A Prospective, Randomized, Multi-centered, Placebo-controlled Clinical Trial of Oral Vancomycin in Adults with Primary Sclerosing Cholangitis

口服万古霉素治疗成人原发性硬化性胆管炎的前瞻性、随机、多中心、安慰剂对照临床试验

• 批准号: 10255494
• 负责人: Elizabeth Carey
• 金额: $ 50万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10255494
• 关键词: Prospective; Randomized; Multi; centered; Placebo

PROJECT SUMMARY Primary sclerosing cholangitis (PSC) is an idiopathic disease of the liver characterized by ongoing inflammation of the intrahepatic- and/or extrahepatic bile ducts, which can ultimately lead to cirrhosis and end-stage liver disease (ESLD). It is often associated with inflammatory bowel disease (IBD), namely ulcerative colitis (UC). PSC patients have a reduced survival compared to the general healthy population, and many PSC patients will eventually require liver transplantation (LT) due to complications such as progression to ESLD, development of cholangiocarcinoma (CCA), a primary bile duct cancer that carries a grave prognosis, recurrent acute cholangitis (a serious biliary tree infection), or extreme symptoms related to liver disease (such as fatigue and pruritus). The diagnosis of PSC is made when there is cholestasis and imaging (narrowing and dilatation) or histological (destruction and fibrosis) evidence of PSC. Currently, there is no medical therapy proven to halt the progression of the disease. The cause of PSC is unknown; however, accumulating evidence suggests a link between PSC and the intestinal microbiota (the bacteria that live in the colon). Open-label clinical trials have shown that the use of oral vancomycin (OV) in PSC patients has resulted in normalization of the serum cholestatic marker alkaline phosphatase (ALP), which has been found to be of prognostic importance in PSC. Specifically, normalization of serum ALP appears to be associated with long-term survival free of CCA, the need for LT, or liver-related death in PSC, and persistently elevated ALP over time has been shown to be associated with serious adverse events (development of CCA, liver-related death, and need for LT). Findings from the clinical reports of OV in PSC have prompted us to examine the role of OV as a potential therapeutic agent in PSC in a larger sample of PSC subjects over an extended period. We hypothesize that in PSC patients, daily treatment with OV results in normalization of serum ALP. The results of this clinical trial will help us determine if OV can be used as treatment for PSC patients. The overall goal of this phase II, randomized, placebo-controlled clinical trial is to examine the safety, tolerability and efficacy of daily dosing (over an 18-month period) with OV, using a stepped-up dosing strategy with three increasing doses, on the clinical course, and the progression of PSC, and to compare the treated patients with those on placebo. Study subjects in the OV and placebo arms will be compared with respect to their clinical and laboratory evaluations at the defined study points.

项目摘要 原发性硬化性胆管炎（PSC）是一种特发性肝脏疾病，其特征在于持续的 肝内和/或肝外胆管的炎症，最终可导致肝硬化， 终末期肝脏疾病（ESLD）。它通常与炎症性肠病（IBD）有关，即 溃疡性结肠炎（UC）。与一般健康人群相比，PSC患者的存活率降低， 并且许多PSC患者由于并发症最终需要肝移植（LT）， 发展为ESLD，胆管癌（CCA）的发展，胆管癌是一种原发性胆管癌， 严重的预后，复发性急性胆管炎（严重的胆道系统感染），或极端症状相关 肝脏疾病（如疲劳和瘙痒）。PSC的诊断是在有胆汁淤积时作出的 以及PSC的成像（狭窄和扩张）或组织学（破坏和纤维化）证据。 目前，没有任何药物治疗被证明可以阻止疾病的进展。 PSC的原因尚不清楚;然而，越来越多的证据表明PSC与 肠道微生物群（生活在结肠中的细菌）。开放标签临床试验表明， PSC患者口服万古霉素（OV）导致血清胆汁淤积标志物正常化 碱性磷酸酶（ALP），已发现其在PSC中具有预后重要性。具体地说， 血清ALP正常化似乎与无CCA的长期生存相关， LT或PSC中的肝脏相关死亡以及ALP随时间持续升高已被证明是 与严重不良事件相关（CCA的发生、肝脏相关死亡和需要LT）。 来自PSC中OV的临床报告的发现促使我们检查OV作为潜在的 在更大的PSC受试者样本中，在延长的时间段内观察治疗剂在PSC中的作用。 我们假设在PSC患者中，每天用OV治疗导致血清ALP正常化。的 这项临床试验的结果将帮助我们确定OV是否可以用作PSC患者的治疗。 这项II期、随机、安慰剂对照临床试验的总体目标是检查安全性， 采用递增剂量，OV每日给药（18个月期间）的耐受性和疗效 三种剂量递增策略对PSC的临床病程和进展的影响，并比较 接受治疗的患者与接受安慰剂的患者进行比较。将比较OV组和安慰剂组的研究受试者 在规定的研究点进行临床和实验室评价。