Futility Study of Deferoxamine Mesylate in Intracerebral Hemorrhage (Hi-DEF)

描述（由申请人提供）：几项研究表明，脑中血红蛋白分解和随后的铁积累在介导脑出血（ICH）后继发性神经元损伤中起作用;并且用铁螯合剂去铁胺（DFO）治疗可在ICH动物模型中提供神经保护。我们最近完成了一项DFO在ICH患者中的I期、安全性和剂量探索研究;连续3天静脉（IV）输注剂量高达62 mg/kg/d的DFO耐受性良好，并且不会增加严重不良事件或死亡率。目前的提案建立在这些结果的基础上，并汇集了一个在ICH和临床试验方面具有世界一流专业知识的团队，以评估DFO作为ICH治疗干预的潜在效用。我们提出了一项前瞻性、多中心、双盲、随机、安慰剂组、II期、无效性临床研究，以确定DFO的最大耐受剂量是否足以改善结局，然后再进行大规模、昂贵的III期研究，以评估其在ICH中的疗效。我们将324例ICH受试者平均（1：1）随机分配至DFO 62 mg/kg/天（最大日剂量为6000 mg/天）或生理盐水安慰剂组，连续IV输注给药5天。治疗将在ICH症状发作后24小时内开始。将基于基线ICH评分（0-2 vs. 3-5）和ICH发作至治疗时间（OTT）窗口（d12 h vs. >12- 24 h）对受试者进行分层，以便在每个ICH评分和OTT窗口分层内所得随机化比率为1：1。我们的主要目标是：1）评估以良好结果为终点，将DFO提前至III期试验是否徒劳（定义为3个月时改良兰金量表评分为0-2分）和效应量的预定差异e12%有利于DFO;和2）收集更多关于治疗相关不良事件的数据，以确定ICH患者可以耐受在延长的5- 10天内给予该剂量。天的输注持续时间，而没有出现不合理的神经系统并发症、死亡率增加或其他与DFO使用相关的严重不良事件。研究结束时，将在无效性分析中比较DFO治疗组结局良好的受试者比例与安慰剂组比例。如果DFO治疗的比例比安慰剂比例高不到12%，那么将DFO推进到未来的III期试验将是徒劳的。我们通常假设DFO治疗将使神经元损伤最小化，从而改善ICH后的总体结局。本研究的成功完成将为ICH中的DFO提供关键的“进行/不进行”信号。无效将阻碍重大的第三阶段试验，而 非无效性将为检测临床疗效的III期研究提供强有力的支持。本研究的结果可以提供有价值的信息，以指导未来潜在的III期试验的设计和样本量估计。ICH是导致残疾和死亡的常见原因。一项成功的研究证明DFO的有效性将具有相当大的公共卫生意义。 公共卫生相关性：每年有6万美国人发生脑出血，是死亡和永久残疾的主要原因。这种毁灭性的疾病给患者、他们的家庭、社会和医疗资源带来的经济和情感负担是巨大的。该项目旨在研究ICH的潜在新治疗方法。因此，它可以有重要的临床意义;改善这些病人及其家属的福利;以及 最大限度地减少ICH患者长期护理相关费用。

DESCRIPTION (provided by applicant): Several studies show that hemoglobin breakdown and subsequent iron accumulation in the brain play a role in mediating secondary neuronal injury after intracerebral hemorrhage (ICH); and that treatment with the iron chelator, deferoxamine (DFO), provides neuroprotection in animal models of ICH. We recently concluded a phase-I, safety and dose-finding study of DFO in patients with ICH; intravenous (IV) infusions of DFO in doses up to 62 mg/kg/day for 3 consecutive days were well-tolerated and did not increase serious adverse events or mortality. The current proposal builds on these results and brings together a team with world-class expertise in ICH and clinical trials to assess the potential utility of DFO as a therapeutic intervention in ICH. We propose a prospective, multi-center, double-blind, randomized, placebo-armed, phase-II, futility clinical study to determine if this maximum tolerated dose of DFO is of sufficient promise to improve outcome prior to embarking on a large-scale and costly phase III study to assess its efficacy in ICH. We will randomize 324 subjects with ICH equally (1:1) to either DFO at 62 mg/kg/day (up to a maximum daily dose of 6000 mg/day), or saline placebo, given by continuous IV infusion for 5 consecutive days. Treatment will be initiated within 24 hours after ICH symptom onset. Subjects will be stratified based on baseline ICH score (0-2 vs. 3-5) and ICH onset-to- treatment time (OTT) window (d12h vs. >12-24h), so that the resulting randomization ratio is 1:1 within each ICH score and OTT window strata. Our main objectives are: 1) To assess whether it would be futile to move DFO forward into a Phase III trial based on the end point of good outcome (defined as dichotomized modified Rankin Scale score of 0-2 at 3 months) and a pre-defined difference in effect size e12% in favor of DFO; and 2) To collect more data on treatment-related adverse events in order to ascertain that patients with ICH can tolerate this dose given over an extended 5-day duration of infusion without experiencing unreasonable neurological complications, increased mortality, or other serious adverse events related to DFO use. At the conclusion of the study, the proportion of DFO-treated subjects with a good outcome will be compared to the placebo proportion in a futility analysis. If the DFO-treated proportion is less than 12% greater than the placebo proportion, then it would be futile to move DFO forward to future Phase III testing. We generally hypothesize that treatment with DFO will minimize neuronal injury and, thus, improve the overall outcome after ICH. Successful completion of this study will provide a crucial "go/no-go" signal for DFO in ICH. Futility will discourage a major phase III trial, whereas non-futility will offer strong support for a phase III study to detect clinical efficacy. Results fom this study can provide valuable information to guide the design and sample size estimation of a potential future Phase III trial. ICH is a frequent cause of disability and death. A successful stuy demonstrating the efficacy of DFO would be of considerable public health significance. PUBLIC HEALTH RELEVANCE: Brain hemorrhage occurs in 60,000 Americans per year, and is a major cause of death and permanent disability. The financial and emotional burden of this devastating condition on the patients, their families, the society, and healthcare resources is enormous. This project aims to investigate a potential new treatment for ICH. It, therefore, can have important clinical implications; improve the welfare of these patients and their families; and minimize expenses related to long-term care of patients with ICH.