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

甲磺酸去铁胺治疗脑出血（Hi-DEF）的无效性研究

• 批准号: 8295116
• 负责人: Magdy H Selim
• 金额: $ 137.22万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8295116
• 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; Cognitive; Continuous Intravenous Infusion; Data; Deferoxamine; Deferoxamine Methanesulfonate; Dose; Double-Blind Method; Edema; Emotional; Evaluation; Exclusion; Family; Futility; Future; 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; Phase III Clinical Trials; Placebo Control; Placebos; Play; Public Health; Randomized; Recovery of Function; Regimen; Relative (related person); 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; cohort; design; disability; efficacy evaluation; experience; functional outcomes; improved; inclusion criteria; mortality; neuroprotection; open label; phase 1 study; phase 3 study; prognostic; prospective; standard of care; treatment effect; trial comparing

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.

描述（由申请人提供）：几项研究表明，血红蛋白的分解和随后的铁在大脑中的积累在脑出血后介导继发性神经元损伤（ICH）中起作用；并用铁螯合剂脱氧胺（DFO）治疗在ICH动物模型中提供神经保护。最近，我们在ICH患者中对DFO进行了I期，安全性和剂量调查研究； DFO的静脉注射（IV）输注连续3天，剂量高达62 mg/kg/day的剂量良好，并未增加严重的不良事件或死亡率。当前的提案以这些结果为基础，并汇集了一个拥有世界一流的ICH和临床试验专业知识的团队，以评估DFO作为ICH的治疗干预措施的潜在效用。我们提出了一项前瞻性，多中心，双盲，随机，安慰剂武装，第三期，徒劳的临床研究，以确定这种最大耐受剂量的DFO是否足以提高预期，然后再进行一项大规模且昂贵的III期研究以评估其在ICH中的效率。我们将以62 mg/kg/天（最高每日剂量为6000 mg/day）或盐水安慰剂，将ICH（1：1）的324名受试者随机，以62 mg/kg/day的dfo为单位，连续5天连续5天给出。 ICH症状发作后24小时内将开始治疗。受试者将根据基线ICH得分（0-2 vs. 3-5）和ICH发作时间（OTT）窗口（D12H vs.> 12-24H）进行分层，以使所得的随机分配比为1：1。我们的主要目标是：1）评估基于良好结果的终点（定义为3个月时二分法改良的Rankin量表得分为0-2）和效应尺寸E12％的效果E12％的预定差差异； 2）为了确定ICH患者可以忍受这种剂量的5天注输注持续时间，而不会遭受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，以便收集有关治疗相关的不良事件的更多数据。在研究结束时，将在徒劳分析中将经过良好结果的DFO治疗受试者的比例与安慰剂比例进行比较。如果经DFO处理的比例比安慰剂比例高12％，那么将DFO转向将来的III期测试是徒劳的。我们通常假设DFO治疗将最大程度地减少神经元损伤，从而改善ICH之后的总体结果。这项研究的成功完成将为ICH中的DFO提供至关重要的“ GO/No-Go”信号。徒劳将阻止重大的第三阶段试验，而 非实现将为III期研究提供大力支持，以检测临床功效。结果本研究可以提供有价值的信息，以指导潜在的未来III期试验的设计和样本量估计。 ICH是残疾和死亡的经常原因。成功证明DFO功效的成功Stuy将具有相当大的公共卫生意义。 公共卫生相关性：每年有60,000名美国人发生大脑出血，是死亡和永久残疾的主要原因。这种毁灭性的状况对患者，家人，社会和医疗保健资源的财务和情感负担是巨大的。该项目旨在调查ICH的潜在新方法。因此，它可以具有重要的临床意义。改善这些患者及其家人的福利；和 最小化与ICH患者长期护理有关的费用。