High Dose Deferoxamine in Intracerebral Hemorrhage (Hi-Def) Trial: Rationale, Design, and Methods

Abstract

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.

Microglial Polarization and Inflammatory Mediators After Intracerebral Hemorrhage

“…Though the use of iron chelators to reduce brain injury needs additional investigation before it can be applied clinically decreasing iron accumulation/toxicity in the brain remains an important goal for treatment of patients with ICH. Deferoxamine is now under phase II clinical trial for treating ICH patients [148]. …”

Brain Iron Metabolism and Brain Injury Following Subarachnoid Hemorrhage: iCeFISH-Pilot (CSF Iron in SAH)

“…2,3 In aneurysmal subarachnoid hemorrhage (SAH), erythrocytes lyse in the subarachnoid space and expose the brain to high concentrations of Hb. 4 The catabolism of heme, mediated by heme-oxygenase, leads to the release of iron, which easily overwhelms the homeostatic mechanisms normally present in the CNS.…”

Neuroprotective strategies following intraparenchymal hemorrhage

“…In contrast, a similar phase II study, ‘High-Dose Deferoxamine in Intracerebral Hemorrhage’ (HI-DEF), conducted in the United States using the same dose (62 mg/kg/day deferoxamine for 3 days) showed an increased incidence of acute respiratory distress syndrome. Consequently, the HI-DEF trial was suspended and restructured as the ‘Intracerebral Hemorrhage Deferoxamine Trial’ (iDEF) using a lower dose of deferoxamine 58. The iDEF trial is currently evaluating the efficacy of low dose deferoxamine (32 mg/kg/day) for 3 days following ICH.…”