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: 10746387
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10746387
• 关键词: Adult; Affect; Affinity; Amantadine; Antioxidants; Area; Beck depression inventory; Biological Markers; Blood; Blood Tests; Caring; Central Nervous System; 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; Intestinal Absorption; Knowledge; Link; Measures; Mental Depression; Methods; Mitochondria; Modafinil; Modality; Modification; Moods; Multiple Sclerosis; Nerve; Nerve Degeneration; Neurons; Oral; Outcome; Oxidative Stress; Oxidative Stress Induction; 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; blood-brain barrier crossing; chemical group; cofactor; cognitive function; cost; design; disability; disabling symptom; efficacy evaluation; gastrointestinal system; improved; innovation; mitochondrial dysfunction; mitoquinone; multiple sclerosis patient; 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.

疲劳是多发性硬化症中一种非常普遍的致残症状，目前尚无 FDA 批准的治疗方法。 金刚烷胺、哌醋甲酯和莫达非尼等兴奋剂通常“超说明书”用于治疗疲劳 用于多发性硬化症 (PwMS) 患者，但其使用受到副作用和疗效有限的限制。类似于70-90% 非退伍军人 PwMS 会受到疲劳的不利影响，患有 MS (VwMS) 的退伍军人也会受到影响。 尽管多发性硬化症疾病修饰疗法得到广泛使用，但疲劳仍然是导致多发性硬化症的一个重要原因。 VwMS 和 PwMS 中的残疾、无法就业和生活质量差。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。虽然多发性硬化症相关疲劳的起源可能是 复杂且多因素，我们认为线粒体功能障碍和由此产生的神经元能量 耗竭可能是导致多发性硬化症疲劳的一个重要因素。最近的一项研究评估了该方法的功效 线粒体辅因子和抗氧化剂补充剂，辅酶 Q10（CoQ10，也称为 泛醇/泛醌），用于改善多发性硬化症的疲劳和情绪。这项研究表明，尽管规模不大，但意义重大 与安慰剂相比，CoQ10 治疗受试者的疲劳和情绪得到改善。口服米托醌 (MitoQ) 是辅酶 CoQ10 的一种更具线粒体特异性的形式，其中 CoQ10 具有共价连接的 赋予线粒体更强亲和力的侧链。该临床试验的目的是评估 MitoQ 对多发性硬化症疲劳的潜在有益作用。这项研究的目的是开发新的方法 影响多发性硬化症的疲劳，并最终确定针对线粒体功能的治疗是否有效果 改变多发性硬化症症状或病程的潜力。核心假设是 MitoQ 及其线粒体 亲和力将通过改善线粒体来改善多发性硬化症相关的疲劳以及认知、生活质量和情绪 神经元的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 治疗的 VwMS 与接受口服 MitoQ 治疗的患者相比是否存在 VwMS 根据 MFIS 评分测量，安慰剂在 12 周治疗期后疲劳程度减轻。 具体目标 2：确定接受口服 MitoQ 的 VwMS 与接受口服 MitoQ 的 VwMS 是否相同 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) 和贝克抑郁量表 - 快速筛查分数。 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：确定经 MitoQ 治疗的 VwMS 中血浆 MitoQ 水平是否与临床相关 疲劳、认知功能、生活质量和抑郁以及血液炎症的结果 免疫和氧化应激生物标志物。 研究设计：我们建议进行一项双盲、安慰剂对照的试点试验来比较 每天一次给予安慰剂 20 和 40 毫克剂量的 MitoQ，作为减轻疲劳的治疗方法 多发性硬化症科目是我们的主要目标，而改善认知、生活质量和抑郁症则是次要目标。 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 研究药物开始后 12 周。安全性将通过评估 MitoQ 副作用来确定。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 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：每个受试者的参与期为 13 周：第一周进行筛选访视， 随后是 12 周的治疗期。该研究需要在 13 周内进行 4 次访问和 4 次电话。全部的 投入时间约为6小时。将招募 60 名诊断患有多发性硬化症的成年患者。科目 将被随机分为 3 个受试者组：20 名受试者接受 20 毫克 MitoQ，20 名受试者将接受 40 毫克 mg MitoQ，20 名受试者将接受安慰剂。