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，由大脑和脊髓运动神经元丢失引起。大多数患者在发病后3至5年内死亡。尽管进行了多次临床试验，并在了解其发病机制方面取得了进展，但利鲁唑是FDA批准的唯一一种ALS药物，仅具有温和的神经保护作用，并给患者和家庭带来了很高的经济负担。虽然运动神经元变性的确切原因尚不清楚，但可能的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，已被FDA批准用于帕金森氏症的对症治疗。然而，除了其症状机制外，雷沙吉兰还在神经细胞培养和动物模型中对各种神经毒素具有广泛的神经保护作用。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，在应激条件下，雷沙吉兰可以稳定线粒体。这些数据为最近的一项帕金森氏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存在的疾病修改效果。雷沙吉兰的这项双盲、延迟启动试验的结果表明，它可能具有神经保护作用。 考虑到线粒体功能在帕金森氏病和ALS中都发生了改变，有理由认为雷沙吉兰也可能具有改善ALS疾病的作用。发起人报告说，已经证明雷沙吉兰延长了SOD1小鼠模型的存活时间，在一个小型的回溯性人类受试者中，分析了雷沙吉兰治疗与病情恶化的缓慢相关。 研究人员现在建议对肌萎缩侧索硬化症患者进行雷沙吉兰的第二阶段研究。这是一项由研究者发起的、多中心、单剂量、安慰剂对照的6个月的雷沙吉兰研究。 在80名受试者中。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上的安慰剂对照数据来丰富统计力量。研究人员还将测量线粒体功能的几个生物标记物，以确定雷沙吉兰治疗是否会影响这些措施。这项研究将在西部肌萎缩侧索硬化症研究组的地点进行。

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.