Translational Research and Evolving Alcoholic hepatitis Treatment (TREAT-IU)

转化研究和不断发展的酒精性肝炎治疗 (TREAT-IU)

• 批准号: 8921359
• 负责人: NAGA P CHALASANI
• 金额: $ 6.68万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8921359
• 关键词: Acids; Acute Alcoholic Hepatitis; Address; Adrenal Cortex Hormones; Adult; Affect; Age; Agonist; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcohols; Antibodies; Back; Bacterial Translocation; Bile Acids; CYP2E1 gene; Caspase Inhibitor; Cells; Clinic; Clinical; Drug Kinetics; Enrollment; Fatty Liver; Feces; Fibroblast Growth Factor; Foundations; Functional disorder; Gender; Genomic DNA; Glossary; Goals; Health; Heavy Drinking; Hepatic; Hepatocyte; Histologic; Homeostasis; Hospitalization; Human; Immune response; Impairment; Incidence; Indiana; Individual; Inflammation; Injury to Liver; Kupffer Cells; Laboratories; Length of Stay; Lipopolysaccharides; Liver; Liver diseases; Metabolism; Modeling; Mononuclear; Morbidity - disease rate; Multiple Abnormalities; Natural Immunity; Nuclear Receptors; Observational Study; Oral; Oral cavity; Oxidative Stress; Pathogenesis; Pathway interactions; Patient Care; Patients; Peripheral; Permeability; Placebo Control; Placebos; Plasma; Public Health; Questionnaires; Race; Randomized; Randomized Controlled Trials; Recording of previous events; Research Personnel; Safety; Sample Size; Sampling; Serious Adverse Event; Severities; Signal Transduction; Staging; Testing; Therapeutic Studies; Time; Tissues; Translational Research; Universities; Urine; Virginia; alcohol research; bile salts; case control; cohort; cytokine; drinking; effective therapy; meetings; member; mortality; named group; novel; novel strategies; patient oriented research; prospective; receptor; repository; response; therapy development; translational study

DESCRIPTION (provided by applicant): In response to the RFA-AA-12-007, Indiana University (IU), Mayo Clinic (Mayo), and Virginia Commonwealth University (VCU) have formed a consortium "Translational Research and Evolving Alcoholic Hepatitis Treatments"(TREAT). Central hypotheses of this application are: (a) a large cohort of patients with well-characterized acute alcoholic hepatitis (AH) and matched controls greatly enhances our ability to conduct translational studies in humans to better understand its pathogenesis and to develop novel treatments, and (b) alcohol-induced impairment of signaling via bile salt receptors impairs gut integrity, permits activation of Kupffer cells, enhances oxidative stress in the liver, stimulates fatty liver, and sensitizes hepatocytes to cytokine-induced necroapoptosis, and that these abnormalities can be reversed with the FXR agonist, obeticholic acid (OCA). We will address these hypotheses by conducting the following patient- oriented studies. Specific Aim 1: To conduct a prospective multicenter observational study of patients with well-characterized AH and suitable controls that serves as the foundation for conducting novel mechanistic and therapeutic studies. A robust central bio-repository of serum/plasma, peripheral mononuclear cells, genomic DNA, urine, stool samples, and liver tissue (where available) will be developed from both cases and controls. Specific Aim 2: To test the hypothesis that alcohol-induced impairment of signaling via farnesoid X receptor (FXR, the bile salt nuclear receptor) interrupts normal bile salt homeostasis, and that this will be reversed with an FXR agonist, obeticholic acids (OCA). A secondary hypothesis is that altered FXR signaling impairs gut integrity, promotes activation of the innate immune response, enhances hepatic oxidative stress, and sensitizes hepatocytes to cytokine-induced necroapoptosis. . To address these hypotheses, we will conduct a study of bile salt metabolism and effects of OCA in heavy drinkers without liver disease (n=15), moderate drinkers (n=15), and non-drinkers (n=15). Specific Aim 3: To test the hypothesis that FXR agonists are effective in treating AH by correcting multiple abnormalities implicated in its pathogenesis. We will test this hypothesis by conducting a proof-of-concept multicenter, placebo-controlled randomized controlled trial of OCA in patients with moderately severe AH. Sixty adults with AH of moderate severity will be randomized to receive either obeticholic acid (10 mg once daily by mouth) or placebo for 4 weeks. Primary efficacy end point is change in MELD score at 4 weeks [5] and the primary safety end point is the incidence of serious adverse events (SAE) at 4 weeks. Specific aim 4: To participate in the two other proof-of-concept studies proposed by the other two members of the TREAT consortium.

描述（由申请人提供）：为了响应 RFA-AA-12-007，印第安纳大学 (IU)、梅奥诊所 (Mayo) 和弗吉尼亚联邦大学 (VCU) 成立了一个“转化研究和不断发展的酒精性肝炎治疗”(TREAT) 联盟。该应用的中心假设是：(a) 一大群患有明确特征的急性酒精性肝炎 (AH) 的患者和匹配的对照极大地增强了我们在人类中进行转化研究的能力，以更好地了解其发病机制并开发新的治疗方法，以及 (b) 酒精引起的胆汁盐受体信号传导损伤会损害肠道完整性，允许库普弗细胞激活，增强肠道中的氧化应激 FXR 激动剂奥贝胆酸 (OCA) 可以逆转这些异常。我们将通过进行以下以患者为导向的研究来解决这些假设。具体目标 1：对具有明确特征的 AH 患者和合适的对照进行前瞻性多中心观察研究，作为开展新机制和治疗研究的基础。血清/血浆、外周单核细胞、基因组 DNA、尿液、粪便样本和肝组织（如果有）的强大中央生物存储库将从病例和对照中开发出来。具体目标 2：检验以下假设：酒精引起的法尼醇 X 受体（FXR，胆汁盐核受体）信号传导受损会中断正常的胆汁盐稳态，而 FXR 激动剂奥贝胆酸 (OCA) 可以逆转这种情况。第二个假设是，改变的 FXR 信号传导会损害肠道完整性，促进先天免疫反应的激活，增强肝脏氧化应激，并使肝细胞对细胞因子诱导的坏死性凋亡敏感。 。为了解决这些假设，我们将在无肝病的重度饮酒者 (n=15)、中度饮酒者 (n=15) 和不饮酒者 (n=15) 中开展胆汁盐代谢和 OCA 影响的研究。具体目标 3：检验 FXR 激动剂通过纠正 AH 发病机制中涉及的多种异常而有效治疗 AH 的假设。我们将通过在中度严重 AH 患者中进行 OCA 多中心、安慰剂对照随机对照试验来验证这一假设。 60 名患有中度 AH 的成人将随机接受奥贝胆酸（10 毫克，每天口服一次）或安慰剂，为期 4 周。主要疗效终点是 4 周时 MELD 评分的变化 [5]，主要安全终点是 4 周时严重不良事件 (SAE) 的发生率。具体目标 4：参与 TREAT 联盟其他两名成员提出的另外两项概念验证研究。