in National Institute of Health Stroke Scale (NIHSS) scores, indicating its potential as an effective treatment for ICH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of desferrioxamine mesylate in intracerebral hematoma: a systemic review and meta-analysis. Zhao, K., Li, J., Zhang, Q., et al.[2022]

Intracerebroventricular (ICV) administration of deferoxamine (DFX) after subarachnoid hemorrhage (SAH) significantly reduced neuronal damage and improved cognitive outcomes in a mouse model, demonstrating superior neuroprotection compared to systemic administration.

The neuroprotective effects of DFX are linked to the expression of heme oxygenase-1 (HO-1) in microglial/macrophages, suggesting that monitoring HO-1 levels in patients could help predict their response to DFX treatment for hemorrhagic stroke.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Heme oxygenase-1-mediated neuroprotection in subarachnoid hemorrhage via intracerebroventricular deferoxamine. LeBlanc, RH., Chen, R., Selim, MH., et al.[2018]

Intranasal administration of deferoxamine (DFO) significantly increases its concentration in the brain compared to intravenous delivery, achieving up to 200 times more targeted delivery to the cortex, which is crucial for treating stroke.

In animal studies, both pre-treatment and post-treatment with intranasal DFO reduced stroke damage by 55%, indicating its potential as an effective treatment and preventive measure for ischemic stroke.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke. Hanson, LR., Roeytenberg, A., Martinez, PM., et al.[2021]

Deferoxamine (DFX) significantly reduced brain water content by 85.7% and improved neurobehavioral scores in animal models of intracerebral hemorrhage (ICH), indicating its potential efficacy as a treatment.

The most effective administration of DFX occurred 2-4 hours after ICH at doses of 10-50 mg/kg, suggesting a critical window for intervention, although further clinical trials are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of deferoxamine in animal models of intracerebral hemorrhage: a systematic review and stratified meta-analysis. Cui, HJ., He, HY., Yang, AL., et al.[2021]

Iron chelation therapy, including deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX), is generally safe for young patients under 25 with hemoglobinopathies, based on safety data from 2040 patients across 34 studies.

While DFO shows minimal serious adverse effects at recommended doses, DFP and DFX can lead to rare but serious reactions, and all therapies have specific safety risks, including increased transaminases and gastrointestinal disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profiles of iron chelators in young patients with haemoglobinopathies. Botzenhardt, S., Li, N., Chan, EW., et al.[2017]

A multicenter phase-I study involving 20 patients with spontaneous intracerebral hemorrhage (ICH) demonstrated that intravenous infusions of deferoxamine mesylate (DFO) are feasible and well-tolerated, with only 10% of subjects discontinuing due to adverse events.

The study identified a maximum tolerated dose of 62 mg/kg per day, and while some patients experienced mild blood-pressure-lowering effects, the overall safety profile was acceptable, paving the way for future efficacy studies of DFO in ICH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage. Selim, M., Yeatts, S., Goldstein, JN., et al.[2021]

In a study of 84 pediatric patients treated with deferoxamine (DFO) for transfusional hemochromatosis, only 1.2% experienced ocular toxicity, indicating that such side effects are rare when regular ophthalmic screenings are conducted.

The single case of ocular toxicity was mild and reversible, suggesting that with proper monitoring and dose adjustments, the risks associated with DFO treatment can be effectively managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deferoxamine-related ocular toxicity: incidence and outcome in a pediatric population. Baath, JS., Lam, WC., Kirby, M., et al.[2013]

Deferoxamine (DFX) was found to effectively limit edema expansion and facilitate hematoma absorption within the first week after intracerebral hemorrhage (ICH) onset, based on a meta-analysis of 7 studies involving various patient outcomes.

However, DFX did not lead to improved neurological outcomes after 3 and 6 months, and it did not significantly increase the risk of serious adverse events, suggesting it may be safe but not necessarily effective for long-term recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deferoxamine in intracerebral hemorrhage: Systematic review and meta-analysis. Sun, T., Zhao, YY., Xiao, QX., et al.[2023]

References

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

High dose deferoxamine in intracerebral hemorrhage (HI-DEF) trial: rationale, design, and methods. [2021]

2. Italy pubmed.ncbi.nlm.nih.gov

Efficacy of desferrioxamine mesylate in intracerebral hematoma: a systemic review and meta-analysis. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Heme oxygenase-1-mediated neuroprotection in subarachnoid hemorrhage via intracerebroventricular deferoxamine. [2018]

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

Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke. [2021]

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

Efficacy of deferoxamine in animal models of intracerebral hemorrhage: a systematic review and stratified meta-analysis. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Safety profiles of iron chelators in young patients with haemoglobinopathies. [2017]

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

Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage. [2021]

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

Deferoxamine-related ocular toxicity: incidence and outcome in a pediatric population. [2013]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Deferoxamine in intracerebral hemorrhage: Systematic review and meta-analysis. [2023]