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

摘要 酒精(AH)是肝脏相关发病率和死亡率的主要原因，具有显著的 缺乏有效的治疗方法。此申请代表协调提交的 几个由NIAAA资助的财团联合起来，成为酒精性肝炎网络 (AlcHepNet)更好地了解AH并开发新的有效和安全的重症治疗方法 阿。该联盟的主要目标是：(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，特别是在严重的急性肝炎中，(2)确定 治疗急性肝炎的新靶点，以及(3)对符合以下条件的化合物进行2B期研究 已经可用，可以作为安全有效的治疗重症急性肝炎的方法。在.之下 在这些更大目标的总括下，这项提议的目的是：1.为了进行预期， 急性呼吸窘迫综合征患者和合适对照的多中心观察性研究 进行新的机制和治疗研究的基础。我们会 整合和扩展我们的纵向数据库，包括(1)临床和实验室信息以及 (2)来自不同严重程度的急性脑出血患者和配对对照的生物样本库。 该数据库将：(A)提供有关急性肝炎预后和病理生物学的独特信息，(B) 支持旨在确定新的治疗目标的转化性研究，以及(C)使用 生成基于系统生物学的信息学集成数据库，这些数据库将用作 为所有对AH感兴趣的研究人员提供的资源。2.执行多中心前瞻性， G-CSF和Anakinra与标准药物的随机2B期临床试验 强的松龙治疗重症急性脑出血这一目标将检验这一假设 G-CSF和IL-1受体拮抗剂Anakinra的主动治疗效果都较好 达到重症急性胰腺炎患者的治疗标准(即强的松龙)。这些代理人的选择 基于：(1)文献表明炎症和炎性小体激活在 重症急性肝炎，(2)几项初步研究显示G-CSF的治疗效果，(3)中期 对一项正在进行的试验的分析表明，Anakinra对AH患者的死亡率有好处。 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 在急性胰腺炎、临床试验行为和治疗方面有相当广泛和深入的专业知识 发展。通过测试治疗急性胰腺炎的有前景的疗法，同时收集了很好的注释 患者样本和数据集，这一提议将对该领域产生强大和持久的影响。

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.