Mitoquinone/mitoquinol mesylate as oral and safe Postexposure Prophylaxis for Covid-19

米托醌/甲磺酸米托喹诺作为 Covid-19 的口服且安全的暴露后预防

• 批准号: 10727092
• 负责人: Theodoros Kelesidis
• 金额: $ 24.6万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-14 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727092
• 关键词: 2019-nCoV; Accounting; Address; Adult; Adverse effects; Aging; Agonist; Anti-Inflammatory Agents; Antiinflammatory Effect; Antioxidants; Antiviral Agents; Antiviral Therapy; Apoptosis; Apoptotic; Attenuated; Binding; Bioinformatics; COVID-19; COVID-19 morbidity; COVID-19 treatment; Cancer Patient; Cell Death; Cell physiology; Clinical; Clinical Trials; Control Groups; Coronavirus; Data; Development; Double-Blind Method; Energy-Generating Resources; Ensure; Epithelial Cells; Exhibits; Exposure to; FDA approved; Foundations; Funding Opportunities; Generations; Goals; Hour; Human; Immune response; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Liver Dysfunction; Long COVID; Lung; Mediating; Mesylates; Mitochondria; Monitor; Morbidity - disease rate; Mus; Nucleosides; Oral; Outpatients; Participant; Pathogenesis; Pathway interactions; Paxlovid; Persons; Phase; Phase II Clinical Trials; Placebo Control; Placebos; Property; Prophylactic treatment; Protease Inhibitor; Public Health; RNA Viruses; Randomized; Reactive Oxygen Species; Research Design; Resistance; Ritonavir; SARS coronavirus; SARS-CoV-2 exposure; SARS-CoV-2 infection; SARS-CoV-2 variant; Safety; Sample Size; Severe Acute Respiratory Syndrome; Signal Transduction; Testing; Therapeutic; Therapeutic Agents; Tissues; Treatment Efficacy; Vaccinee; Vascular Diseases; Viral; Viral Physiology; Virus; Virus Diseases; Virus Replication; Work; airway epithelium; anti-viral efficacy; attenuation; clinically relevant; comorbidity; design; dietary supplements; efficacy evaluation; efficacy outcomes; efficacy study; follow-up; high risk; high risk population; in vivo; innovation; lung injury; mitoquinone; nirmatrelvir; novel; novel therapeutics; nucleoside analog; open label; phase 2 study; post SARS-CoV-2 infection; pre-exposure prophylaxis; prevent; primary outcome; recruit; safety outcomes; severe COVID-19; therapeutic target; tissue injury; treatment group; variants of concern

PROJECT SUMMARY/ABSTRACT Current oral antivirals used against SARS-CoV-2 infection such as protease inhibitors have limitations such as absence of anti-inflammatory effects and rebound COVID-19 after a 5-day course of outpatient antiviral treatment. Novel antiviral therapies against SARS-CoV-2 are urgently needed that ideally also limit inflammatory responses that contribute to morbidity from COVID-19. Reactive oxygen species (ROS) impair cellular functions and drive pro-inflammatory signaling and pathogenesis of infections with RNA viruses like coronavirus. Mitochondria are the main source of energy and ROS (mito-ROS). Mito-ROS are regulated by the antioxidant Nrf2 pathway that mediates pathogenesis and tissue damage of viral infections. We showed that MitoQ, a mitochondrial antioxidant and Nrf2 agonist, inhibits in vitro and in vivo viral replication of several SARS-CoV-2 variants of concern (VOC) and associated inflammatory response and apoptosis in airway epithelial cells through the Nrf2 pathway. Given that MitoQ is a diet supplement that is safe and immediately available to humans for use as possible therapeutic, we also showed antiviral efficacy of MitoQ in humans in a carefully designed open label clinical trial of post exposure prophylaxis (PEP) of MitoQ, compared to no MitoQ (control group), to prevent development of SARS-CoV-2 infection after high-risk exposure to a person with confirmed SARS-CoV-2 infection. MitoQ was well tolerated. We hypothesize that MitoQ attenuates the SARS- CoV-2-induced aberrant mito-ROS and Nrf2 pathway in epithelial cells and ultimately tissue injury that drives development and progression of severe COVID-19. The goal of this application is to determine if MitoQ can be used as novel oral safe outpatient post-exposure prophylaxis treatment against development of severe COVID-19. We propose the first proof-of concept randomized, double-blind, placebo-controlled Phase II efficacy study (RCT) with oral MitoQ use in adults at high risk for development of COVID-19, to further establish the safety and the efficacy of MitoQ against development of SARS-CoV-2 infection. We will include 2 treatment groups (MitoQ 20 mg daily, placebo) and we aim to recruit a total of 112 participants in total (50 per group accounting for 10% attrition). The primary outcome of efficacy will be the development of SARS- CoV-2 infection after high-risk exposure. The primary outcome of safety will be the proportion of participants exhibiting adverse effects of any grade. Given that attenuation of detrimental host responses that propagate viral replication may impose a higher barrier to generation of resistant viruses, this study will directly test MitoQ as a novel oral, safe, potent therapeutic strategy for COVID-19 against emerging SARS-CoV-2 VOCs. Our proposal will set the foundation of larger clinical trial that will advance use of MitoQ for COVID-19 to supplement existing treatments.

