Deferoxamine In the Treatment of Aneurysmal Subarachnoid Hemorrhage (aSAH) (DISH)

Deferoxamine In the Treatment of Aneurysmal Subarachnoid Hemorrhage (DISH)

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.

Study Overview

• Status: Recruiting
• Conditions: Aneurysmal Subarachnoid Hemorrhage
• Intervention / Treatment: Drug: Deferoxamine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sravanthi Koduri; Phone Number: 734-647-7960; Email: skoduri@med.umich.edu
• Study Contact Backup: Name: Aditya Pandey, MD; Phone Number: 734-615-2763; Email: adityap@umich.edu

Study Locations

• China
  • Beining
    • Beijing, Beining, China
      • Not yet recruiting
      • Peking University Health Science Center
      • Contact: Yining Huang, MD; Phone Number: +86 10 83572857; Email: ynhuang@bjmu.edu.cn
• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan
      • Contact: Koduri Sravanthi; Email: skoduri@med.umich.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aneurysmal SAH confirmed with vascular imaging
• Aneurysm treated with endovascular or microsurgical intervention
• Hunt-Hess ≤ 4
• Modified Fisher Grade I-IV
• Glasgow Coma Scale (GCS) ≥ 7 following External Ventricular Drain (EVD) placement if indicated
• First dose of drug can be administered within 24 hours of symptom onset
• Functional independence prior to SAH, Modified Rankin Scale (mRS) ≤ 1
• Informed consent obtained by patient or legal authorized representative (LAR)

Exclusion Criteria:

• Previous hypersensitivity to or treatment with deferoxamine
• Presence of giant aneurysm (>25 mm in size)
• Known severe iron deficiency anemia, Hemoglobin (Hgb) g/dl ≤ 7 or transfusion dependent
• Irreversibly impaired brainstem function
• Abnormal renal function, Serum Creatinine> 2 mg/dL
• Pre-existing severe disability, mRS ≥ 2
• Coagulopathy, including use of anti-platelet or anticoagulant drugs
• Known severe hearing loss
• Patients with significant respiratory disease such as chronic obstructive pulmonary disease, pulmonary fibrosis, or on home oxygen (O2)
• Taking iron supplements containing > 325 mg of ferrous iron
• Pregnancy
• Life expectancy less than 90 days due to co-morbidities
• Concurrent participation in another research protocol for investigation of another experimental therapy, though observational studies are allowed
• Prior history of hepatic dysfunction
• Known cytopenia (platelets < 50,000, Absolute neutrophil count < 500)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Deferoxamine lower dose; Deferoxamine 32 Milligram Per Kilogram (mg/kg)	Drug: Deferoxamine; There will be 3 doses given to the patients days 1-3. Dose will be given intravenous with a fixed rate of 7.5 milligram per kilogram per hour (mg/kg/hr). The second dose will be given 24 hours after the first dose, and the third dose will be given 48 hours after the initial dose. Patients will be randomized to 32 mg/kg or 48 mg/kg of Deferoxamine.; Other Names: Desferal
Experimental: Deferoxamine higher dose; Deferoxamine 48 mg/kg	Drug: Deferoxamine; There will be 3 doses given to the patients days 1-3. Dose will be given intravenous with a fixed rate of 7.5 milligram per kilogram per hour (mg/kg/hr). The second dose will be given 24 hours after the first dose, and the third dose will be given 48 hours after the initial dose. Patients will be randomized to 32 mg/kg or 48 mg/kg of Deferoxamine.; Other Names: Desferal
Placebo Comparator: Placebo; normal saline	Drug: Placebo; There will be 3 doses given to the patients days 1-3. Dose will be given intravenous with a fixed rate of 7.5 mg/kg/hr. The second dose will be given 24 hours after the first dose, and the third dose will be given 48 hours after the initial dose.; Other Names: Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Utility-weighted modified Rankin Scale (UW-mRS) at 6 months	Overall a Bayesian, longitudinal model will be used, this will be adjusted for baseline expected 6 month mRS using the FRESH score. At baseline, the expected 6 month UW-mRS (based on prognostic variables such as age and Hunt Hess) will be entered as the first value for the patient. Therefore, patients with greater severity at baseline, who achieve excellent outcomes will contribute a larger treatment effect. Similarly, patients with greater severity who have disability, but perform better than expected can still contribute useful information.	6 months (after hospital discharge)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Montreal Cognitive Assessment (MOCA)	Montreal cognitive assessment is a rapid sensitive screening tool for assessment of impaired cognitive function. The main domains of MoCA scale include attention, executive functions, memory, language, attention, naming, orientation, and visual-spatial ability. The total score is 30 points. A score of 25 points or less indicated impaired cognitive function. For patients with less than 12 years of education, one point was added to the total score.	At discharge from hospital (approximately 3-4 weeks)
Montreal Cognitive Assessment (MOCA)	Montreal cognitive assessment is a rapid sensitive screening tool for assessment of impaired cognitive function. The main domains of MoCA scale include attention, executive functions, memory, language, attention, naming, orientation, and visual-spatial ability. The total score is 30 points. A score of 25 points or less indicated impaired cognitive function. For patients with less than 12 years of education, one point was added to the total score.	6 months (after hospital discharge)
Percentage of patients requiring permanent cerebrospinal fluid (CSF) diversion due to hydrocephalus at 6 months		6 months
Partial pressure of oxygen (PaO2) and fraction of inspired oxygen (FiO2) ratio (worst value for each parameter for each day of infusion, and 48 hours after end of infusion)	Worst value for each parameter for each day of infusion, and 48 hours after end of infusion.	up to 48 hours after day 3 infusion
To estimate the proportion of non-intubated participants at each dose who experience intubation or initiation of non-invasive positive pressure ventilation during the DFO		infusion days 1-3
Incidence of delayed cerebral ischemia/vasospasm	This is based on radiographic evidence on computed tomography angiogram and clinical correlation with neurologic exam.	up to 14 days after aSAH

Collaborators and Investigators

• Sponsor: Aditya S. Pandey, MD
• Collaborators: Michigan Medicine PKUHSC Joint Institute for Translational & Clinical Research
• Investigators: Principal Investigator: Aditya Pandey, MD, University of Michigan

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2022
• Primary Completion (Estimated): October 1, 2025
• Study Completion (Estimated): October 1, 2025

Study Registration Dates

• First Submitted: September 22, 2020
• First Submitted That Met QC Criteria: September 22, 2020
• First Posted (Actual): September 28, 2020

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 25, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Placebo; Deferoxamine
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Subarachnoid Hemorrhage; Molecular Mechanisms of Pharmacological Action; Chelating Agents; Sequestering Agents; Iron Chelating Agents; Siderophores; Deferoxamine
• Other Study ID Numbers: HUM00163868

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No