Safety and Tolerability of Deferoxamine in Acute Cerebral Hemorrhage

描述（由申请人提供）：几项动物研究表明，血红蛋白分解和随后的脑中铁积累在介导脑出血（ICH）后继发性神经元损伤和脑水肿中起作用;并且用铁螯合剂（如去铁胺（DFO））治疗可提供神经保护。去铁胺已广泛应用于临床实践超过30年。它耐受性好，价格低廉，因此可能是治疗ICH患者的潜在新疗法。到目前为止，还没有临床研究来检查DFO对ICH患者的影响。我们拟开展一项前瞻性、开放标签、非随机、多层次、剂量探索、多中心、初步的临床研究，以评价DFO治疗ICH患者的安全性和耐受性。我们将测试递增剂量方案，从7 mg/kg剂量开始，最大剂量为125 mg/kg。剂量毒性的连续再评估方法将用于确定递增剂量水平，剂量层之间的最大增量增加将不超过25 mg/kg。药物将在卒中症状发作后12小时内开始每日IV输注给药，连续3天。受试者将接受长达90天的重复临床评估，以及给药前后的CT成像。我们的主要目标是：1）通过确定ICH患者中治疗相关的不良事件，评估不同剂量DFO的安全性和耐受性; 2）确定后续II/III期研究中采用的最大耐受剂量，以确定最佳治疗时间窗和持续时间，并测试DFO在改善ICH后结局方面的疗效。我们假设DFO在ICH患者中耐受性良好，严重不良反应最小。本研究将提供将临床前有效策略应用于ICH治疗的机会，并将使我们能够制定药物管理的后勤工作，并实施指导未来II/III期试验计划所需的标准化程序。这些结果可能会为改善ICH患者的结局带来新的方法。ICH是导致残疾和死亡的常见原因。一项成功的研究证明铁修饰疗法的疗效将具有相当大的公共卫生意义。

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.