Safety and Tolerability of Deferoxamine in Acute Cerebral Hemorrhage

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DESCRIPTION (provided by applicant): Several animal studies show that hemoglobin breakdown and subsequent iron accumulation in the brain play a role in mediating secondary neuronal injury and brain edema after intracerebral hemorrhage (ICH); and that treatment with iron chelators, such as deferoxamine (DFO), provides neuroprotection. Deferoxamine has been extensively used in clinical practice for more than 30 years. It is well-tolerated, inexpensive, and therefore, may be a potential novel therapy to treat patients with ICH. To date, there have been no clinical studies to examine the effects of DFO in patients with ICH. We propose to conduct a prospective, open-label, non-randomized, multiple-tier, dose-finding, multi-center, preliminary, clinical study to evaluate the safety and tolerability of treatment with DFO in patients with ICH. We will test escalating dose-regimens, starting at a dose of 7 mg/kg up to a maximum dose of 125 mg/kg. A Continuous Reassessment Method of dose toxicity will be used to determine escalating dose levels, and the maximal increment increase between dose-tiers will not exceed 25 mg/kg. The drug will be administered as IV infusion daily for 3 consecutive days, starting within 12 hours of stroke symptom onset. Subjects will undergo repeated clinical assessments up to 90 days, and CT imaging pre- and post-drug administration. Our main objectives are: 1) to evaluate the safety and tolerability of varying doses of DFO, by determining the treatment related adverse events, in patients with ICH; and 2) to determine the maximal tolerated dose to be adopted in subsequent phase II/III studies to determine the optimal treatment time window, and duration, and to test the efficacy of DFO in improving outcome after ICH. We hypothesize that DFO is well-tolerated and has minimal serious adverse effects in patients with ICH. This study will afford the opportunity to apply preclinical efficacious strategy to the treatment of ICH, and will allow us to work out the logistics of drug administration, and implementation of standardized procedures needed to guide the planning of future phase II/III trials. The results can potentially bring into account new means to improve the outcome of patients with ICH. ICH is a frequent cause of disability and death. A successful study demonstrating the efficacy of iron-modifying therapy would be of considerable public health significance.