Lipoic acid for the treatment of progressive multiple sclerosis

硫辛酸用于治疗进行性多发性硬化症

• 批准号: 10541796
• 负责人: Rebecca I Spain
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541796
• 关键词: Adverse event; Animal Model; Antioxidants; Biological Process; Brain Diseases; Canes; Cardiotoxicity; Central Nervous System Diseases; Chronic; Clinical; Cognition; Community Participation; Controlled Clinical Trials; Data; Data Analyses; Databases; Development; Disease; Dose; Double-Blind Method; Dropout; Drug Kinetics; Enrollment; Exhibits; Explosion; FDA approved; Gold; Health; Healthcare Systems; Home; Inflammation; Laboratories; Lead; Magnetic Resonance Imaging; Measures; Medical center; Mitochondria; Mitoxantrone; Monitor; Moods; Multiple Sclerosis; Neurodegenerative Disorders; Neurologic; Nucleic Acids; Online Systems; Oral; Outcome; Outcome Measure; Oxidation-Reduction; Participant; Pathogenesis; Persons; Phase III Clinical Trials; Phenotype; Pilot Projects; Placebo Control; Placebos; Play; Population; Primary Progressive Multiple Sclerosis; Quality of life; Randomized; Reading; Relapse; Reporting; Resources; Respiration; Risk; Role; Safety; Sample Size; Sampling; Secondary Progressive Multiple Sclerosis; Serum; Site; Site Visit; Spinal Diseases; Testing; Therapeutic; Thioctic Acid; Time; Transportation; United States; United States Department of Veterans Affairs; Vascular Endothelium; Veterans; Visit; Walking; Wheelchairs; arm; base; cerebral atrophy; cohort; design; dihydrolipoic acid; disability; effective therapy; experience; falls; foot; functional decline; improved; leukemia; magnetic resonance imaging biomarker; multiple sclerosis patient; multiple sclerosis treatment; neuroinflammation; oral supplementation; pilot trial; pre-clinical; primary outcome; radiological imaging; randomized placebo controlled trial; secondary endpoint; secondary outcome; small molecule; symposium; transcription factor; trend

At any time, nearly half of the 500,000 people in the United States living with multiple sclerosis (MS), a common and disabling neuro-inflammatory disease of the central nervous system, have a progressive course. Despite the explosion of new MS therapies, there remains a frustrating lack of disease-modifying therapies that can alter the functional decline of progressive MS (PMS) that resulting in reduced community participation, low quality of life, and high burdens on health care systems and caretakers. Lipoic acid (LA) is an inexpensive, endogenously-produced, oral antioxidant with multiple biological functions implicated in the pathogenesis of PMS. LA reduces disability in a dose- dependent fashion in the animal model of MS, and is safe and tolerated in people with MS. A 2- year randomized, double-blind, placebo-controlled clinical trial of daily oral LA in secondary progressive MS, a subset of PMS patients, demonstrated a remarkable 68% reduction in the annualized rate of whole brain atrophy, the current gold-standard MRI biomarker in PMS. While not powered to do so, the LA cohort exhibited a trend toward improvement in walking tests and a reduction in falls. This study proposes to expand on the highly promising preliminary results to confirm the effects of LA on reducing rates of brain atrophy and to determine its associated clinical benefits. The design is a multi-center, double-blind, randomized, placebo-controlled trial of oral daily LA in a PMS population with the following objectives: 1. Determine if LA is superior to placebo in maintaining a clinically meaningful outcome, mobility, as measured by the primary outcome of change in completion time of the Timed 25 Foot Walk as suggested by the pilot study. Falls and other walking tests will be evaluated to confirm the primary outcome results. 2. Determine if LA is superior to placebo in slowing whole brain atrophy with an estimated 40-50%% effect size. This will confirm our previous findings of a significant 68% reduction in brain atrophy rate at a more modest effect size that is in line with protection of brain atrophy rates from relapsing MS trials. Additional secondary outcome measures will include neurological disability, cognition, mood, and quality of life. 3. Monitor safety and tolerability via laboratory testing and adverse event reporting. Participants at 3 or 4 sites with PMS will be randomized on a 1:1 basis to LA or placebo. Participants will be enrolled over 18 months and complete 7 study visits over 2 years. Walking tests will be performed at every visit. MRIs will be completed at baseline and study end. Secondary endpoints not related to MRI will be collected at study visits every 6 months. Safety labs will be collected at every study visit and adverse events every 3 months. The sample size of 50 per arm will allow for a 15% drop-out rate. The Portland VA Medical Center will be the lead coordinating site. Monthly conference calls and biannual site visits will assure uniformity and high quality of study data. A web-based database, centralized MRI reading center, and experienced data analysis center will be utilized. The results of this study, once confirmed, will set the stage for large-scale phase 3 clinical trials of LA for the treatment of PMS, filling a much needed gap in MS therapeutics, and resulting in improved health, safety, and quality of life for Veterans with MS.

