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

项目摘要/摘要 肌萎缩侧索硬化症(ALS)是一种致命的神经退行性疾病，影响 每年有3万美国人。在这些30,000,000的美国人中，有人建议高达500/O 会经历额颞叶功能障碍形式的认知和行为变化 高达+OZO将符合额颞叶痴呆(FTD)的标准(42，43)。利鲁唑是唯一的FDA 已批准的ALS药物可将患者的生命延长2-3个月，并且有经验证的Flo 治疗与肌萎缩侧索硬化症相关的认知改变。对此更有效的治疗方法 普遍致命的疾病是迫切需要的 美金刚10 mg，2次/d治疗20例患者的开放式皮托试验结果 建议联合使用美金刚和利鲁唑可延缓ALS疾病 递推(1)。这项试验还表明，脑脊液中特定蛋白质生物标记物的水平 B“S-乙胺与疾病进展速度相关。(1)一项同时进行的II期研究 由Carvalho博士进行的研究发现，类似剂量的药物没有效果；然而，这项研究 就权力而言，这是不可能的。关于ALS以前失败的药物试验的评论增加了 令人担忧的是，许多ALS试验只研究一种潜在的治疗剂，因此 可能会错过hon fda批准的d-oses的潜在疗效；因此，这项拟议的研究将 Tesi高剂量美金刚，20 mg BLD，双盲，安慰剂对照，随机 美金刚与利鲁唑联合治疗肌萎缩侧索硬化症的临床研究 与单独使用利鲁唑治疗相比，可以减缓疾病的进展。主要结果是 衡量标准是通过ALS功能分级衡量的疾病进展率 SCATE-修订(ALSFRS-R)。此外，我们还将检查ALS患者的认知缺陷 患者通过ALS认知行为筛查(ALS-CBS)和 I.L.精神病学调查问卷(NLP-Q)。最后，我们将检验特定的验证性 在脑脊液中发现的蛋白质印迹标记物确定是否与 这些生物标志物的水平和疾病进展的速度。具体来说，我们将测量 磷酸化重神经丝与补体3的比率(31)，看看这一比率是否 预测疾病进展以及美金刚治疗期间水平是否发生变化 ‘ 这个项目将为这种无法治愈的疾病提供独特的见解。如果这项研究证实 早期结果表明，美金刚与利鲁唑联合使用时，显著 延缓疾病进展，改善患者的认知缺陷 有了前端临时功能，它将为进行更大的阶段11试验奠定基础。

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'