Alcoholic Hepatitis Clinical and Translational Network - Late Phase Clinical Trials and Observational Studies (Collaborative U01)

研究机构：克利夫兰诊所 PI：Srinivasan Dasarathy 原始申请摘要： 酒精性肝炎（AH）是肝脏相关发病率和死亡率的主要原因， 有效的治疗方法。此应用程序代表了几个NIAAA资助的财团的协调提交 这些组织被称为酒精性肝炎网络（AlcHepNet）。总的来说，网络将协同 努力和专业知识，以更好地了解AH和开发新的有效和安全的治疗严重AH。 为了支持这一目标，这个新联盟的总体目标是：1）进行研究，以更好地了解 结果的发病机制和主要决定因素，特别是在严重AH中; 2）确定新的靶点， AH的治疗，以及3）对已经FDA批准和可用的化合物进行2B期研究 并且可以被重新利用为严重AH的安全有效的疗法。在这些更大目标的保护伞下， 该AlcHepNet提案的目标是：目标1。进行一项前瞻性、多中心、观察性研究， AH患者和适当的对照，作为基础，进行新的机制， 治疗研究。我们将巩固和扩展我们的纵向数据库，包括1）临床和 实验室信息和2）来自不同严重程度和匹配的AH受试者的生物样本储存库 对照该数据库将发挥三项功能：（a）提供关于成果的独特信息， AH的病理生物学，（B）支持旨在鉴定治疗新靶点的转化研究，以及（c） 作为一种催化剂，开发系统生物学为基础的，信息学综合数据库，将作为一个 所有对AH感兴趣的研究人员的资源;目标2。进行一项多中心、前瞻性、随机化II B期研究 粒细胞集落刺激因子GCSF与阿那白滞素（加锌）与标准医疗的临床试验 严重AH患者的泼尼松治疗。这一目标将检验这一假设，即积极治疗 G-CSF和IL-1受体拮抗剂阿那白滞素（加锌）组优于标准治疗（即， 泼尼松）严重AH患者。这些试剂的选择基于：1）文献证明 炎症和炎性小体激活在严重AH中的作用，2）几项初步研究表明， G-CSF的治疗获益，以及3）正在进行的试验的中期分析表明， 阿那白滞素在AH患者中的应用这项2B期疗效试验将在9个临床中心进行， 由两个数据协调中心（DCC）协调。主要终点为第90天的死亡率。的 研究人员和AlcHepNet处于独特的地位，可以进行拟议的研究， 与AH、临床试验实施和相关治疗开发相关的专业知识的广度、深度和历史。 通过测试有希望的AH疗法并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。

Institution: Cleveland Clinic PI: Srinivasan Dasarathy ABSTRACT of the original application: Alcoholic hepatitis (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 that have come together as the Alcoholic Hepatitis Network (AlcHepNet). Collectively, the network will synergize efforts and expertise to better understand AH and develop novel effective and safe therapies for severe AH. Buttressing that goal, the overarching aims of this new consortium are to: 1) perform studies to better understand the pathogenesis and main determinants of outcomes, particularly in severe AH; 2) identify novel targets for therapy of AH, and 3) perform phase 2B studies of compounds that are already FDA approved and available and can be repurposed as safe and effective therapies for severe AH. Under the umbrella of these larger aims, the aims of this AlcHepNet proposal are to: Aim 1. 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 containing 1) clinical and laboratory information and 2) bio-sample repository from subjects with AH of varying severity and matched controls. This database will serve three functions: (a) provide unique information on the outcomes and pathobiology of AH, (b) support translational research designed to identify novel targets for treatment, and (c) serve as a catalyst to develop systems biology-based, informatics integrated databases that will serve as a resource for all researchers interested in AH; Aim 2. Perform a multicenter, prospective, randomized phase 2B clinical trial of granulocyte colony stimulating factor GCSF versus Anakinra (plus zinc) versus standard medical therapy with Prednisone 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 (plus zinc) are superior to the standard of care (i.e. Prednisone) 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, and 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 two Data Coordinating Centers (DCCs). The primary endpoint will be mortality at Day 90. The investigators and the AlcHepNet are uniquely positioned to perform the proposed study given the substantial breadth, depth, and history of expertise related to AH, clinical trial conduct, and related therapeutic development. By testing promising therapies for AH and collecting well-annotated patient samples and datasets, this proposal will have a strong and lasting impact on the field.