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MS中一种高度流行和致残的症状，目前尚无FDA批准的治疗方法。 兴奋剂如金刚烷胺、哌甲酯和莫达非尼通常被“标签外”使用来治疗疲劳 在患有MS（PwMS）的人中，但它们的使用受到副作用和有限功效的限制。类似于70-90%的 非退伍军人PwMS谁是疲劳的不利影响，退伍军人与MS（VwMS）也受到影响。 尽管广泛使用MS疾病修饰疗法，但疲劳仍然是MS疾病的重要原因。 残疾、无就业能力和生活质量差。因此迫切 需要开发新的方法来影响MS中的疲劳。虽然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量 消耗可能是MS中疲劳的重要因素。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（CoQ 10，也称为 泛醇/泛醌），用于MS的疲劳和情绪改善。 与安慰剂相比，CoQ 10治疗受试者的疲劳和情绪改善。口服米托醌 （MitoQ）是辅酶CoQ 10的一种更具有组织特异性的形式，其中CoQ 10具有共价连接的 赋予线粒体更强亲和力的侧链。本临床试验的目的是评估 MitoQ对MS疲劳的潜在有益作用。这项研究的目的是开发新的方法， 影响MS中的疲劳，并最终确定靶向线粒体功能的治疗是否具有 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功能来改善MS相关的疲劳以及认知、生活质量和情绪。 功能和由此产生的神经元能量消耗。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 安慰剂组在12周的治疗期后，通过MFIS评分测量的疲劳程度较低。 具体目标2：确定接受口服MitoQ的VwMS与接受 使用符号数字模态测试，安慰剂改善了认知功能、生活质量和抑郁症 （SDMT）、MS影响量表-29（MSIS-29）和Beck抑郁量表快速筛查评分。 具体目标3：使用副作用和血液检查确定MitoQ在VwMS中的安全性和耐受性。 具体目的4：确定用MitoQ治疗的VwMS中的血浆MitoQ水平是否与临床 疲劳、认知功能、生活质量和抑郁症的结局，以及基于血液的炎症 免疫和氧化应激生物标志物。 研究设计：我们建议进行一项双盲、安慰剂对照的初步试验， 在一个实施方案中，将20和40 mg剂量的MitoQ每日一次施用至安慰剂，作为减轻患者疲劳的治疗。 我们的首要目标是MS科目，其次是改善认知，生活质量和抑郁症。 我们将测量疲劳、认知、生活质量和抑郁评分与基线的差异， 研究药物开始后12周。将通过评估MitoQ副作用来确定安全性。我们还将 定量给药后1小时MitoQ的血浆浓度，并评估血液免疫和 在研究过程中的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：每例受试者的参与期为13周：第一周进行筛选访视， 然后是12周的治疗期。本研究需要在13周内进行4次访视和4次电话访视。总 时间承诺约为6小时。将入组60例诊断为MS的成人患者。科目 将随机分为3个受试者组：20例受试者接受20 mg MitoQ，20例受试者将接受40 mg MitoQ mg MitoQ，20名受试者接受安慰剂。