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

描述(由申请人提供)：作为对RFA-AA-12-007的响应，印第安纳大学(IU)、梅奥诊所(Mayo)和弗吉尼亚联邦大学(VCU)组成了一个联盟“转化研究和进化酒精性肝炎治疗”(Treat)。这一应用的中心假设是：(A)一大群具有良好特征的急性酒精性肝炎(AH)患者和匹配的对照组极大地增强了我们在人类身上进行翻译研究以更好地了解其发病机制和开发新疗法的能力，以及(B)酒精通过胆盐受体诱导的信号障碍损害肠道完整性，允许激活Kupffer细胞，增强肝脏的氧化应激，刺激脂肪肝，并使肝细胞对细胞因子诱导的坏死凋亡敏感，并且这些异常可被FXR激动剂乙酰胆酸(OCA)逆转。我们将通过以下以患者为中心的研究来解决这些假设。具体目标1：对具有良好特征和合适对照的急性肝炎患者进行前瞻性多中心观察研究，作为进行新的机制和治疗研究的基础。一个强大的血清/血浆、外周血单核细胞、基因组DNA、尿液、粪便样本和肝组织(如果有)的中央生物库将从病例和对照中发展出来。具体目的2：验证酒精通过法尼醇X受体(FXR，胆盐核受体)诱导的信号损伤干扰正常胆盐稳态的假设，并用FXR激动剂乙酰胆酸(OCA)逆转这一假说。第二种假设是，FXR信号改变损害肠道完整性，促进天然免疫反应的激活，增强肝脏氧化应激，并使肝细胞对细胞因子诱导的坏死凋亡敏感。。为了解决这些假设，我们将对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)的胆盐代谢和OCA的影响进行研究。具体目标3：验证FXR激动剂通过纠正与其发病机制有关的多种异常而有效治疗AH的假说。我们将通过一项概念验证、多中心、安慰剂对照的OCA随机对照试验来验证这一假设。60名患有中度严重急性肝炎的成年人将被随机分为两组，分别接受奥替胆酸(每天10毫克，口服)或安慰剂治疗，疗程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4：参加Treat联盟其他两名成员提出的另外两项概念验证研究。

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.