MitoQ for Fatigue in Multiple Sclerosis: A Placebo Controlled Trial

MitoQ 治疗多发性硬化症疲劳：安慰剂对照试验

• 批准号: 10417025
• 负责人: VIJAYSHREE YADAV
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417025
• 关键词: Adult; Affect; Affinity; Amantadine; Antioxidants; Area; Beck depression inventory; Biological Markers; Blood; Blood Tests; Brain; Caring; Chronic Disease; Clinical; Clinical Trials; Coenzyme Q10; Coenzymes; Cognition; Complex; Data; Demyelinations; Diagnosis; Digit structure; Disease; Dose; Double-Blind Method; Enrollment; FDA approved; Failure; Fatigue; Functional disorder; Goals; Health Care Costs; Healthcare Systems; High Prevalence; Hour; Immune; Impaired cognition; Inflammation; Inflammatory; Knowledge; Link; Measures; Mental Depression; Methods; Mitochondria; Modafinil; Modality; Modification; Moods; Multiple Sclerosis; Nerve; Nerve Degeneration; Neuraxis; Neurons; Oral; Outcome; Oxidative Stress; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Personal Communication; Persons; Pharmaceutical Preparations; Phase II Clinical Trials; Pilot Projects; Placebo Control; Placebos; Plasma; Play; Production; Publications; Quality of life; Quinones; Reporting; Research; Research Design; Research Personnel; Resource Allocation; Ritalin; Role; Safety; Services; Severities; Stimulant; Study Subject; Surveys; Symptoms; Telephone; Testing; Time; Ubiquinone; Veterans; Veterans Health Administration; Visit; Work; base; chemical group; cofactor; cognitive function; cost; design; disability; disabling symptom; efficacy evaluation; gastrointestinal system; improved; improved functioning; innovation; mitochondrial dysfunction; mitoquinone; multiple sclerosis treatment; new therapeutic target; novel; novel strategies; off-label use; oral supplementation; pilot trial; placebo controlled trial; placebo group; screening; side effect; treatment duration; treatment program; trend; ubiquinol

Fatigue is a highly prevalent and disabling symptom in MS that has no current FDA approved therapy. Stimulants such as amantadine, methylphenidate and modafinil are commonly used “off-label” to treat fatigue in people with MS (PwMS), but their use is limited by side effects and limited efficacy. Similar to the 70-90% of the non-Veteran PwMS who are impacted by fatigue adversely, Veterans with MS (VwMS) are affected too. Despite the wide spread use of MS disease modifying therapies, fatigue remains a significant cause of disability, non-employability and poor quality of life in both VwMS and PwMS. There is therefore an urgent need to develop novel ways to impact fatigue in MS. While the origins of MS related fatigue is likely complex and multifactorial, we believe that mitochondria dysfunction and resultant neuronal energy depletion may be an important contributor to fatigue in MS. A recent study evaluated the efficacy of the mitochondrial cofactor and antioxidant supplement, coenzyme Q10 (CoQ10, also known as ubiquinol/ubiquinone), for fatigue and mood improvement in MS. This study showed significant albeit modest improvement in fatigue and mood in CoQ10 treated subjects as compared to placebo. Oral Mitoquinone (MitoQ) is a more mitochondrial-specific form of coenzyme CoQ10 in which CoQ10 has a covalently linked sidechain that imparts a stronger affinity for the mitochondria. The objective of this clinical trial is to evaluate the potential beneficial effects of MitoQ on MS fatigue. This research purposes to develop novel ways to impact fatigue in MS and ultimately to determine whether treatment targeting mitochondrial function have a potential to alter the symptoms or course of MS. The central hypothesis is that MitoQ with its mitochondrial affinity will improve MS related fatigue as well as cognition, quality of life and mood by improving mitochondrial function and resultant neuronal energy depletion in neurons. We propose the following aims: Specific Aim 1: Determine whether VwMS who receive oral MitoQ in comparison to those who receive placebo have less fatigue after a 12-week treatment period as measured by MFIS Score. Specific Aim 2: Determine whether VwMS who receive oral MitoQ in comparison to those who receive placebo have improved cognitive function, quality of life and depression using Symbol Digit Modality Test (SDMT), MS Impact Scale -29 (MSIS-29) and the Beck Depression Inventory–Fast Screen scores respectively. Specific Aim 3: Determine the safety and tolerability of MitoQ in VwMS using side effects and blood tests. Specific Aim 4: Determine whether plasma MitoQ levels in VwMS treated with MitoQ correlate with clinical outcomes of fatigue, cognitive function, quality of life and depression and with blood based inflammatory immune and oxidative stress biomarkers. Research Design: We propose to conduct a double-blind, placebo-controlled, pilot trial to compare the administration of a 20 and 40 mg once a day dose of MitoQ to a placebo, as a treatment to reduce fatigue in MS subjects as our primary aim and to improve cognition, quality of life, and depression as secondary aims. We will measure the difference from baseline in fatigue, cognition, quality of life, and depression scores and at 12 weeks post study drug initiation. Safety will be determined by assessing MitoQ side effects. We will also quantify plasma concentrations of MitoQ 1 hour post-dose administration and evaluate blood immune and oxidative stress biomarkers at three time points during the study and assess correlation with clinical outcomes. Methods: The participation period for each subject will be 13 weeks: screening visit during the first week, followed by a 12-week treatment period. The study will require 4 visits and 4 phone calls over 13 weeks. Total time commitment is approximately 6 hours. Sixty adult patients diagnosed with MS will be enrolled. Subjects will be randomly divided into 3 subject groups: 20 subjects receiving 20 mg MitoQ, 20 subjects will receiving 40 mg MitoQ, and 20 subjects will receiving a placebo.

