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: 10474350
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10474350
• 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.

项目总结 原发性硬化性胆管炎(PSC)是一种特发性肝脏疾病，其特征是持续 肝内和/或肝外胆管发炎，最终可导致肝硬化和 终末期肝病(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， 许多PSC患者最终将需要肝移植(LT)，因为并发症包括 进展为ESLD，发展为胆管癌(CCA)，这是一种携带 严重的预后、反复发作的急性胆管炎(一种严重的胆道感染)或相关的极端症状 对肝病(如疲倦和瘙痒)。PSC的诊断是在胆汁淤积时做出的。 以及PSC的影像(狭窄和扩张)或组织学(破坏和纤维化)证据。 目前，还没有被证明可以阻止疾病发展的药物疗法。 PSC的原因尚不清楚；然而，越来越多的证据表明PSC与 肠道微生物区系(生活在结肠中的细菌)。开放标签临床试验已经表明，使用 口服万古霉素(OV)导致PSC患者血清胆汁淤积标志物正常化 碱性磷酸酶(ALP)已被发现对PSC的预后有重要意义。具体来说， 血清碱性磷酸酶正常化似乎与摆脱CCA的长期生存有关，需要 即PSC中与肝脏相关的死亡，随着时间的推移，持续升高的ALP已被证明是 与严重的不良事件相关(发生CCA、肝脏相关死亡和需要肝移植)。 PSC中OV临床报告的发现促使我们研究OV作为一种潜在的 在较大样本的PSC受试者中，治疗剂在较长时间内有效。 我们假设，在PSC患者中，OV的日常治疗会导致血清ALP正常化。这个 这项临床试验的结果将有助于我们确定OV是否可以用于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， 口服避孕药每日给药的耐受性和有效性(超过18个月)，使用递增剂量 策略采用三次递增剂量，对PSC的临床病程和进展情况进行比较 接受治疗的患者与服用安慰剂的患者相比。OV组和安慰剂组的研究对象将进行比较 关于他们在确定的研究点的临床和实验室评估。