ALIAS Phase IIi Multicenter Clincal Trial -- Albumin in Acute Ischemic Stroke

描述（由申请人提供）：本竞争性更新申请的目的是完成ALIAS（白蛋白治疗急性卒中）多中心临床试验，其目的是确定高剂量人血白蛋白治疗（ALB）是否对急性缺血性卒中受试者具有神经保护作用。这项由NINDS资助的试验在美国和加拿大约60个临床研究中心进行，此前进行了广泛的临床前研究，表明ALB治疗具有高度神经保护作用;以及一项剂量递增的初步试验，其中证明了该疗法在中风患者中的安全性和耐受性，并获得了初步的疗效信号。基于ALIAS多中心试验的前434例受试者中出现的DSMB确定的安全性问题，进行了详细的非盲安全性分析，并确定了纳入修订方案的因素（包括年龄上限、强制性液体限制、强制性利尿治疗），以提高安全性。ALIAS第2部分试验随后于2009年2月重新开始，此后招募了1，100例受试者中的280多例。ALIAS第2部分试验是一项随机、双盲、安慰剂对照的III期多中心临床试验，在基线NIHSS评分>6且可在卒中发作5小时内接受研究药物治疗的急性缺血性卒中患者中进行。允许标准治疗溶栓治疗（IV和/或IA tPA和机械性溶栓）。该试验的主要目的是确定ALB治疗是否能提供超过最佳标准治疗的神经保护作用：具体而言，确定与安慰剂治疗相比，ALB治疗是否能增加结局良好的受试者比例。有利结局定义为随机化后3个月时NIHSS评分为0或1，或改良兰金评分（mRS）为0或1，或两者均为。受试者随访至12个月。共入组1,100例受试者。可以添加选定的欧洲网站。ALIAS试验提供了独特的机会，可以应用临床前高效策略来治疗缺血性中风，使用的剂量和时间与显示疗效的临床前环境非常相似。 公共卫生相关性：中风是第三大死亡原因，也是慢性残疾的主要原因。目前还没有临床证明的药物可以保护大脑免受中风中不可逆的损伤。实验室研究表明，高剂量白蛋白治疗在卒中模型中具有很强的保护作用。ALIAS多中心试验是一项随机、安慰剂对照研究，旨在评估该疗法是否改善缺血性卒中患者的神经和功能结局。如果它这样做，它将成为全世界的护理标准。

DESCRIPTION (provided by applicant): The objective of this competitive renewal application is to bring to completion the ALIAS (Albumin in Acute Stroke) Multicenter Clinical Trial, whose aim is to ascertain whether high-dose human albumin therapy (ALB) confers neuroprotection in subjects with acute ischemic stroke. This NINDS-funded trial, in progress at around 60 U.S. and Canadian clinical sites, follows upon extensive preclinical studies showing that ALB therapy is highly neuroprotective; and a dose-escalation Pilot Trial, in which the safety and tolerability of this therapy in stroke patients were demonstrated and a preliminary signal of efficacy was obtained. Based on DSMB-identified safety concerns arising in the first 434 subjects of the ALIAS Multicenter Trial, detailed unblinded safety analyses were conducted and factors were identified that were incorporated into a revised protocol (including upper age limit, mandatory fluid restriction, mandatary diuretic therapy) to improve safety. The ALIAS Part 2 Trial then re-commenced in Feb. 2009 and has since enrolled over 280 subjects of the 1,100 required. The ALIAS Part 2 Trial Is a randomized, double-blinded, placebo-controlled Phase III multicenter clinical trial in patients with acute ischemic stroke whose baseline NIHSS score is >6 and who can be treated with study drug within 5 hours of stroke onset. Standard-of-care thrombolytic therapy (IV and/or IA tPA and mechanical clot lysis) Is permitted. The primary aim of the trial is to ascertain whether ALB therapy confers neuroprotection over and above the best standard of care: specifically, to determine whether ALB therapy increases the proportion of subjects with favorable outcome compared to placebo therapy. Favorable outcome is defined as either an NIHSS score of 0 or 1, or a modified Rankin Score (mRS) of 0 or 1, or both, measured at 3 months from randomization. Subjects are followed out to 12 months. A total of 1,100 subjects will be enrolled. Selected European sites may be added. The ALIAS Trial affords the unique opportunity to apply a preclinically highly effective strategy to treat ischemic stroke using a dose and timing that closely replicate the preclinical setting in which efficacy was shown. PUBLIC HEALTH RELEVANCE: Stroke is the third leading cause of death and the major cause of chronic disability. There are currently no clinically proven agents to protect the brain from irreversible Injury in stroke. Lab studies have shown that high-dose albumin therapy is strongly protective in stroke models. The ALIAS Multicenter Trial is a randomized, placebo-controlled study to assess whether this therapy improves neurological and functional outcome in ischemic stroke patients. If it does so, it will become a standard of care throughout the world.