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

甲磺酸去铁胺治疗脑出血（i-DEF）的无效性研究

基本信息

批准号：
9131817
负责人：
Magdy H Selim
金额：
$ 145.65万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9131817
关键词：
Adverse event Aftercare American Animal Model Animals Biological Biological Markers Brain Brain hemorrhage Cause of Death Cerebral Edema Cerebral hemisphere hemorrhage Cessation of life Chelating Agents Clinical Clinical Research Clinical Trials Continuous Intravenous Infusion Data Deferoxamine Deferoxamine Methanesulfonate Dose Double-Blind Method Edema Emotional Evaluation Exclusion Family Futility Future Health Healthcare Hemoglobin Hospitalization Hour Incidence Infusion procedures Intravenous infusion procedures Iron Long-Term Care Maximum Tolerated Dose Mediating Nervous System Trauma Neurologic Neuronal Injury Neuroprotective Agents Outcome Patients Phase Phase II Clinical Trials Placebo Control Placebos Play Public Health Randomized Recovery of Function Regimen Residual state Resources Role Safety Saline Sample Size Serious Adverse Event Signal Transduction Social Welfare Societies Specific qualifier value Stroke Symptoms Testing Therapeutic Intervention Time Translating United States National Institutes of Health X-Ray Computed Tomography arm base brain tissue cerebral atrophy clinical efficacy cognitive testing cohort design disability efficacy evaluation experience functional outcomes improved improved outcome inclusion criteria mortality neuroprotection open label phase 1 study phase 3 study phase III trial prognostic prospective standard of care treatment effect trial comparing

项目摘要

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.

描述（由申请人提供）：多项研究表明，脑内血红蛋白分解和随后的铁积累在脑出血（ICH）后的继发性神经元损伤中起介导作用；铁螯合剂去铁胺（DFO）对脑出血动物模型具有神经保护作用。我们最近完成了DFO在脑出血患者中的i期安全性和剂量研究；连续3天静脉（IV）输注剂量高达62 mg/kg/天的DFO耐受性良好，不会增加严重不良事件或死亡率。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具有世界级专业知识的团队，以评估DFO作为脑出血治疗干预措施的潜在效用。我们建议进行一项前瞻性、多中心、双盲、随机、安慰剂组、ii期无效临床研究，以确定DFO的最大耐受剂量是否有足够的希望改善结果，然后再进行大规模和昂贵的III期研究，以评估其对脑出血的疗效。我们将324名脑出血患者平均（1:1）随机分配至DFO剂量为62 mg/kg/天（最大每日剂量为6000 mg/天）或生理盐水安慰剂，连续静脉输注5天。脑出血症状出现后24小时内开始治疗。受试者将根据基线ICH评分（0-2 vs. 3-5）和ICH发病至治疗时间（OTT）窗口（d12h vs. bbb12 -24h）进行分层，使每个ICH评分和OTT窗口分层的随机化比例为1:1。我们的主要目标是：1)评估基于良好结局的终点（定义为3个月时二分类修正Rankin量表得分为0-2）和预先定义的有利于DFO的效应大小差异（12%）将DFO推进到III期试验是否无效；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在延长的5天输注时间内给予该剂量，而不会出现不合理的神经系统并发症、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，在无效分析中将dfo治疗的受试者中获得良好结果的比例与安慰剂的比例进行比较。如果DFO治疗比例小于安慰剂比例的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ICH的DFO提供一个关键的“去/不去”信号。无效将阻碍重要的三期试验，而