Multicentered Randomized Trial of High-dose Urso in PSC

描述（由申请人提供）： 原发性硬化性胆管炎（PSC）是一种病因不明的进行性慢性胆汁淤积性肝病，通常与慢性结肠炎相关。PSC通常导致晚期肝病和肝功能衰竭，因此是肝移植的重要指征。不幸的是，目前还没有有效的药物治疗PSC。在我们之前进行的一项研究中，在PSC患者中以13-15 mg/kg/d的剂量使用熊去氧胆酸（UDCA）导致生化改善，但不影响其他临床重要终点。我们进行的另一项研究的初步数据表明，更高剂量的UDCA（28-30 mg/kg/d）不仅可能对肝脏检查产生更大的影响，而且有望改善临床结局。这些数据得到了另一组数据的支持，该数据显示，在一项小型随机试验中，与安慰剂相比，高剂量熊去氧胆酸在两年时导致生化、组织学和胆管造影改善。我们已成功完成这项安慰剂对照试验的入组，该试验采用高剂量熊去氧胆酸（28-30 mg/kg/d）治疗PSC。在本次提交中，我们计划完成一项大型多中心安慰剂对照随机试验，对150例原发性硬化性胆管炎患者进行至少5年的随访。我们的研究小组在胆汁淤积性肝脏疾病的临床试验方面拥有长期的经验记录，似乎非常适合完成这项重要的研究。研究的主要终点包括肝硬化的组织学进展、食管或胃静脉曲张的记录、胆管癌的发展、肝移植的需要和死亡。次要终点将包括熊去氧胆酸（28-30 mg/kg/d）作用的测量值 采用经验证的调查问卷，对肝脏生化、组织学分期、胆管造影特征、马约风险评分和生活质量进行评估。这项研究将是有史以来在PSC中进行的最大规模的研究之一，后续行动也将是最广泛的。这项研究将为研究这种疾病的自然史提供宝贵的资源。作为本研究的一部分，我们还将继续收集血清、用于提取DNA的细胞、胆汁以及来自肝脏和结肠的组织，作为未来研究的资源。本试验的多中心性质允许从代表该疾病性别和种族分布的不同患者人群中招募患者进入本研究。本研究的成功完成取决于入组受试者在本试验中的持续良好保留，这将通过该组研究者在胆汁淤积性肝病临床试验中建立的长期跟踪记录得到加强。

DESCRIPTION (provided by applicant): Primary sclerosing cholangitis (PSC) is a progressive chronic cholestatic liver disease of unknown etiology that is commonly associated with chronic colitis. PSC usually leads to advanced liver disease and liver failure, and as such, is an important indication for liver transplantation. Unfortunately, no effective medical therapy currently exists for PSC. Ursodeoxycholic acid (UDCA) used at a dose of 13-15 mg/kg/d in patients with PSC led to biochemical improvement but did not affect other clinically important endpoints in a previous study that we performed. Pilot data from another study we performed suggested that higher doses of UDCA (28-30 mg/kg/d) may have not only more effect on liver tests but may be expected to improve clinical outcome. These data were supported by data from another group showing in a small, randomized trial that high-dose ursodeoxycholic acid led to biochemical, histologic, and cholangiographic improvement compared to placebo at two years. We have successfully completed enrollment into this placebo-controlled trial of high-dose ursodeoxycholic acid (28-30 mg/kg/d) for PSC. In this submission, we propose to complete the large-scale multi-center placebo-controlled randomized trial with a minimum follow-up of five years for 150 patients with primary sclerosing cholangitis. Our group of investigators has a long track record of experience with clinical trials in cholestatic liver disease and seems ideally suited to complete this important study. Primary endpoints of the study will include histologic progression to cirrhosis, documentation of esophageal or gastric varices, development of cholangiocarcinoma, need for liver transplantation, and death. Secondary endpoints will include measurements of the effects of ursodeoxycholic acid (28-30 mg/kg/d) on liver biochemistries, histologic stage, cholangiographic features, Mayo risk score, and quality of life using validated questionnaires. This study will be among the largest ever conducted in PSC, and the follow-up will be the most extensive. This study will provide an invaluable resource for studying the natural history of this disease. As part of this study we will also continue to collect serum, cells for extraction of DNA, bile, and tissue from the liver and colon as a resource for future studies. The multicentered nature of this trial allowed recruitment of patients into this study from a diverse patient population, representative of the gender and racial distribution of this disease. Successful completion of this study is dependent on the continued excellent retention of the enrolled subjects in this trial which will be enhanced by the longstanding track record in clinical trials in cholestatic liver disease established bv this group of investigators.