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Deferoxamine in Aneurysmal Subarachnoid Hemorrhage Trial (DASH)

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ClinicalTrials.gov Identifier: NCT02875262
Recruitment Status : Not yet recruiting
First Posted : August 23, 2016
Last Update Posted : September 28, 2017
Sponsor:
Collaborator:
University Medical Center Groningen
Information provided by (Responsible Party):
Radboud University

Brief Summary:
Aneurysmal subarachnoid hemorrhage (SAH) is a form of stroke in which secondary neurological deterioration is an important cause of mortality and morbidity. These secondary changes, so called delayed cerebral ischemia (DCI), are caused by lysis of erythrocytes which can react to form iron, an toxic substance to the brain. Iron chelators remove the excess of iron and are standard care in iron-overloaded patients. Deferoxamine (DFO) an chelator has not been evaluated in SAH patients. This study evaluates the safety of deferoxamine in SAH patients

Condition or disease Intervention/treatment Phase
Intracranial Aneurysm Subarachnoid Hemorrhage Drug: Deferoxamine Other: placebo Phase 1 Phase 2

Detailed Description:

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating form of stroke affecting relatively young patients. It has an incidence of about 7 per 100,000. Associated economic costs are high. Treatment of the aneurysm to prevent rebleeding is the primary goal. Nevertheless, 3 to 12 days after the initial bleeding secondary ischemic changes occur in 30% of the patients. This delayed cerebral ischemia (DCI) remains the most important cause of mortality and morbidity in patients surviving aneurysm treatment.

Aneurysmal SAH exposes the brain to erythrocytes. Several days after the hemorrhage lysis of erythrocytes takes place and the brain is exposed to high concentrations of hemoglobin. Elevated hemoglobin concentrations are present not only at the basal surface of the brain, but also distributed around the brain and into deeper layers of the cortex. Heme is degraded by heme-oxygenase into carbon monoxide, biliverdin and iron. Free iron can react with H2O and O2- to form hydroxyl radicals (OH*). The generation of hydroxyl radicals in this cascade, known as the Haber-Weiss or Fenton reaction, leads to extraction of hydrogen from unsaturated lipids in the cell membrane and initiates lipid peroxidation. Additionally it can exacerbate excitotoxicity by increased intracellular iron accumulation.

Iron chelators remove the excess of iron and are standard care in iron-overloaded patients. The use of iron chelators for SAH has been subject of animal studies with promising results on reduced vasospasm, oxidative stress, neuronal cell death and mortality. No clinical study for the use of deferoxamine in aneurysmal subarachnoid hemorrhage has been performed. A safety study for the use of Deferoxamine in patients in intracerebral hemorrhage (which is distinct from subarachnoid hemorrhage) has been performed. There were no associated serious adverse events or mortality, Deferoxamine is a chelator is used for more than 40 years in patients with iron overload diseases. This study investigates the safety and tolerability of deferoxamine versus placebo in patients with SAH for 3 consecutive days.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Deferoxamine in Aneurysmal Subarachnoid Hemorrhage Trial
Estimated Study Start Date : December 1, 2017
Estimated Primary Completion Date : December 1, 2017
Estimated Study Completion Date : June 1, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bleeding

Arm Intervention/treatment
Experimental: Treatment
Patients will be given deferoxamine 32 mg/kg/day (max iv rate 15 mg/kg/hr), patients with ferritin levels between 2,000 and 3,000 ng/ml will receive 32 mg/kg/day and patients with serum ferritin levels below 2,000 ng/ml wil receive 25 mg/kg/day. duration 3 days
Drug: Deferoxamine
Patients will be given deferoxamine 32 mg/kg/day (max iv rate 15 mg/kg/hr), patients with ferritin levels between 2,000 and 3,000 ng/ml will receive 32 mg/kg/day and patients with serum ferritin levels below 2,000 ng/ml wil receive 25 mg/kg/day.during 3 days
Other Name: desferal

Placebo Comparator: placebo
NaCl 0.9% in similar dosis to treatment arm
Other: placebo
placebo (NaCl 0.9%) in equal dose to treatment




Primary Outcome Measures :
  1. safety (drug related adverse events; i.e. renal and hepatic dysfunction) [ Time Frame: 6 months ]
    drug related adverse events; i.e. renal and hepatic dysfunction, ARDS


Secondary Outcome Measures :
  1. efficacy [ Time Frame: 6 months ]
    number of patients with delayed cerebral ischemia, which is defined by new, not treatment related cerebral ischemia as registered on CT or MR imaging



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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • subarachnoid hemorrhage diagnosed by CT on admission,
  • Randomizable within 72 hours of subarachnoid hemorrhage,
  • Saccular intracranial aneurysm proven by cerebral angiography or CTA,
  • Surgical or endovascular obliteration is performed,
  • Able to obtain written informed consent from patient or surrogate.
  • Patients in a good clinical grade (WFNS 1-3)

Exclusion Criteria:

  • Pregnancy, as confirmed by routine urine test on admission,
  • Abnormal renal function at time of randomization (GFR <60 mL/min)
  • Elevated liver function test at time of randomization (AST > 45 U/L and ALT > 35 U/L.)
  • History of liver disease or active liver disease, Active renal disease,
  • Hypersensitivity to deferoxamine,
  • Patient taking medication not recommended for concomitant use with deferoxamine as per the product label (e.g. high dose vit. C medication).
  • Patients not able to complete the study follow-up the presence of 4 or more of the following exclusion criteria (risk modifiers for ARDS):

    • Tachypnea (respiratory rate >30)
    • SpO2 <95%
    • Obesity (BMI >30)
    • Acidosis (pH <7.35)
    • Hypoalbuminemia (albumin <3.5 g/dL)
    • concurrent use of chemotherapy

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): NCT02875262


Contacts
Contact: Jeroen Boogaarts, M.D., Ph.D. 00310243615085 jeroen.boogaarts@radboudumc.nl
Contact: Ronald Bartels, M.D., Ph.D. 00310243615085 ronald.bartels@radboudumc.nl

Locations
Netherlands
Radboudumc Not yet recruiting
Nijmegen, Gelderland, Netherlands, 6500 HB
Contact: Jeroen Boogaarts, M.D., Ph.D.    0031243615085    jeroen.boogaarts@radboudumc.nl   
Contact: Joost de Vries, M.D., Ph.D.    0031243615085    joost.devries@radboudumc.nl   
University Medical Center Groningen Not yet recruiting
Groningen, Netherlands, 9713 GZ
Contact: Marc van Dijk, M.D., Ph.,D.    00310503616161    j.m.c.van.dijk@umcg.nl   
Contact: Rob Groen, M.D., Ph.,D.    00310503616161    r.j.m.groen@umcg.nl   
Sponsors and Collaborators
Radboud University
University Medical Center Groningen
Investigators
Principal Investigator: Jeroen Boogaarts, M.D., Ph.D. Radboud University

Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT02875262     History of Changes
Other Study ID Numbers: NL58448.091.16
First Posted: August 23, 2016    Key Record Dates
Last Update Posted: September 28, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: core data will be published

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

Keywords provided by Radboud University:
intracranial aneurysm
subarachnoid hemorrhage
stroke
chelator

Additional relevant MeSH terms:
Hemorrhage
Aneurysm
Subarachnoid Hemorrhage
Intracranial Aneurysm
Pathologic Processes
Vascular Diseases
Cardiovascular Diseases
Intracranial Hemorrhages
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Intracranial Arterial Diseases
Deferoxamine
Siderophores
Iron Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action