Novel Therapies for Alcoholic Hepatitis

描述（由申请人提供）：酒精性肝炎（AH）具有高发病率和死亡率，4年生存率范围为35%至60%，取决于是否存在肝硬化。尽管对AH的研究已经超过40年，但仍然没有FDA批准治疗这种疾病。AH最常用的标签外药物是皮质类固醇和喷替福林。不幸的是，即使用皮质类固醇治疗的AH患者6个月死亡率也为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的不完全理解。因此，迫切需要针对这种恶性疾病的有效新疗法。这项多中心研究将 四个医学中心（克利夫兰诊所、路易斯维尔大学、UT西南大学和马萨诸塞州大学）的合作努力，其最终目标是通过将新颖和创新的基础科学发现快速转化为临床实践来改变AH的临床治疗。在拨款的前2.5年，两项临床试验将测试正常肠道屏障功能的破坏，炎症级联反应的过度激活和先天免疫激活是AH复杂发病机制的主要因素。在重度AH患者中，第一项试验将比较阿那白滞素（一种IL-1活性抑制剂）、喷替福林（一种抑制炎性细胞因子级联反应的磷酸二酯酶抑制剂）和锌（改善肠道屏障功能）的新型药物组合与目前使用皮质类固醇治疗的标准治疗。第二项试验将在中度AH患者中比较益生菌（改善肠道屏障功能）与安慰剂。两项临床试验的主要结局均为6个月死亡率。这两项试验还将为UO 1联盟的转化/基础科学部分提供样本，以识别新型生物标志物和改变的药物遗传学，从而预测疾病的严重程度和对药物治疗的反应，并识别AH新型治疗的独特药物靶点。这些新发现将在最后2.5年的拨款中迅速转化为临床试验。还将建立收集临床数据和患者样本的生物储存库， 成为改变AH治疗临床实践的重要国家资源。 公共卫生相关性：动物研究增加了对酒精诱导肝损伤机制的认识。尽管有这些知识，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化研究一直缺乏。尽管AH具有涉及多种损伤机制的复杂病理生理学，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将基础科学方法快速转化为临床实践的能力，使该基金与改善AH患者的临床护理高度相关。

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.