项目摘要/摘要 针对SARS-COV-2感染（例如蛋白酶抑制剂）使用的当前口服抗病毒药物具有限制 在门诊抗病毒5天后，缺乏抗炎作用和COUND COVID-19 治疗。迫切需要针对SARS-COV-2的新型抗病毒疗法，理想情况下也需要限制 导致COVID-19的发病率的炎症反应。活性氧（ROS）受损 细胞功能和驱动RNA病毒感染的促炎信号传导和发病机理 新冠病毒。线粒体是能源和ROS（Mito-ROS）的主要来源。 Mito-Ros受 抗氧化剂NRF2途径介导病毒感染的发病机理和组织损伤。我们表明了这一点 Mitoq是一种线粒体抗氧化剂和NRF2激动剂，抑制了几种体外和体内病毒复制 SARS-COV-2的关注（VOC）和相关炎症反应和气道凋亡的变体 上皮细胞通过NRF2途径。鉴于Mitoq是一种安全且立即的饮食补充剂 我们可以作为可能的治疗性使用，我们还表现出Mitoq在人类中的抗病毒功效 精心设计的MITOQ暴露后预防后预防（PEP）的开放标签试验，而没有MITOQ （对照组），以防止高风险接触到患有患者的SARS-COV-2感染 确认的SARS-COV-2感染。 Mitoq的耐受性很好。我们假设MITOQ减弱了SARS- COV-2诱导的上皮细胞中的异常线索ROS和NRF2途径，并最终驱动组织损伤 严重的共同19岁的发展和进展。该应用程序的目的是确定Mitoq是否可以 用作新型口腔安全门诊后暴露后预防治疗，以防止发生严重的发展 新冠肺炎。我们提出了第一个随机的概念验证验证验证，双盲，安慰剂对照阶段II 在成年人中使用口服MITOQ的疗效研究（RCT），可在Covid-19的高风险中使用，以进一步进一步 建立Mitoq免于开发SARS-COV-2感染的安全性和功效。我们将包括 2个治疗组（Mitoq每天20毫克，安慰剂），我们的目标是总共112名参与者（50个参与者 每个小组占10％的损耗）。功效的主要结果将是SARS的发展 高风险暴露后的COV-2感染。安全的主要结果将是参与者的比例 表现出任何等级的不利影响。鉴于传播的有害宿主反应的衰减 病毒复制可能对抗性病毒产生更高的障碍，该研究将直接测试Mitoq 作为与新兴SARS-COV-2 VOC的新型口头，安全，有效的治疗策略。我们的 提案将奠定更大的临床试验的基础 补充现有治疗方法。