Phase 2 Study of Rasagiline for Treatment of Amyotrophic Lateral Sclerosis

雷沙吉兰治疗肌萎缩侧索硬化症的 2 期研究

• 批准号: 8543461
• 负责人: Richard J. Barohn
• 金额: $ 39.04万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-14 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8543461
• 关键词: Phase; Study; Rasagiline; Treatment; Amyotrophic

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder caused by loss of motor neurons in the brain and spinal cord. The majority of patients die within 3 to 5 years from onset. Despite multiple clinical trials and advances in understanding its pathogenesis riluzole, the only FDA approved ALS drug, has only a modest neuroprotective effect and carries a high financial burden to patient and family. While the exact underlying cause of this motor neuron degeneration remains uncertain, candidate mechanisms include glutamate excitotoxicity, free radical-mediated oxidative cytotoxicity, neuroinflammation, mitochondrial dysfunction, autoimmune processes, protein aggregation, and cytoskeletal abnormalities. Rasagiline, a monoamine-oxide inhibitor, is approved for the symptomatic treatment of Parkinson's disease by the FDA. In addition to its symptomatic mechanism, however, rasagiline has broad neuroprotective activities against a variety of neurotoxins in neuronal cell cultures and in animal models. These properties are presumed to arise through effects on mitochondria. In vitro experiments indicate rasagiline stabilizes mitochondria under stress conditions. Those data provided the scientific rationale for a recent Parkinson's disease clinical trial that tested whether rasagiline also has disease-modifying effects that exist independent of its symptomatic activity. The results of this double-blind, delayed-start trial of rasagiline suggested that there may be a neuroprotective effect. Considering that mitochondrial function is altered in both Parkinson's disease and ALS, it is reasonable to consider that rasagiline could have an ALS disease-modifying effect as well. The sponsor reports that it has been demonstrated that rasagiline prolongs survival in the SOD1 mouse model, and in one small retrospective human subjects analysis rasagiline treatment was associated with slower deterioration. The investigators now propose a Phase 2 investigation of rasagiline in ALS. This is an investigator-initiated, multi-center, single dose, placebo controlled six month study of rasagiline in 80 subjects. Sixty subjects will receive rasagiline, and 20 subjects will receive placebo. The investigators will use a "bleed-in" of historical placebo control data to enrich the statistical power. The investigators will also measure several biomarkers of mitochondrial function to determine if rasagiline treatment can affect these measures. The study will be performed at sites in the Western ALS Study group.

描述（由申请人提供）： 肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，由大脑和脊髓运动神经元丧失引起。大多数患者在发病后 3 至 5 年内死亡。尽管进行了多项临床试验并在了解其发病机制方面取得了进展，但利鲁唑是 FDA 唯一批准的 ALS 药物，其神经保护作用有限，并且给患者和家庭带来沉重的经济负担。虽然这种运动神经元变性的确切根本原因仍不确定，但候选机制包括谷氨酸兴奋毒性、自由基介导的氧化细胞毒性、神经炎症、线粒体功能障碍、自身免疫过程、蛋白质聚集和细胞骨架异常。 雷沙吉兰是一种单胺氧化物抑制剂，被 FDA 批准用于帕金森病的对症治疗。然而，除了其症状机制之外，雷沙吉兰在神经细胞培养物和动物模型中还具有针对多种神经毒素的广泛神经保护活性。这些特性被认为是通过对线粒体的影响而产生的。体外实验表明雷沙吉兰在应激条件下可以稳定线粒体。这些数据为最近的帕金森病临床试验提供了科学依据，该试验测试了雷沙吉兰是否也具有独立于其症状活性而存在的疾病缓解作用。这项雷沙吉兰双盲、延迟启动试验的结果表明，雷沙吉兰可能具有神经保护作用。 考虑到线粒体功能在帕金森病和 ALS 中都会发生改变，因此可以合理地认为雷沙吉兰也可能具有缓解 ALS 疾病的作用。 申办者报告称，已证明雷沙吉兰可延长 SOD1 小鼠模型的生存期，并且在一项小型回顾性人体受试者分析中，雷沙吉兰治疗与病情恶化速度减缓相关。 研究人员现在提议对雷沙吉兰治疗 ALS 进行第二阶段研究。这是一项由研究者发起、多中心、单剂量、安慰剂对照的为期六个月的雷沙吉兰研究 80 个科目。 60 名受试者将接受雷沙吉兰治疗，20 名受试者将接受安慰剂治疗。研究人员将使用历史安慰剂对照数据的“渗入”来丰富统计能力。研究人员还将测量线粒体功能的几种生物标志物，以确定雷沙吉兰治疗是否会影响这些措施。该研究将在西方 ALS 研究小组的地点进行。