Alcoholic Hepatitis Clinical and Translational Network Late Phase Clinical Trials and Observational Studies 4/9

酒精性肝炎临床和转化网络后期临床试验和观察研究 4/9

• 批准号: 10022622
• 负责人: Gyongyi Szabo
• 金额: $ 33.63万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-24 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022622
• 关键词: Adrenal Cortex Hormones; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Collection; Conduct Clinical Trials; Consumption; Data; Data Coordinating Center; Data Set; Databases; Development; Disease; Economic Burden; Educational workshop; Eligibility Determination; FDA approved; Foundations; Funding; Future; Goals; Granulocyte Colony-Stimulating Factor; Hepatitis B; Infection; Inflammasome; Inflammation; Informatics; Institution; Interleukin-1 Receptors; Interleukin-1 beta; Label; Laboratories; Life; Light; Literature; Liver; Liver diseases; Medical; Mission; Morbidity - disease rate; National Institute on Alcohol Abuse and Alcoholism; Observational Study; Oral cavity; Outcome; Pathogenesis; Patient Care; Patient Recruitments; Patients; Pentoxifylline; Pharmaceutical Preparations; Phase; Pilot Projects; Positioning Attribute; Predisposition; Prednisone; Public Health; Randomized; Recording of previous events; Research Design; Research Personnel; Resources; Role; Sampling; Severities; Systems Biology; Testing; Therapeutic; Therapeutic Studies; Translational Research; Treatment Efficacy; Validation; Work; Zinc; active method; anakinra; base; catalyst; drug testing; effective therapy; efficacy trial; evidence base; improved; insight; interest; liver injury; longitudinal database; meetings; mortality; new therapeutic target; novel; primary endpoint; prospective; receptor; repository; research study; secondary endpoint; standard of care; targeted treatment; therapeutic development; translational study; 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.!

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。本申请是由美国国家航空航天局资助的几个 组成酒精性肝炎网络(AlcHepNet)的财团。总体而言，网络 将协同努力和专业知识，以更好地了解急性肝炎并开发新的有效和安全的治疗方法 严重的啊。为了支持这一目标，这个新财团的首要目标是：1)进行研究 更好地了解发病机制和预后的主要决定因素，特别是在严重急性呼吸综合征中；2)确定 治疗急性肝炎的新靶点，以及3)对已经通过FDA的化合物进行2B期研究 已获批准并可供使用，可作为治疗严重急性肝炎的安全有效疗法。在.之下 作为这些更大目标的总括，AlcHepNet提案的目标是：目标1.进行前瞻性、 急性呼吸窘迫综合征患者和合适的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。我们将巩固和扩大我们的 包含1)临床和实验室信息和2)生物样本库的纵向数据库 不同严重程度的急性脑出血患者和匹配的对照组。该数据库将发挥三项作用：(A)提供 关于急性呼吸窘迫综合征结果和病理生物学的独特信息，(B)支持旨在 确定新的治疗目标，以及(C)作为发展以系统生物学为基础的信息学的催化剂-- 综合数据库，将作为对AH感兴趣的所有研究人员的资源；目标2。执行 粒细胞集落刺激因子G-B期多中心前瞻性随机2B期临床试验 脑脊液与阿纳金纳(加锌)与泼尼松标准药物治疗的比较 严重的啊。这一目标将检验这样的假设，即积极的治疗都使用G-CSF和IL-1受体 拮抗剂阿纳金拉(加锌)在重症患者中优于标准护理(即强的松) 阿。这些药物的选择是基于：1)文献表明炎症和 重症急性肝炎的炎性小体激活，2)几项先导性研究显示了G-CSF的治疗效果， 以及3)正在进行的一项试验的中期分析，该试验表明Anakinra对AH患者的死亡率有好处。这 2B期疗效试验将在九个临床中心进行，并由两个数据协调中心协调 中心(DCC)。主要终点将是第90天的死亡率。调查人员和AlcHepNet是 考虑到大量的广度、深度和历史，处于执行建议研究的独特地位 与急性胰腺炎、临床试验和相关治疗发展相关的专业知识。通过测试前景看好 治疗急性肝炎并收集注释良好的患者样本和数据集，这一建议将具有强大的 并对赛场产生持久的影响。