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: 9905320
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905320
• 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; Diagnostic radiologic examination; Disease; Dose; Double-Blind Method; Dropout; Drug Kinetics; Enrollment; Exhibits; Explosion; FDA approved; Gold; Health; Healthcare Systems; Home environment; 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; Phase III Clinical Trials; Phenotype; Pilot Projects; 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; 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; neuroinflammation; oral supplementation; pilot trial; pre-clinical; primary outcome; 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，美国50万患有多发性硬化症的人中， (MS)是一种常见的中枢神经系统神经炎性疾病， 渐进的过程。尽管新的多发性硬化症疗法的爆炸，仍然有令人沮丧的 缺乏可以改变进展性MS功能下降的疾病修饰疗法 (PMS)导致社区参与减少，生活质量低下， 医疗保健系统和护理人员。 硫辛酸（LA）是一种廉价的内源性口服抗氧化剂， 与PMS发病机制有关的生物学功能。LA减少残疾的剂量- 在MS的动物模型中以依赖的方式，并且在MS患者中是安全和耐受的。 一项为期3年的在继发性高血压患者中每日口服LA的随机、双盲、安慰剂对照临床试验 进行性MS，PMS患者的一个子集，表现出显著的68%的减少， 全脑萎缩的年化率，目前PMS的黄金标准MRI生物标志物。而 没有动力这样做，洛杉矶队列表现出步行测试改善的趋势， 减少福尔斯。 这项研究建议扩大非常有前途的初步结果，以确认影响 降低脑萎缩率，并确定其相关的临床效益。的 设计是一项多中心、双盲、随机、安慰剂对照试验，在一个 PMS人群，目标如下： 1.确定LA在维持有临床意义的结局方面是否上级安慰剂， 流动性，以按时完成工作的时间变化的主要结果衡量 根据试点研究的建议，步行25分钟。福尔斯和其他步行测试将 评估以确认主要结局结果。 2.确定LA在减缓全脑萎缩方面是否上级安慰剂， 40- 50%%效应大小。这将证实我们之前的发现，即显著减少68%， 在脑萎缩率在更适度的影响大小，这是符合脑保护 复发性MS试验的萎缩率。其他次要结局指标将 包括神经功能障碍、认知、情绪和生活质量。 3.通过实验室检测和不良事件报告监测安全性和耐受性。 3个或4个研究中心的PMS受试者将以1：1的比例随机分配至LA组或安慰剂组。 受试者将在18个月内入组，并在2年内完成7次研究访视。步行 将在每次访视时进行检查。将在基线和研究结束时完成MRI。 将在每6个月一次的研究访视时收集与MRI无关的次要终点。安全 将在每次研究访视时收集实验室数据，并每3个月收集一次不良事件。样本量 每组50例将允许15%的脱落率。 波特兰退伍军人医疗中心将作为牵头协调中心。每月电话会议， 一年两次的现场访问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， 将使用集中的MRI阅读中心和经验丰富的数据分析中心。的 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PMS，填补了MS治疗中急需的空白，并导致 改善MS退伍军人的健康，安全和生活质量。