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: 9891871
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891871
• 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; Pharmaceutical Preparations; Phase II Clinical Trials; Pilot Projects; Placebos; Plasma; Play; Production; Publications; Quality of life; Quinones; Reporting; Research; Research Design; Research Personnel; Resource Allocation; Ritalin; Role; Safety; Services; Severities; Study Subject; Surveys; Symptoms; Telephone; Testing; Time; Ubiquinone; Veterans; Visit; Work; base; chemical group; cofactor; cognitive function; cost; design; disability; disabling symptom; 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.

在MS中，疲劳是一种高度普遍且残疾的症状，目前尚无FDA批准的治疗。 通常使用刺激剂，例如半达丁丁，哌醋甲酯和莫达非尼 在MS（PWMS）的人中，但其使用受到副作用和有限的有效性的限制。类似于70-90％ 受到疲劳影响的非退伍军人PWM，MS（VWM）的退伍军人也受到影响。 尽管MS疾病修饰疗法的传播广泛使用，但疲劳仍然是 VWM和PWM的残疾，非就业性和生活质量差。因此有紧急的 需要开发新的方法来影响MS的疲劳。而与MS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 耗竭可能是MS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 泛醇/泛素酮），用于MS的疲劳和情绪改善。这项研究显示出明显的谦虚 与安慰剂相比，COQ10治疗受试者的疲劳和情绪的改善。口服线喹酮 （mitoq）是一种更具线粒体特异性的辅酶COQ10，其中coq10具有共价链接 Sidechain意味着对线粒体具有更强的亲和力。该临床试验的目的是评估 MITOQ对MS疲劳的潜在有益作用。这项研究目的是开发新颖的方法 影响MS的疲劳，并最终确定针对线粒体功能的治疗是否具有 改变MS的症状或过程的潜力。中心假设是Mitoq及其线粒体 亲和力将通过改善线粒体来改善与MS相关的疲劳以及认知，生活质量和情绪 神经元中的功能和由此产生的神经元能消耗。我们提出以下目标： 特定目标1：确定与接受口服Mitoq的VWM相比是否接受口服Mitoq 通过MFIS评分测量，安慰剂在12周的治疗期后的疲劳较少。 特定目标2：确定与接受口服MITOQ的VWM相比是否接受口服MITOQ 安慰剂具有改善的认知功能，使用符号数字测试的认知功能，生活质量和抑郁症 （SDMT），MS Impact量表-29（MSIS -29）和贝克抑郁量表 - 快速屏幕得分。 特定目标3：使用副作用和血液测试确定MITOQ在VWM中的安全性和耐受性。 特定目标4：确定用Mitoq处理的VWM中的血浆MITOQ水平是否与临床相关 疲劳的结果，认知功能，生活质量和抑郁症以及血液基炎症的结果 免疫和氧化应激生物标志物。 研究设计：我们建议进行双盲，安慰剂对照，试点试验，以比较 每天给予20和40 mg的MITOQ对安慰剂，以减轻疲劳的治疗方法 MS受试者是我们的主要目的，并以次要目的改善认知，生活质量和抑郁症。 我们将衡量疲劳，认知，生活质量和抑郁得分的基线差异以及在 研究药物倡议后12周。安全将通过评估Mitoq副作用来确定。我们也会 量化MITOQ的血浆浓度1小时给药并评估血液免疫和 在研究期间三个时间点的氧化应激生物标志物以及与临床结果的评估相关性。 方法：每个主题的参与期为13周：第一周的筛查访问， 然后是一个为期12周的治疗期。该研究将在13周内需要4次访问和4次电话。全部的 时间投入约为6小时。六十名被诊断为MS的成年患者将被招募。主题 将随机分为3个主题组：20名受试者接受20毫克Mitoq，20个受试者将收到40个受试者 MG Mitoq和20名受试者将获得安慰剂。