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: 9341908
• 负责人: Richard J. Barohn
• 金额: $ 21.49万
• 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 2020-08-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9341908
• 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。阿曲唑是FDA批准的唯一用于ALS的药物，可延长患者的寿命2-3个月，并且没有经过证实的治疗与ALS相关的认知变化的疗法。需要对这种普遍致命的疾病进行更有效的治疗。 一项对20名接受美金刚胺10 mg每日两次（BID）治疗的患者进行的开放标签先导试验的结果表明，美金刚胺和利鲁唑的联合治疗减缓了ALS疾病的进展。该试验还表明，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率相关。一项并行的II期研究发现相似剂量无影响;然而，该研究的把握度有限。对先前在ALS中失败的药物试验的评论引起了人们的关注，即许多ALS试验仅以单剂量研究潜在的治疗剂，因此可能错过非FDA批准剂量的潜在疗效;因此，本研究将在双盲，安慰剂对照，90例ALS患者的随机试验，以确定美金刚与利鲁唑的联合治疗与利鲁唑单独治疗相比是否可以减缓疾病进展。主要结局指标将是通过ALS功能评定量表修订版（ALSFRS-R）测量的疾病进展率。此外，研究者将检查通过ALS认知行为筛查（ALS-CBS）和神经精神调查问卷（NIP-Q）测量的ALS患者中观察到的认知缺陷。最后，将检查CSF中发现的特定经验证的蛋白质生物标志物，以确定这些生物标志物的水平与疾病进展速率之间是否存在相关性。特别地，研究者将测量磷酸化重神经丝与补体3（pNFH/C3）的比率，以观察该比率是否预测疾病进展以及在用美金刚治疗期间水平是否变化。