Phase 2 Study of Rasagiline for Treatment of Amyotrophic Lateral Sclerosis

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，由脑和脊髓中运动神经元的丧失引起。大多数患者在发病后3至5年内死亡。尽管有多项临床试验和对其发病机制的理解取得了进展，但唯一一种FDA批准的ALS药物利鲁唑仅具有适度的神经保护作用，并给患者和家庭带来了沉重的经济负担。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性毒性、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，除了其症状机制外，雷沙吉兰在神经元细胞培养物和动物模型中对多种神经毒素具有广泛的神经保护活性。据推测，这些特性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稳定线粒体。这些数据为最近的一项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的疾病改善作用。这项双盲、延迟开始的雷沙吉兰试验的结果表明，雷沙吉兰可能具有神经保护作用。 考虑到帕金森病和ALS中线粒体功能都发生了改变，因此认为雷沙吉兰也可能具有ALS疾病改善作用是合理的。 申办方报告称，已证明雷沙吉兰在SOD 1小鼠模型中的存活率较低，在一项小型回顾性人类受试者分析中，雷沙吉兰治疗与较慢的恶化相关。 研究人员现在提出了雷沙吉兰在ALS中的第二阶段研究。这是一项雷沙吉兰治疗启动、多中心、单次给药、安慰剂对照的6个月研究 80个科目。60例受试者将接受雷沙吉兰，20例受试者将接受安慰剂。研究者将使用历史安慰剂对照数据的“纳入”来丰富统计学把握度。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指标。本研究将在西部ALS研究组的研究中心进行。

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.