在任何时候，在美国的50万多发性硬化症患者中，近一半 (MS)是一种常见的致残中枢神经系统炎症性疾病， 一条进步的路线。尽管新的多发性硬化症疗法呈爆炸式增长，但仍有令人沮丧的 缺乏可以改变进行性多发性硬化症功能衰退的疾病修正疗法 (PMS)，导致社区参与减少，生活质量降低，负担沉重 卫生保健系统和照顾者。 硫辛酸(LA)是一种廉价的、内源性的口服抗氧化剂，具有多种 生物学功能参与了经前综合征的发病机制。洛杉矶在一定剂量内减少残疾- 在多发性硬化症的动物模型中依赖时尚，并且在患有多发性硬化症的人中是安全和耐受的。 一年随机、双盲、安慰剂对照的每日口服LA在继发性心脏病中的临床试验 进展性多发性硬化症是经前综合症患者的一个亚组，表现出显著的68%的减少。 全脑萎缩的年率，目前经前综合征的金标准磁共振生物标记物。而当 没有能力这样做，洛杉矶的队列显示出步行测试和 跌落的减少。 这项研究建议对极具前景的初步结果进行扩展，以证实其效果 研究LA在降低脑萎缩率方面的作用，并确定其相关的临床益处。这个 设计是一项多中心、双盲、随机、安慰剂对照的每日口服LA试验。 具有以下目标的经前综合症人群： 1.确定LA在维持临床有意义的结果方面是否优于安慰剂， 移动性，通过计时的完成时间的变化的主要结果来衡量 根据初步研究的建议，步行25英尺。跌倒和其他步行测试将是 评估以确认主要结果结果。 2.确定LA在延缓全脑萎缩方面是否优于安慰剂，估计 40-50%的效果大小。这将证实我们之前的发现，即显著减少了68% 在更温和的效果大小，符合脑保护的脑萎缩率 复发性多发性硬化症试验的萎缩率。其他次要结果衡量标准将 包括神经残疾、认知、情绪和生活质量。 3.通过实验室测试和不良事件报告来监测安全性和耐受性。 3个或4个地点的经前综合症患者将按1：1随机分为LA组或安慰剂组。 参与者将在18个月内注册，并在2年内完成7次考察访问。步行 每一次访问都会进行测试。核磁共振成像将在基线和研究结束时完成。 与MRI无关的次要终端将在每6个月的研究访问中收集。安全问题 实验室将在每次研究访问时收集，每3个月收集不良事件。样本大小 每只手臂50人将允许15%的辍学率。 波特兰退伍军人医疗中心将是牵头协调地点。每月电话会议和 一年两次的实地考察将确保研究数据的一致性和高质量。一个基于网络的数据库， 将利用集中的MRI阅读中心和经验丰富的数据分析中心。这个 这项研究的结果一旦得到证实，将为大规模的3期临床试验奠定基础 LA用于治疗经前综合症，填补了MS疗法中亟需的空白，并导致 多发性硬化改善了退伍军人的健康、安全和生活质量。