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

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ClinicalTrials.gov Identifier: NCT04566991
Recruitment Status : Not yet recruiting
First Posted : September 28, 2020
Last Update Posted : April 6, 2021
Sponsor:
Collaborator:
Michigan Medicine PKUHSC Joint Institute for Translational & Clinical Research
Information provided by (Responsible Party):
Aditya S. Pandey, MD, University of Michigan

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

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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)
Estimated Study Start Date : June 2021
Estimated Primary Completion Date : October 2025
Estimated Study Completion Date : October 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bleeding

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




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.



Information from the National Library of Medicine

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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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04566991


Contacts
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Contact: Sravanthi Koduri 734-647-7960 skoduri@med.umich.edu
Contact: Aditya Pandey, MD 734-615-2763 adityap@umich.edu

Locations
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United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
Contact: Bell Jenny    734-647-5436    jennbell@umich.edu   
China, Beining
Peking University Health Science Center
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
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Principal Investigator: Aditya Pandey, MD University of Michigan
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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    Key Record Dates
Last Update Posted: April 6, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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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