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

描述(申请人提供)：多项研究表明，血红蛋白分解和随后在脑内积聚的铁在介导脑出血(ICH)后继发性神经元损伤方面发挥了作用；铁络合剂去铁胺(DFO)的治疗在脑出血动物模型中提供了神经保护。我们最近完成了一项DFO在脑出血患者中的I期、安全性和剂量发现研究；静脉(IV)输注剂量高达62毫克/公斤/天、连续3天的DFO耐受性良好，不会增加严重的不良事件或死亡率。目前的建议建立在这些结果的基础上，并汇集了一个在脑出血和临床试验方面拥有世界级专业知识的团队，以评估DFO作为脑出血治疗干预的潜在用途。我们提出了一项前瞻性、多中心、双盲、随机、安慰剂对照的II期无效性临床研究，以确定在开始大规模且昂贵的III期研究以评估其对脑出血的疗效之前，DFO的最大耐受剂量是否有足够的改善结果的前景。我们将324名脑出血患者按1：1的比例随机分为DFO组和生理盐水安慰剂组，DFO剂量为62 mg/kg/d(每日最大剂量为6000 mg/d)，生理盐水为安慰剂，连续静脉滴注5天。治疗将在脑出血症状出现后24小时内开始。受试者将根据基线脑出血评分(0-2比3-5)和脑出血发病至治疗时间窗口(d12小时比12-24小时)进行分层，因此在每个脑出血评分和治疗窗口层次内所产生的随机化比率为1：1。我们的主要目标是：1)评估根据良好结果的终点(定义为3个月时DFO的二分改良Rankin量表评分0-2)和预先定义的效果大小差异e12%支持DFO，将DFO推进到III期试验是否徒劳；以及2)收集更多与治疗相关的不良事件的数据，以确定脑出血患者可以耐受长达5天的输液时间，而不会出现不合理的神经并发症、死亡率增加或其他与使用DFO相关的严重不良事件。在研究结束时，在无效性分析中，将比较接受DFO治疗的受试者和安慰剂受试者的结果良好的比例。如果DFO治疗的比例比安慰剂的比例高出12%以下，那么将DFO推进到未来的第三阶段测试将是徒劳的。我们一般假设DFO治疗可以最大限度地减少神经元损伤，从而改善脑出血后的整体预后。这项研究的成功完成将为脑出血的DFO提供一个关键的“去/不去”的信号。徒劳无益将阻碍重大的第三阶段试验，而 非徒劳将为第三阶段研究提供强有力的支持，以检测临床疗效。这项研究的结果可以为未来潜在的III期试验的设计和样本量估计提供有价值的信息。ICH是致残和死亡的常见原因。一项成功的研究证明了DFO的有效性，将具有相当大的公共卫生意义。

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.