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

机构：克利夫兰诊所 少年派：斯里尼瓦桑·达萨拉西 原申请摘要： 酒精性肝炎(AH)是与肝脏相关的发病率和死亡率的主要原因，显著缺乏 有效的治疗方法。这份申请是由几个由NIAAA资助的财团协调提交的 它们聚集在一起，成为酒精性肝炎网络(AlcHepNet)。总体而言，该网络将协同 努力和专业知识，以更好地了解急性肝炎和开发新的有效和安全的治疗严重急性肝炎的方法。 为了支持这一目标，这个新财团的首要目标是：1)进行研究，以更好地了解 发病机制和预后的主要决定因素，特别是在重度急性肝炎中；2)确定新的靶点 治疗急性肝炎，以及3)对已经获得FDA批准并可用的化合物进行2B期研究 可作为治疗重症急性肝炎的安全、有效的治疗方法。在这些更大目标的保护伞下， AlcHepNet建议的目的是：目标1.进行前瞻性、多中心、观察性研究 AH患者和适当的对照，这是进行新的机械和 治疗性研究。我们将整合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受试者的生物样本库 控制。该数据库将发挥三项作用：(A)提供关于结果和 急性肝炎的病理生物学，(B)支持旨在确定新的治疗靶点的转化研究，(C) 作为开发基于系统生物学的信息学集成数据库的催化剂，该数据库将作为 为所有对AH感兴趣的研究人员提供资源；目标2.执行多中心、前瞻性、随机化阶段2B 粒细胞集落刺激因子GCSF与Anakinra(加锌)与标准药物的临床试验 强的松治疗重症急性脑出血这一目标将检验这一假设，即两种积极治疗 使用G-CSF和IL-1受体拮抗剂Anakinra(加锌)的ARM优于护理标准(即 强的松)治疗重症急性胰腺炎。这些代理人的选择是基于：1)文献表明 炎症和炎性小体激活在重度急性脑出血中的作用，2)几项先导性研究证实 G-CSF的治疗益处，以及3)一项正在进行的试验的中期分析，该试验表明使用G-CSF可提高死亡率 急性胰腺炎患者的Anakinra。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。主要终点将是第90天的死亡率。这个 调查人员和AlcHepNet处于独特的地位，可以执行拟议的研究，因为 与急性胰腺炎、临床试验和相关治疗发展相关的专业知识的广度、深度和历史。 通过测试有前景的治疗急性肝炎的方法，并收集经过良好注释的患者样本和数据集，这项建议 将对这一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.