Novel Therapies for Alcoholic Hepatitis

酒精性肝炎的新疗法

• 批准号: 8428267
• 负责人: CRAIG J. MCCLAIN
• 金额: $ 112.21万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8428267
• 关键词: Abstinence; Acute; Acute Alcoholic Hepatitis; Adrenal Cortex Hormones; Alcoholic Hepatitis; Alcoholic Liver Diseases; Animals; Basic Science; Biological Markers; Cause of Death; Cessation of life; Chronic Kidney Failure; Cirrhosis; Clinic; Clinical; Clinical Data; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Complex; Cost Analysis; Creatinine; Data; Deterioration; Development; Disease; Drug Combinations; Drug Delivery Systems; Elements; Endotoxins; Enzymes; FDA approved; Functional disorder; Future; Genotype; Goals; Grant; Hepatorenal Syndrome; Inflammation; Inflammatory; Injury; Innovative Therapy; Interleukin-1; Knowledge; Label; Lead; Liver; Liver diseases; Massachusetts; Measures; Medical center; Modeling; Morbidity - disease rate; Multicenter Studies; Organ failure; Outcome; Pathogenesis; Patients; Pentoxifylline; Permeability; Pharmaceutical Preparations; Pharmacogenetics; Phosphodiesterase Inhibitors; Pilot Projects; Placebos; Probiotics; Publishing; Randomized; Research; Research Design; Resources; Sampling; Serum; Severities; Severity of illness; Site; Specimen; Staging; Steroids; Stratification; Subcutaneous Injections; Syndrome; TNF gene; Testing; Time; Tissues; Translating; Translational Research; Transplantation; Tumor Necrosis Factor-alpha; Universities; Zinc; Zinc Sulfate; anakinra; base; biobank; clinical care; clinical practice; cytokine; immune activation; improved; inhibitor/antagonist; innovation; mortality; novel; novel therapeutics; prednisolone; prevent; primary outcome; prognostic indicator; programs; research clinical testing; response; secondary outcome; standard care; standard of care; translational study

DESCRIPTION (provided by applicant): Alcoholic hepatitis (AH) has a high morbidity and mortality with a four year survival ranges from 35% to 60 %, dependent on the presence or absence of cirrhosis. Despite over 40 years of research on AH, there is still no FDA approved treatment for this disease. The most commonly used off-label drugs for AH are corticosteroids and pentoxifylline. Unfortunately, even patients with AH treated with corticosteroids have a 6 month mortality of 40%. These poor clinical outcomes are due, in large part, to an incomplete understanding of the pathophysiology of alcohol-mediated liver injury. Therefore, there is an urgent need for effective new therapies for this pernicious disease. This multicenter study will be a collaborative effort of four medical centers (Cleveland Clinic, University of Louisville, UT Southwestern, and University of Massachusetts) with its ultimate goal of transforming the clinical treatment of AH by rapidly translating novel and innovative basic science discoveries into clinical practice. In the first 2.5 years of the grant, two clinical trials will test the hypohesis that disruption of the normal gut-barrier function, over-activation of the inflammatory cascade, and innate immune activation are the primary elements of the complex pathogenesis of AH. In patients with severe AH, the first trial will compare a novel drug combination of anakinra (an inhibitor of IL-1 activity), pentoxifylline (a phosphodiesterase inhibitor that suppresses the inflammatory cytokine cascade), and zinc (which improves gut-barrier function) with the current standard of care therapy of treatment with corticosteroids. The second trial will compare probiotics (to improve gut-barrier function) to placebo in patients with moderate AH. The primary outcomes of both clinical trials will be 6 month mortality. Both trials will also supply specimens o the translational/basic science components of this UO1 consortium to identify novel biomarkers and altered pharmacogenetics that predict disease severity and response to pharmacologic therapy as well as to identify unique drug targets for novel treatments for AH. These new discoveries will then be translated rapidly to clinical testing in the last 2.5 years of the grant.A biorepository of the collected clinical data and patient samples will also be established that will be an important national resource for transforming clinical practice for the treatment of AH. PUBLIC HEALTH RELEVANCE: Animal studies have increased the knowledge of mechanisms of alcohol induced liver injury. Despite this knowledge, the morbidity and mortality of AH has not improved and there remains a pressing need for new therapeutic strategies and prognostic indicators. Translational studies between basic science and clinical testing have been lacking. There also have been limited trials of combination therapies even though AH has a complex pathophysiology involving multiple mechanisms of injury. Therefore, the highly innovative therapies proposed in our clinical trials and the ability of this consortium to rapidly translate basic science approaches into clinical practice makes the grant highly relevant to the improved clinical care of patients with AH.

描述(申请人提供)：酒精性肝炎(AH)有很高的发病率和死亡率，四年存活率从35%到60%，取决于是否有肝硬变。尽管对AH的研究已经有40多年了，但FDA仍然没有批准这种疾病的治疗方法。治疗AH最常用的非标签药物是皮质类固醇和己酮可可碱。不幸的是，即使接受皮质类固醇治疗的急性肝炎患者的6个月死亡率也有40%。这些不良的临床结果在很大程度上是由于对酒精介导的肝损伤的病理生理学认识不完全。因此，迫切需要有效的新疗法来治疗这种致命的疾病。这项多中心研究将是 四个医学中心(克利夫兰诊所、路易斯维尔大学、德克萨斯大学西南分校和马萨诸塞大学)的合作努力，其最终目标是通过迅速将新颖和创新的基础科学发现转化为临床实践来改变AH的临床治疗。在拨款的头两年半，两项临床试验将测试低热，即正常肠道屏障功能的破坏，炎症级联反应的过度激活，以及先天免疫激活是AH复杂发病机制的主要因素。在重症急性肝炎患者中，第一项试验将比较阿纳金拉(一种IL-1活性的抑制剂)、己酮可可碱(一种抑制炎症细胞因子级联的磷酸二酯酶抑制剂)和锌(改善肠道屏障功能)的新药组合与目前使用皮质类固醇治疗的护理治疗标准。第二个试验将比较益生菌(改善肠道屏障功能)和安慰剂在中度急性肝炎患者中的作用。这两项临床试验的主要结果将是6个月死亡率。这两项试验还将为这个UO1联盟的翻译/基础科学部分提供样本，以确定预测疾病严重程度和对药物治疗反应的新生物标记物和改变的药物遗传学，并为治疗AH的新疗法确定独特的药物靶点。这些新发现将在授予的最后2.5年内迅速转化为临床测试。还将建立收集的临床数据和患者样本的生物储存库， 是转变治疗急性肝炎临床实践的重要资源。 公共卫生相关性：动物研究增加了对酒精所致肝损伤机制的了解。尽管如此，AH的发病率和死亡率并没有改善，仍然迫切需要新的治疗策略和预后指标。基础科学和临床试验之间的转换研究一直缺乏。尽管AH具有复杂的病理生理机制，涉及多种损伤机制，但联合治疗的试验也有限。因此，在我们的临床试验中提出的高度创新的疗法，以及该联盟迅速将基础科学方法转化为临床实践的能力，使这笔赠款与改善急性肝炎患者的临床护理密切相关。