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

酒精性肝炎临床和转化网络 - 后期临床试验和观察研究（合作 U01）

• 批准号: 9764890
• 负责人: Srinivasan Dasarathy
• 金额: $ 0.84万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764890
• 关键词: Alcoholic Hepatitis; CSF3 gene; Clinic; Clinical; Clinical Trials; Conduct Clinical Trials; Data Coordinating Center; Data Set; Databases; FDA approved; Foundations; Funding; Goals; Granulocyte Colony-Stimulating Factor; Hepatitis B; Inflammasome; Inflammation; Informatics; Institution; Interleukin-1 Receptors; Laboratories; Literature; Liver; Medical; Morbidity - disease rate; National Institute on Alcohol Abuse and Alcoholism; Observational Study; Outcome; Pathogenesis; Patients; Phase; Pilot Projects; Positioning Attribute; Prednisone; Randomized; Recording of previous events; Research Design; Research Personnel; Resources; Role; Sampling; Severities; Systems Biology; Testing; Therapeutic; Therapeutic Studies; Translational Research; Treatment Efficacy; Zinc; active method; anakinra; base; catalyst; effective therapy; efficacy trial; interest; longitudinal database; mortality; new therapeutic target; novel; primary endpoint; prospective; repository; standard of care; therapeutic development; treatment arm

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.

机构：克利夫兰诊所 PI：斯里尼瓦桑·达萨拉蒂 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，但其发病率却非常低 有效的治疗方法。该申请代表了多个 NIAAA 资助的财团的协调提交 这些组织已合并为酒精性肝炎网络 (AlcHepNet)。网络将共同发挥协同作用 努力和专业知识更好地了解 AH 并开发针对严重 AH 的新型有效且安全的疗法。 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 发病机制和结果的主要决定因素，特别是严重的 AH； 2）确定新目标 AH 的治疗，以及 3) 对已获得 FDA 批准且可用的化合物进行 2B 期研究 并且可以重新用作严重 AH 的安全有效的治疗方法。在这些更大目标的保护下， AlcHepNet 提案的目标是： 目标 1. 开展一项前瞻性、多中心、观察性研究 AH 患者和合适的对照作为进行新机制和 治疗研究。我们将巩固和扩展我们的纵向数据库，其中包含 1) 临床和 实验室信息和 2) 来自不同严重程度且匹配的 AH 受试者的生物样本库 控制。该数据库将提供三个功能：(a) 提供有关结果的独特信息和 AH 的病理学，(b) 支持旨在确定新治疗靶点的转化研究，以及 (c) 作为开发基于系统生物学的信息学综合数据库的催化剂，该数据库将作为 为所有对 AH 感兴趣的研究人员提供的资源；目标 2. 进行多中心、前瞻性、随机 2B 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 患者使用泼尼松治疗。这一目标将检验以下假设：积极治疗 使用 G-CSF 和 IL-1 受体拮抗剂阿那白滞素（加锌）的手臂优于护理标准（即 泼尼松）用于严重 AH 患者。这些药物的选择基于：1）文献证明 炎症和炎性体激活在严重 AH 中的作用，2) 多项试点研究表明 G-CSF 的治疗益处，以及 3) 一项正在进行的试验的中期分析表明，使用 G-CSF 可以降低死亡率 AH 患者使用阿那白滞素 (Anakinra)。这项 2B 期疗效试验将在九个临床中心进行 由两个数据协调中心（DCC）协调。主要终点是第 90 天的死亡率。 鉴于大量研究人员和 AlcHepNet 处于独特的地位来执行拟议的研究 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。 通过测试有前景的 AH 疗法并收集注释良好的患者样本和数据集，该提案 将会对该领域产生强烈而持久的影响。