疲劳是目前没有FDA批准的治疗方法的多发性硬化症的一种高度普遍和致残的症状。 金刚烷胺、哌甲酸甲酯和莫达非尼等兴奋剂通常被用来治疗疲劳。 在患有多发性硬化症(PWMS)的人中，但它们的使用受到副作用和疗效有限的限制。与70%-90%的 受疲劳影响的非退伍军人PWMS，退伍军人多发性硬化症(VwMS)也会受到影响。 尽管多发性硬化症疾病调整疗法的广泛使用，疲劳仍然是导致 VWMS和PWMS的残疾、失业和生活质量差。因此，有一个紧急的 需要开发新的方法来影响多发性硬化症的疲劳，而多发性硬化症相关疲劳的起源可能是 复杂和多因素，我们认为线粒体功能障碍和由此产生的神经元能量 精疲力竭可能是导致女士疲劳的重要因素。最近的一项研究评估了 线粒体辅因子和抗氧化剂补充剂辅酶Q10(CoQ10，也称为 泛喹酚/泛醌)，用于改善MS患者的疲劳和情绪。这项研究显示，尽管规模不大，但意义重大 与安慰剂相比，辅酶Q10治疗的受试者在疲劳和情绪方面的改善。口服米托醌 (MitoQ)是一种更具线粒体特异性的辅酶CoQ10，其中CoQ10具有共价连接 给予线粒体更强亲和力的侧链。这项临床试验的目的是评估 MitoQ对MS疲劳的潜在有益作用。这项研究旨在开发新的方法来 MS患者的冲击性疲劳，并最终确定针对线粒体功能的治疗是否对 可能改变MS的症状或病程中心假设是MitoQ及其线粒体 亲和力将通过改善线粒体改善MS相关性疲劳以及认知、生活质量和情绪 神经元的功能和由此导致的神经元能量耗竭。我们提出以下目标： 具体目标1：确定接受口服MitoQ的VwMS与接受口服MitoQ的VwMS是否进行比较 根据MFIS评分，安慰剂在12周的治疗期后疲倦程度较低。 具体目标2：确定接受口服MitoQ的VwMS与接受口服MitoQ的VwMS是否进行比较 安慰剂改善认知功能、生活质量和抑郁的符号数字通道测试 (SDMT)、MS Impact Scale-29(MSIS-29)和Beck抑郁量表-Fast Screen得分。 具体目标3：通过副作用和血液测试确定MitoQ在VwMS中的安全性和耐受性。 具体目标4：确定接受MitoQ治疗的VwMS患者的血浆MitoQ水平是否与临床相关 疲劳、认知功能、生活质量、抑郁和血源性炎症的结果 免疫和氧化应激生物标记物。 研究设计：我们建议进行一项双盲、安慰剂对照的试点试验，以比较 每天给安慰剂服用一次20和40毫克的MitoQ，作为减轻疲劳的治疗方法 以理科为主要目标，以提高认知、生活质量和抑郁为次要目标。 我们将测量疲劳、认知、生活质量和抑郁评分与基线的差异，并在 研究后12周开始用药。安全性将通过评估MitoQ的副作用来确定。我们还将 定量给药后1小时的血浆MitoQ浓度，并评估血液免疫和 研究期间三个时间点的氧化应激生物标志物，并评估与临床结果的相关性。 方法：每个受试者的参与时间为13周：第一周筛查访问， 然后进行为期12周的治疗。这项研究将在13周内进行4次访问和4次电话通话。总计 时间承诺约为6小时。60名被诊断为多发性硬化症的成人患者将入选。科目 将随机分为3组：20名受试者服用20 mg MitoQ，20名受试者服用40 mg Mg MitoQ，20名受试者将接受安慰剂。