High dose deferoxamine in intracerebral hemorrhage (HI-DEF) trial: rationale, design, and methods.
BACKGROUND
Hemoglobin degradation products, in particular iron, have been implicated in secondary neuronal injury following intracerebral hemorrhage (ICH). The iron chelator Deferoxamine Mesylate (DFO) exerts diverse neuroprotective effects, reduces perihematoma edema (PHE) and neuronal damage, and improves functional recovery after experimental ICH. We hypothesize that treatment with DFO could minimize neuronal injury and improve outcome in ICH patients. As a prelude to test this hypothesis, we conducted a Phase I, open-label study to determine the tolerability, safety, and maximum tolerated dose (MTD) of DFO in patients with ICH. Intravenous infusions of DFO in doses up to 62 mg/kg/day (up to a maximum of 6000 mg/day) were well-tolerated and did not seem to increase serious adverse events (SAEs) or mortality. We have initiated a multi-center, double-blind, randomized, placebo-controlled, Phase II clinical trial (High Dose Deferoxamine [HI-DEF] in Intracerebral Hemorrhage) to determine if it is futile to move DFO forward to Phase III efficacy evaluation.


METHODS
We will randomize 324 subjects with spontaneous ICH to either DFO at 62 mg/kg/day (up to a maximum daily dose of 6000 mg/day) or saline placebo, given by intravenous infusion for 5 consecutive days. Treatment will be initiated within 24 hours after ICH symptom onset. All subjects will be followed for 3 months and will receive standard of care therapy while participating in the study. At 3 months, the proportion of DFO-treated subjects with a good clinical outcome, assessed by modified Rankin Scale, will be compared to the placebo proportion in a futility analysis.


CONCLUSIONS
The Hi-Def trial is expected to advance our understanding of the pathopgysiology of secondary neuronal injury in ICH and will provide a crucial "Go/No Go" signal as to whether a Phase III trial to investigate the efficacy of DFO is warranted.
Data Coordination Unit, Department of Public Health Sciences, College of Medicine, Medical University of South Carolina, Charleston, SC, USA.
Sharon D
SD
Yeatts
Yuko Y
YY
Palesch
Claudia S
CS
Moy
Magdy
M
Selim
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000503:physiopathology; D003422:Critical Care / Q000379:methods*; D003676:Deferoxamine / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D006801:Humans; D008875:Middle Aged; D010919:Placebos; D012107:Research Design; D017262:Siderophores / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult
D010919:Placebos; D017262:Siderophores; D003676:Deferoxamine