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

• ClinicalTrials.gov Identifier: NCT04566991
• Recruitment Status: Recruiting
• First Posted: September 28, 2020
• Last Update Posted: February 28, 2024
• Sponsor: Aditya S. Pandey, MD
• Collaborator: Michigan Medicine PKUHSC Joint Institute for Translational & Clinical Research
• Information provided by (Responsible Party): Aditya S. Pandey, MD, University of Michigan

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Aneurysmal Subarachnoid Hemorrhage	Drug: Deferoxamine; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Masking Description: All patients and investigators who will be directly involved in the care of these patients or in data analysis will be blinded to randomization status.This trial uses a Bayesian adaptive randomization protocol, where there are three groups that patients will be randomized into: placebo, DFO 32 mg/kg and DFO 48 mg/kg. The first 50 patients will be randomized evenly into each of these groups. The randomization ratio will be adjusted based on the design report after 50 subjects and then every 10 patients.
• Primary Purpose: Treatment
• Official Title: Deferoxamine In the Treatment of Aneurysmal Subarachnoid Hemorrhage (DISH)
• Actual Study Start Date: March 20, 2022
• Estimated Primary Completion Date: October 2025
• Estimated Study Completion Date: October 2025

Arms and Interventions

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 Name: 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 Name: 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 Name: Normal Saline

Outcome Measures

Primary Outcome Measures :

1. Utility-weighted modified Rankin Scale (UW-mRS) at 6 months [ Time Frame: 6 months (after hospital discharge) ]
   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.

Secondary Outcome Measures :

1. Montreal Cognitive Assessment (MOCA) [ Time Frame: At discharge from hospital (approximately 3-4 weeks) ]
   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.
2. Montreal Cognitive Assessment (MOCA) [ Time Frame: 6 months (after hospital discharge) ]
   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.
3. Percentage of patients requiring permanent cerebrospinal fluid (CSF) diversion due to hydrocephalus at 6 months [ Time Frame: 6 months ]
4. 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) [ Time Frame: up to 48 hours after day 3 infusion ]
   Worst value for each parameter for each day of infusion, and 48 hours after end of infusion.
5. 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 [ Time Frame: infusion days 1-3 ]
6. Incidence of delayed cerebral ischemia/vasospasm [ Time Frame: up to 14 days after aSAH ]
   This is based on radiographic evidence on computed tomography angiogram and clinical correlation with neurologic exam.

Eligibility Criteria

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

Criteria

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)

Contacts and Locations

Contacts

Contact: Sravanthi Koduri; 734-647-7960; skoduri@med.umich.edu

Contact: Aditya Pandey, MD; 734-615-2763; adityap@umich.edu

Locations

United States, Michigan

University of Michigan; Recruiting

Ann Arbor, Michigan, United States, 48109

Contact: Koduri Sravanthi skoduri@med.umich.edu

China, Beining

Peking University Health Science Center; Not yet recruiting

Beijing, Beining, China

Contact: Yining Huang, MD +86 10 83572857 ynhuang@bjmu.edu.cn

Sponsors and Collaborators

Aditya S. Pandey, MD

Michigan Medicine PKUHSC Joint Institute for Translational & Clinical Research

Investigators

• Principal Investigator: Aditya Pandey, MD; University of Michigan

More Information

• Responsible Party: Aditya S. Pandey, MD, Associate Professor of Neurosurgery and Associate Professor of Radiology, University of Michigan
• ClinicalTrials.gov Identifier: NCT04566991
• Other Study ID Numbers: HUM00163868
• First Posted: September 28, 2020
• Last Update Posted: February 28, 2024
• Last Verified: February 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Aditya S. Pandey, MD, University of Michigan:

Deferoxamine; Placebo

Additional relevant MeSH terms:

Subarachnoid Hemorrhage; Hemorrhage; Pathologic Processes; Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Deferoxamine; Siderophores; Iron Chelating Agents; Chelating Agents; Sequestering Agents; Molecular Mechanisms of Pharmacological Action