DASH: Deferoxamine in Aneurysmal Subarachnoid Hemorrhage Trial

Sponsor

Radboud University Medical Center (Other)

Overall Status

Unknown status

CT.gov ID

NCT02875262

Collaborator

University Medical Center Groningen (Other)

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

3.3

Patients Per Site Per Month

Study Details

Study Description

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 Design

Study Type:

Interventional

Anticipated 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

Anticipated Study Start Date :

Dec 1, 2017

Anticipated Primary Completion Date :

Dec 1, 2017

Anticipated Study Completion Date :

Jun 1, 2018

Arms and Interventions

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

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

Other Names:

desferal

Placebo Comparator: placebo

NaCl 0.9% in similar dosis to treatment arm

Other: placebo

placebo (NaCl 0.9%) in equal dose to treatment

Outcome Measures

Primary Outcome Measures

safety (drug related adverse events; i.e. renal and hepatic dysfunction) [6 months]
drug related adverse events; i.e. renal and hepatic dysfunction, ARDS

Secondary Outcome Measures

efficacy [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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