ALCOHOLIC HEPATITIS CLINICAL AND TRANSLATIONAL NETWORK: LATE PHASE CLINICAL TRIALS AND OBSERVATIONAL STUDIES 6/9

酒精性肝炎临床和转化网络：后期临床试验和观察研究 6/9

• 批准号: 10173034
• 负责人: Srinivasan Dasarathy
• 金额: $ 15.36万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10173034
• 关键词: Acute; Adult Respiratory Distress Syndrome; Alcohol consumption; Alcoholic Hepatitis; Alcohols; Amino Acids; Antiviral Agents; COVID-19; COVID-19 pandemic; Chronic; Cirrhosis; Clinic; Clinical; Clinical Trials; Critical Illness; Data; Deterioration; Disease; Disease Outbreaks; Early Intervention; Essential Amino Acids; Ethanol; Etiology; Failure; Functional disorder; Grant; Hepatitis; Hospitalization; Hospitals; Human; Hypoxemia; Hypoxia; Immunosuppression; Impairment; In Vitro; Incidence; Infection; Inflammatory; Information Resources Management; Intensive Care; Interleukin-6; Intervention; Leucine; Liver diseases; Lung; Malnutrition; Measures; Mediating; Middle East Respiratory Syndrome; Modeling; Monitor; Morbidity - disease rate; Mus; Muscle; Muscle Fibers; Muscle function; Muscular Atrophy; Myopathy; National Institute on Alcohol Abuse and Alcoholism; Observational Study; Outcome; Pathway interactions; Patients; Phase; Phenotype; Pilot Projects; Plasma; Pneumonia; Prevalence; Prevention therapy; Production; Property; Proteolysis; Publishing; Randomized; Reaction; Recovery; Registries; Reporting; Respiratory Diaphragm; Risk; SARS coronavirus; Safety; Sales; Sepsis; Severe Acute Respiratory Syndrome; Severities; Signal Transduction; Skeletal Muscle; Social Distance; Social isolation; Supportive care; Testing; Transaminases; Translations; Viral; Visit; adverse outcome; base; circulating biomarkers; clinical biomarkers; clinical database; clinical practice; clinically significant; comorbidity; coronavirus disease; cytokine release syndrome; epidemiology study; high risk; imaging biomarker; immune function; improved; improved outcome; inflammatory marker; inhibitor/antagonist; innovation; interest; liver injury; methyl butyrate; mortality; muscle form; muscle strength; prevent; problem drinker; response; sarcopenia; secondary infection; septic; skeletal muscle wasting; tissue injury

ABSTRACT Despite the high clinical significance, there is limited knowledge of the management and treatment of COVID- 19. Patients with alcohol associated liver disease (ALD) and COVID-19 are at increased risk for severe disease, morbidity and mortality. There are also data that alcohol consumption increases during isolation, like that caused by social distancing measures enacted during the COVID-19 pandemic, therefore the incidence and severity of ALD is likely to increase. Current treatment approaches for patients with severe COVID-19 include antiviral agents and supportive care. In our preliminary and pilot studies we have observed sarcopenia or loss of skeletal muscle mass and impaired muscle strength in patients with ALD. Sarcopenia and accompanying contractile dysfunction contribute to longer hospital and intensive care stay, greater need for ventilatory support and poor outcomes in acute respiratory distress syndrome (ARDS), a hallmark of severe COVID-19. The “cytokine storm” that occurs in patients with COVID-19 is accompanied by elevated circulating IL-6, and emerging data suggests that IL-6 inhibitors improve survival in patients with severe COVID-19. Despite the significant interest in IL-6 inhibitors with multiple ongoing clinical trials underway, these agents increase the risk for secondary infections (a common occurrence in COVID-19) and are contraindicated in those with significant elevated plasma transaminases. β-hydroxy β-methyl butyrate (HMB), a non-nitrogenous leucine metabolite with anabolic properties, also inhibits plasma IL-6 while improving muscle mass and contractile function. We therefore hypothesize that COVID-19 worsens clinical outcomes and muscle loss in ALD patients, and that reversal of muscle loss by HMB through an IL-6 dependent manner will improve clinical outcomes in ALD patients. This hypothesis will be tested through two interrelated, but independent specific aims: (1) establish the natural course of COVID-19 infection in patients with ALD by determining whether COVID-19 is more severe in ALD and whether COVID-19 worsens liver injury in ALD; (2) determine whether treatment with HMB improves the acute and long-term consequences of COVID-19 in terms of skeletal muscle mass, skeletal muscle function, and clinical outcomes in ALD patients. We will use clinical and biosamples to determine outcomes and responses to intervention targeting the skeletal muscle in these patients. We anticipate HMB will reduce inflammatory markers including circulating IL-6, improve clinical outcomes in-hospital, reverse sarcopenia, and improve long-term clinical outcomes. These human studies have the potential for immediate translation into clinical practice to rapidly improve immediate and long-term outcomes in ALD patients with COVID-19. These studies will supplement the applicant’s ongoing alcoholic hepatitis network grant supported by the NIAAA.

抽象的 尽管具有很高的临床意义，但对COVID的管理和治疗的了解有限 19。与酒精相关的肝病患者（ALD）和Covid-19患者患严重疾病的风险增加， 发病率和死亡率。还有数据表明，在隔离期间饮酒会增加，例如 通过社会疏远措施在COVID-19大流行期间制定的措施，因此 ALD可能会增加。当前针对严重共vid患者19的患者的治疗方法包括抗病毒 代理商和支持性护理。在我们的初步和初步研究中，我们观察到肌肉减少症或骨骼丧失 ALD患者的肌肉质量和肌肉力量受损。肌肉减少症和参与收缩 功能障碍会导致更长的医院和重症监护室，更大的通风支持和差的需求 急性呼吸窘迫综合征（ARDS）的结果，这是严重的Covid-19的标志。 “细胞因子风暴” 在Covid-19患者中发生的情况发生在循环升高的IL-6，而新兴数据表明 IL-6抑制剂改善了严重COVID-19患者的生存率。尽管对IL-6很感兴趣 进行了多次正在进行的临床试验的抑制剂，这些药物增加了继发感染的风险 （在COVID-19中的常见发生），在血浆显着升高的患者中是禁忌的 转氨酶。 β-羟基β-甲基丁酸酯（HMB），一种非硝基亮氨酸代谢物，具有合成代谢 性质，还可以抑制血浆IL-6，同时改善肌肉质量和收缩功能。因此，我们 假设COVID-19使ALD患者的临床结局和肌肉丧失恶化，并逆转 HMB通过IL-6依赖性方式损失肌肉将改善ALD患者的临床结果。这 假设将通过两个相互关联但独立的特定目的进行检验：（1）建立自然 通过确定Covid-19的ALD患者的Covid-19感染过程是否更严重 ALD以及COVID-19是否会在ALD中恶化肝损伤； （2）确定是否使用HMB处理 在骨骼肌肉质量方面，改善了Covid-19的急性和长期后果 ALD患者的肌肉功能和临床结局。我们将使用临床和生物样本来确定 针对这些患者骨骼肌的结果和对干预的反应。我们预计HMB会 减少炎症标记，包括循环IL-6，改善院内临床结果，反向 肌肉减少症，改善长期临床结果。这些人类研究有可能立即 转化为临床实践，以快速改善ALD患者的直接和长期结局 新冠肺炎。这些研究将补充申请人持续的酒精性肝炎网络赠款 由NIAAA。