High dose deferoxamine in intracerebral hemorrhage (HI-DEF) trial: rationale, design, and methods.
High dose deferoxamine in intracerebral hemorrhage (HI-DEF) trial: rationale, design, and methods.
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DOI：
10.1007/s12028-013-9861-y
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发表时间：
2013-10
影响因子：
3.5
通讯作者：
Selim, Magdy
中科院分区：
文献类型：
--
作者：
Yeatts, Sharon D.;Palesch, Yuko Y.;Moy, Claudia S.;Selim, Magdy
血红蛋白降解产物，特别是铁，已被牵连在脑出血（ICH）后继发性神经元损伤。铁螯合剂甲磺酸去铁胺（DFO）具有多种神经保护作用，可减轻血肿周围水肿（PHE）和神经元损伤，并促进实验性ICH后的功能恢复。我们假设DFO治疗可以最大限度地减少神经元损伤，改善ICH患者的预后。作为检验这一假设的前奏，我们进行了一项I期、开放标签研究，以确定DFO在ICH患者中的耐受性、安全性和最大耐受剂量（MTD）。DFO静脉输注剂量高达62 mg/kg/天（最高达6000 mg/天）耐受性良好，似乎不会增加严重不良事件（SAE）或死亡率。我们已经启动了一项多中心、双盲、随机、安慰剂对照的II期临床试验（大剂量去铁胺[HI-DEF]治疗脑出血），以确定将DFO推进到III期疗效评估是否无效。我们将324名自发性ICH受试者随机分配至DFO 62 mg/kg/天（最大日剂量为6000 mg/天）或盐水安慰剂组，连续5天静脉输注。治疗将在ICH症状发作后24小时内开始。所有受试者将接受3个月的随访，并在参与研究期间接受标准治疗。在3个月时，将在无效性分析中比较通过改良兰金量表评估的具有良好临床结局的DFO治疗受试者比例与安慰剂比例。Hi-Def试验预计将促进我们对ICH继发性神经元损伤病理生理学的理解，并将提供一个关键的“Go/No Go”信号，以确定是否有必要进行III期试验来研究DFO的疗效。
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. 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. 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.
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影响因子：
8.3
作者：
Venkatasubramanian C;Mlynash M;Finley-Caulfield A;Eyngorn I;Kalimuthu R;Snider RW;Wijman CA
通讯作者：
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Kipp, Deborah E.