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: 10886490
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10886490
• 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; Frustration; 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; cerebral atrophy; cofactor; 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，美国 50 万人中近一半患有多发性硬化症 (MS) 是一种常见且致残的中枢神经系统神经炎症性疾病， 一个渐进的过程。尽管新的多发性硬化症疗法呈爆炸式增长，但仍然存在令人沮丧的问题 缺乏可以改变进行性多发性硬化症功能衰退的疾病缓解疗法 (PMS) 导致社区参与减少、生活质量低下和负担沉重 卫生保健系统和看护者。 硫辛酸 (LA) 是一种廉价的内源性口服抗氧化剂，具有多种功效 与 PMS 发病机制有关的生物学功能。 LA 可减少剂量中的残疾 在多发性硬化症动物模型中存在依赖性时尚，并且在多发性硬化症患者中是安全且耐受的。一个 2- 中学每日口服 LA 的一年随机、双盲、安慰剂对照临床试验 进行性多发性硬化症 (PMS 患者的一个子集) 表现出显着的 68% 下降 全脑萎缩的年化率，是目前经前综合症的金标准 MRI 生物标志物。尽管 由于没有能力这样做，洛杉矶队列在步行测试和测试中表现出改善的趋势 跌倒次数减少。 这项研究建议扩展非常有希望的初步结果以确认其效果 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 设计是一项多中心、双盲、随机、安慰剂对照试验，每天口服 LA 经前综合症人群具有以下目标： 1. 确定 LA 在维持具有临床意义的结果方面是否优于安慰剂， 流动性，通过定时完成时间变化的主要结果来衡量 试点研究建议步行 25 英尺。跌倒和其他步行测试将 进行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优于安慰剂（估计值） 40-50%% 效果大小。这将证实我们之前的发现，即显着减少 68% 脑萎缩率处于更适中的效应大小，与大脑保护一致 复发性多发性硬化症试验引起的萎缩率。额外的次要结果指标将 包括神经功能障碍、认​​知、情绪和生活质量。 3. 通过实验室测试和不良事件报告监测安全性和耐受性。 3 或 4 个地点患有 PMS 的参与者将按照 1:1 的比例随机分配到 LA 或安慰剂组。 参与者将入组 18 个月以上，并在 2 年内完成 7 次研究访问。步行 每次访问时都会进行测试。 MRI 将在基线和研究结束时完成。 与 MRI 无关的次要终点将在每 6 个月的研究访视中收集一次。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数据。样本量 每支 50 人将允许 15% 的退出率。 波特兰退伍军人医疗中心将成为主要协调地点。每月电话会议和 每年两次的实地考察将确保研究数据的一致性和高质量。基于网络的数据库， 将利用集中的MRI读取中心和经验丰富的数据分析中心。这 这项研究的结果一旦得到证实，将为大规模3期临床试验奠定基础 LA 用于治疗经前综合症，填补了多发性硬化症治疗中急需的空白，并导致 改善患有多发性硬化症的退伍军人的健康、安全和生活质量。