Alcoholic Hepatitis Clinical and Translational Network Late Phase Clinical Trials and Observational Studies 9/9

摘要 酒精中毒（AH）是肝脏相关发病率和死亡率的主要原因， 缺乏有效的治疗方法。此应用程序是一个协调的提交， 几个由NIAAA资助的财团组成了酒精性肝炎网络， （AlcHepNet），以更好地了解AH，并开发新的有效和安全的治疗严重 啊该联盟的首要目标是：（1）进行研究，以更好地了解 发病机制和结果的主要决定因素，特别是在严重AH中，（2）确定 AH治疗的新靶点，以及（3）对 已经可用，可以重新用作重度AH的安全有效治疗。下 在这些更大目标的保护伞下，本提案的目标是：1.进行前瞻性研究， 对AH患者和合适的对照组进行的多中心、观察性研究，作为 进行新的机制和治疗研究的基础。我们将 巩固和扩大我们的纵向数据库（1）临床和实验室信息， (2)来自不同严重程度AH受试者和匹配对照的生物样本库。 该数据库将：（a）提供关于AH结局和病理学的独特信息，（B） 支持旨在确定新的治疗靶点的转化研究，以及（c）用于 生成基于系统生物学的信息集成数据库， 所有对AH感兴趣的研究人员的资源。2.为了进行多中心前瞻性研究， G-CSF和阿那白滞素与标准药物的随机2B期临床试验 泼尼松龙治疗重度AH患者。这一目标将检验以下假设： 使用G-CSF和IL-1受体拮抗剂阿那白滞素的两个积极治疗组均上级 严重AH患者的标准治疗（即泼尼松龙）。这些代理人的选择 基于：（1）文献证明了炎症和炎性小体激活在 重度AH，（2）几项初步研究证实了G-CSF的治疗获益，（3）中期 一项正在进行的试验的分析表明阿那白滞素对AH患者的死亡率有益处。 这项2B期疗效试验将在9个临床中心进行，并由 数据协调中心（DCC）。主要终点为第90天的死亡率。的 研究人员和AlcHepNet是唯一的定位，以执行拟议的研究， 与AH、临床试验实施和治疗相关的专业知识的广度和深度 发展通过测试有希望的AH疗法，同时收集注释良好的 患者样本和数据集，该提案将对该领域产生强大而持久的影响。

Abstract Alcoholic (AH) is a leading cause of liver-related morbidity and mortality with a remarkable paucity of effective therapeutics. This application represents a coordinated submission of several NIAAA-funded consortia which have come together as the Alcoholic Hepatitis Network (AlcHepNet) to better understand AH and develop novel effective and safe therapy for severe AH. The overarching aims of this consortium are to: (1) perform studies to better understand the pathogenesis and main determinants of outcome, particularly in severe AH, (2) identify novel targets for therapy of AH, and (3) perform phase 2B studies of compounds that are already available and can be repurposed as safe and effective therapy for severe AH. Under the umbrella of these larger aims, the aims of this proposal are: 1. To conduct a prospective, multicenter, observational study of patients with AH and suitable controls that serves as the foundation for conducting novel mechanistic and therapeutic studies. We will consolidate and extend our longitudinal database of (1) clinical and laboratory information and (2) a bio-sample repository from subjects with AH of varying severity and matched-controls. This database will: (a) provide unique information on the outcomes and pathobiology of AH, (b) support translational research designed to identify novel targets for treatment, and (c) be used to generate systems biology based informatics-integrated databases that will serve as a resource for all researchers interested in AH. 2. To perform a multicenter prospective, randomized phase 2B clinical trial of G-CSF and Anakinra versus standard medical therapy with Prednisolone in patients with severe AH. This aim will test the hypothesis that both active treatment arms with G-CSF and the IL-1 receptor antagonist Anakinra are superior to the stardard of care (i.e. prednisolone) in patients with severe AH. The choice of these agents is based on: (1) literature demonstrating a role for inflammation and inflammasome activation in severe AH, (2) several pilot studies demonstrating therapeutic benefit with G-CSF, (3) interim analysis of an ongoing trial suggesting a mortality benefit with Anakinra in patients with AH. This phase 2B efficacy trial will be conducted across nine clinical centers and coordinated by a Data Coordinating Center (DCC). The primary endpoint will be mortality at day 90. The investigators and the AlcHepNet is uniquely positioned to perform the proposed study given substantial breadth and depth of expertise related to AH, clinical trial conduct, and therapeutic development. By testing promising therapies for AH and concurrently collecting well annotated patient samples and datasets, this proposal will have a strong and lasting impact on the field.