ALCOHOLIC HEPATITIS CLINICAL AND TRANSLATIONAL NETWORK: LATE PHASE CLINICAL TRIALS AND OBSERVATIONAL STUDIES6/9

酒精性肝炎临床和转化网络：后期临床试验和观察研究6/9

• 批准号: 10876683
• 负责人: Srinivasan Dasarathy
• 金额: $ 10万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10876683
• 关键词: Alcoholic Hepatitis; Biological Specimen Banks; CSF3 gene; Clinical; Clinical Trials; Conduct Clinical Trials; Data Coordinating Center; Data Set; Databases; FDA approved; Foundations; Funding; Goals; Granulocyte Colony-Stimulating Factor; Inflammasome; Inflammation; Informatics; 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; Zinc; active method; anakinra; antagonist; catalyst; clinical center; effective therapy; efficacy trial; interest; longitudinal database; mortality; new therapeutic target; novel; primary endpoint; prospective; standard of care; synergism; therapeutic development; therapeutically effective; treatment arm

ABSTRACT 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 G- CSF 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.

抽象的 酒精性肝炎（AH）是与肝有关的发病率和死亡率的主要原因，显着匮乏 有效的治疗学。该申请代表了几项NIAAA资助的协调提交 作为酒精性肝炎网络（Alchepnet）的财团。集体，网络 将协同努力和专业知识，以更好地理解AH并开发新颖的有效疗法 严重的啊。为了支撑这个目标，这个新财团的总体目的是：1）进行研究 更好地了解结局的发病机理和主要决定因素，尤其是在严重的AH中； 2）识别 AH治疗的新靶标和3）对已经是FDA的化合物进行2阶段的研究 批准并获得，可以重新使用为严重AH的安全有效疗法。在 这些较大目标的保护伞，该炼金术提案的目的是：AIM 1。进行前瞻性， 多中心的AH患者和适当对照的观察性研究， 进行新的机械和治疗研究基金会。我们将合并并扩展我们的 包含1）临床和实验室信息的纵向数据库以及2）来自 具有不同严重性和匹配对照的AH受试者。该数据库将提供三个功能：（a）提供 有关AH的结果和病理学的独特信息，（b）支持旨在的转化研究 确定新的治疗目标，（c）作为开发基于系统生物学的信息学的催化剂 - 集成的数据库将为所有对AH感兴趣的研究人员提供资源；目标2。执行 多中心，前瞻性，随机阶段2b粒细胞菌落刺激因子g-的临床试验 CSF与Anakinra（加锌）与泼尼松的标准药物治疗患者的患者 严重的啊。该目标将测试具有G-CSF和IL-1受体的主动治疗臂的假设 拮抗剂Anakinra（加锌）优于严重患者的护理标准（即泼尼松） 啊。这些药物的选择是基于：1）文献证明了炎症和 严重AH中的炎性体激活，2）几项试验研究，证明了G-CSF治疗益处， 3）对正在进行的试验的临时分析表明，ANAKINRA对AH患者的死亡率受益。这 2B阶段疗效试验将在9个临床中心进行，并通过两个数据协调进行协调 中心（DCC）。主要终点将是第90天的死亡率。调查人员和炼金术人员是 鉴于具有实质性的广度，深度和历史 与AH，临床试验和相关治疗开发有关的专业知识。通过测试有希望的 AH的疗法和收集良好的患者样品和数据集的疗法，该提案将具有很强的 并对现场的持久影响。