Phase 2B Trial of Memantine for the Treatment of Amyotrophic Lateral Sclerosis

美金刚治疗肌萎缩侧索硬化症的 2B 期试验

• 批准号: 10242456
• 负责人: Richard J. Barohn
• 金额: $ 10.58万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-17 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242456
• 关键词: Phase; 2B; Trial; Memantine; Treatment

Project Summary/Abstract Amyotropnic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects 30,000 Americans each year. Of these 3O,OO0 Americans, it has been suggested that up to 50o/o will experience cognitive and behavioral changes in the form of frontotemporal dysfunction and up to +OZo will meet criteria for frontotemporal dementia (FTD) (42, 43). Riluzole the only FDA approved agent for ALS extends a patient's lifespan by 2-3 months, and there are flo proven therapies tor tne cognitive changes associated with ALS. More effective therapy for this universally fatal disease is desperately needed' Results from an open label pitot trial of 20 patients treated with memantine at 10 mg BID suggested that treatment with the combination of memantine and riluzole slowed ALS disease pro{ression (1). This trial also showed that levels of specific protein biomarkers in the CSF at b"s-etine correlated with the rate of disease progression. (1). A concurrent phase ll study performed by Dr Carvalho, found no effect with similar dosing(16); however, the study was iiriteO in terms of power. Comtnents on previous failed drug trials in ALS have raised the concern that many ALS trials study a potential therapeutic agent at only a single dose and thus may miss the potential efficacy of hon FDA approved d-oses; therefore, this proposed study will tesi a higher dose of memantine, 20 mg BlD, in a double blind, placebo controlled, randomized trial of g6 patients with ALS to determine if a combination therapy of memantine with riluzole can slow disease progression compared to treatment with riluzole alone. The primary outcome measure will be the rate of disease progression as measured by the ALS Functional Rating Scate- Revised (ALSFRS-R). ln addition we will examine the cognitive deficits seen in ALS patients measured by the ALS Cognitive Behavioral Screen (ALS-CBS) and the i.l"rropsychiatric lnventory Questionnaire (NlP-Q). Finally we will examine specific validated protein blomarkers found in the cerebrospinal fluid to determine if there is a correlation between ihe levels of these biomarkers and the rate of disease progression. ln particular we will measure the ratio of phosphorylated heavy neurofilament to Complement 3 (31) to see if this ratio is predictive of disease progression and if the levels change during therapy with memantine' ' This project witl otfer unique insights into this untreatable disease. lf this study confirms earlier results and suggests that memantine, when used in conjunction with riluzole, significantly slows down the progression of the disease, as well as ameliorates cognitive deficits in patients with fronto-temporaidysfunction, it will set the groundwork for conducting a larger phase lll trial'

项目总结/摘要 肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病， 每年3万美国人。在这3万名美国人中，有多达50人被认为 将经历认知和行为变化，表现为额颞叶功能障碍， 高达+OZO将符合额颞叶痴呆（FTD）的标准（42，43）。阿舒唑是唯一的FDA 一种被批准的ALS药物可以延长患者的寿命2-3个月，并且已经证明， 治疗与ALS相关的认知变化。更有效的治疗方法 我们迫切需要一种普遍致命的疾病 20例接受美金刚10 mg BID治疗的患者的开放标签皮托管试验结果 美金刚和利鲁唑联合治疗减缓了ALS疾病， proximation（1）.该试验还显示，在24小时内， B-β与疾病进展率相关。（一）.同期II期研究 Carvalho博士进行的研究发现，类似的剂量没有效果（16）;然而，这项研究 在权力方面。关于以前在ALS中失败的药物试验的评论已经提高了 关注许多ALS试验仅以单剂量研究潜在的治疗剂， 可能会错过FDA批准的d-oses的潜在疗效;因此，这项拟议的研究将 在一项双盲、安慰剂对照、随机 对患有ALS的g6患者进行试验，以确定美金刚与利鲁唑的联合治疗是否 与单独使用利鲁唑治疗相比，可以减缓疾病进展。主要结局 测量将是通过ALS功能评定测量的疾病进展速率 Scate-修订版（ALSFRS-R）。此外，我们还将检查ALS患者的认知缺陷 通过ALS认知行为筛查（ALS-CBS）和 I.I.精神病学调查问卷（NIP-Q）。最后，我们将研究具体的验证 在脑脊液中发现的蛋白质生物标志物，以确定是否有相关性， 这些生物标志物的水平和疾病进展的速率。特别是我们将测量 磷酸化重神经丝与补体3的比率（31），以观察该比率是否 预测疾病进展以及在美金刚治疗期间水平是否改变 ' 这个项目将提供对这种无法治愈的疾病的独特见解。如果这项研究证实 早期的结果表明，美金刚，当与利鲁唑联合使用时， 减缓疾病的进展，以及改善患者的认知缺陷 由于锋-时功能障碍，它将为进行更大规模的第三阶段试验奠定基础。