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）： 肌萎缩性外侧硬化症（ALS）是由大脑和脊髓中运动神经元丧失引起的进行性神经退行性疾病。大多数患者在发病后3至5年内死亡。尽管多次临床试验和理解其发病机理的进展，但唯一获得FDA批准的ALS药物的病理学，只有适度的神经保护作用，并给患者和家人带来了很大的经济负担。虽然这种运动神经元变性的确切根本原因尚不确定，但候选机制包括谷氨酸兴奋性，自由基介导的氧化细胞毒性，神经炎性，神经软骨功能障碍，自身免疫性过程，蛋白质聚集和细胞骨骼效果。 Rasagiline是一种单胺 - 氧化物抑制剂，已通过FDA批准对帕金森氏病的症状治疗。然而，除了其症状机制外，rasagiline还具有针对神经元细胞培养物和动物模型中各种神经毒素的广泛神经保护活性。假定这些特性是通过对线粒体的影响而产生的。体外实验表明rasagiline在应力条件下稳定线粒体。这些数据为最近的帕金森氏病临床试验提供了科学原理，该试验测试了rasagiline是否还具有与症状性活动无关的疾病改良作用。这项双盲，延迟启动的rasagiline的结果表明，可能存在神经保护作用。 考虑到帕金森氏病和ALS都改变了线粒体功能，因此可以合理地认为rasagiline也可能具有ALS疾病调整作用。 赞助商报告说，已经证明rasagiline延长了SOD1小鼠模型中的生存​​，并且在一个小的回顾性人体受试者中，分析拉萨吉林治疗与较慢的恶化有关。 研究人员现在提出了对ALS中Rasagiline的2期研究。这是研究者发动的，多中心的单剂量，安慰剂控制的六个月研究 在80个受试者中。 60名受试者将接受rasagiline，20名受试者将接受安慰剂。研究人员将使用历史安慰剂控制数据的“出血”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rasagiline治疗是否会影响这些措施。该研究将在西部ALS研究组的地点进行。