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: 8683099
• 负责人: Richard J. Barohn
• 金额: $ 18.5万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 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 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8683099
• 关键词: Phase; 2B; Trial; Memantine; Treatment

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects 30,000 Americans each year. Of these 30,000 Americans, it has been suggested that up to 50% will experience cognitive and behavioral changes in the form of frontotemporal dysfunction and up to 40% will meet criteria for frontotemporal dementia (FTD). Riluzole the only FDA approved agent for ALS extends a patient's lifespan by 2-3 months, and there are no proven therapies for the cognitive changes associated with ALS. More effective therapy for this universally fatal disease is needed. Results from an open label pilot trial of 20 patients treated with memantine at 10 mg twice a day (BID) suggested that treatment with the combination of memantine and riluzole slowed ALS disease progression. This trial also showed that levels of specific protein biomarkers in the cerebrospinal fluid (CSF) at baseline correlated with the rate of disease progression. A concurrent Phase 2 study found no effect with similar dosing; however, the study was limited in terms of power. Comments 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 non FDA approved doses; therefore, this proposed study will test a higher dose of memantine, 20 mg BlD, in a double blind, placebo controlled, randomized trial of 90 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 Scale-Revised (ALSFRS-R). ln addition the investigators will examine the cognitive deficits seen in ALS patients measured by the ALS Cognitive Behavioral Screen (ALS-CBS) and the Neuropsychiatric lnventory Questionnaire (NlP-Q). Finally, specific validated protein biomarkers found in the CSF will be examined to determine if there is a correlation between the levels of these biomarkers and the rate of disease progression. ln particular the investigators will measure the ratio of phosphorylated heavy neurofilament to complement 3 (pNFH/C3) to see if this ratio is predictive of disease progression and if the levels change during therapy with memantine.

描述(由申请人提供)： 肌萎缩侧索硬化症(ALS)是一种致命的神经退行性疾病，每年影响3万美国人。在这30,000名美国人中，有研究表明，高达50%的人将经历额颞叶功能障碍形式的认知和行为变化，高达40%的人将符合额颞叶痴呆(FTD)的标准。利鲁唑是FDA批准的唯一一种治疗肌萎缩侧索硬化症的药物，可以将患者的寿命延长2-3个月，而且还没有得到证实的治疗与肌萎缩侧索硬化症相关的认知变化的方法。需要对这种普遍致命的疾病进行更有效的治疗。一项对20名患者进行的开放标签试点试验的结果表明，美金刚和利鲁唑的联合治疗减缓了ALS疾病的进展。美金刚每天两次10毫克。这项试验还表明，基线时脑脊液(CSF)中特定蛋白质生物标志物的水平与疾病进展速度相关。同时进行的一项第二阶段研究发现，类似剂量的药物没有效果；然而，这项研究在功率方面是有限的。对之前在ALS失败的药物试验的评论引发了人们的担忧，即许多ALS试验只研究一种潜在的治疗剂，因此可能会错过非FDA批准剂量的潜在疗效；因此，这项拟议的研究将在90名ALS患者的双盲、安慰剂对照、随机试验中测试更大剂量的美金刚，20 mg BLD，以确定与单独使用利鲁唑相比，美金刚与利鲁唑联合治疗是否可以减缓疾病的进展。主要的结果衡量标准将是ALS功能评定量表(ALSFRS-R)修订后的疾病进展率。此外，研究人员将检查ALS患者的认知缺陷，采用ALS认知行为筛查(ALS-CBS)和神经精神病学调查问卷(NLP-Q)进行测量。最后，将检查在脑脊液中发现的特定的有效蛋白质生物标记物，以确定这些生物标记物的水平与疾病进展速度之间是否存在相关性。具体地说，研究人员将测量磷酸化的重神经丝与补体3的比率(pNFH/C3)，以确定这一比率是否可以预测疾病的进展，以及在美金刚治疗期间，水平是否发生变化。