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

基本信息

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
项目类别：
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

项目摘要

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，但人们对新冠肺炎的管理和治疗知之甚少。 19. 患有相关肝病 (ALD) 和 COVID-19 的饮酒患者患严重疾病的风险增加，还有数据表明，隔离期间饮酒量会增加，就像那样造成的。由于在 COVID-19 大流行期间制定的社会疏远措施，因此，目前针对重症 COVID-19 患者的治疗方法可能会增加，包括抗病毒药物。在我们的初步和试点研究中，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力受损以及伴随的收缩。功能障碍会导致住院和重症监护时间延长、对通气支持的需求增加以及身体状况不佳急性呼吸窘迫综合征（ARDS）的结果，这是严重的“细胞因子风暴”的一个标志。 COVID-19 患者中发生的这种情况伴随着循环 IL-6 升高，新的数据表明尽管人们对 IL-6 很感兴趣，但 IL-6 抑制剂可以改善重症 COVID-19 患者的生存率。多项正在进行的临床试验正在进行中，这些药物会增加继发感染的风险（在 COVID-19 中常见）并且血浆浓度显着升高的患者禁用 β-羟基β-甲基丁酸（HMB），一种具有合成代谢作用的非氮亮氨酸代谢物。特性，还抑制血浆 IL-6，同时改善肌肉质量和收缩功能。随着 COVID-19 恶化 ALD 患者的临床结果和肌肉损失，并且逆转 HMB 通过 IL-6 依赖性方式导致的肌肉损失将改善 ALD 患者的临床结果。假设将通过两个相互关联但独立的具体目标进行检验：（1）建立自然通过确定 ALD 患者中的 COVID-19 是否更严重来了解 ALD 患者的 COVID-19 感染病程 ALD 以及 COVID-19 是否会加重 ALD 中的肝损伤 (2) 确定是否使用 HMB 治疗；改善 COVID-19 在骨骼肌质量、骨骼肌质量方面的急性和长期后果我们将使用临床和生物样本来确定 ALD 患者的肌肉功能和临床结果。我们预计 HMB 会影响这些患者的骨骼肌干预的结果和反应。减少炎症标志物，包括循环 IL-6，改善院内临床结果，逆转肌肉减少症，并改善长期临床结果，这些人体研究有可能立即发挥作用。转化为临床实践，以快速改善 ALD 患者的近期和长期结果这些研究将补充申请人正在进行的酒精性肝炎网络资助。由 NIAAA 制定。