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）是一种进行性慢性胆汁淤积性肝病 病因不明的疾病，通常与慢性结肠炎相关。 PSC 是成人常见的肝脏疾病，通常会导致晚期肝脏疾病 疾病和肝功能衰竭，因此是肝病的重要指征 移植。不幸的是，目前尚无有效的药物治疗方法 对于 PSC。该研究小组拥有长期的临床跟踪记录 慢性胆汁淤积性肝病，特别是原发性硬化性肝病的试验 胆管炎。最近，我们从一项试点研究中获得了有希望的结果 使用高剂量熊去氧胆酸治疗 PSC。较低剂量 PSC 患者服用熊去氧胆酸可导致生化改善，但 不影响先前研究中的其他临床重要终点。我们的 试点数据得到了另一组以小规模显示的数据的支持， 随机试验表明高剂量熊去氧胆酸会导致生化， 与安慰剂相比，两年后组织学和胆管造影有所改善。 在本次提交中，我们提出了一项大规模多中心安慰剂对照研究 对 150 名患有此病的患者进行至少四年随访的随机试验 原发性硬化性胆管炎。该研究的主要终点将包括 组织学进展为肝硬化、食管或胃部病变 静脉曲张、肝移植的需要和生存。次要终点将 包括测量尿去氧胆酸（28-30 mg/kd/d）对 肝脏生化、组织学分期、胆管造影特征、Mayo 风险 分数和生活质量，使用经过验证的问卷。这项研究将 这是 PSC 有史以来规模最大的一次，后续行动也将是最广泛的。 这将为研究自然历史提供宝贵的资源。 这种疾病，作为这项研究的一部分，我们还将收集血清、细胞 从肝脏和结肠中提取 DNA、胆汁和组织作为资源 未来的研究。该试验的多中心性质将允许招募 参与本研究的患者来自不同的患者群体，具有代表性 该疾病的性别和种族分布。成功的机会 大量 PSC 患者群体促进了本研究的完成 参与中心目前管理并承认这些地点为 PSC 新患者转诊中心以及长期跟踪路线 胆汁淤积性肝病临床试验记录。

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, a common liver disease among adults, 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. The group of investigators has a longstanding track record of clinical trials in chronic cholestatic liver disease, particularly in primary sclerosing cholangitis. Recently we have generated promising results from a pilot study using high doses of ursodeoxycholic acid in the treatment of PSC. Lower doses of ursodeoxycholic acid in patients with PSC led to biochemical improvement but did not affect other clinically important endpoints in a previous study. Our pilot data is 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. In this submission, we propose a large-scale multi-center placebo-controlled randomized trial with a minimum follow-up of four years for 150 patients with primary sclerosing cholangitis. Primary endpoints of the study will include histologic progression to cirrhosis, development of esophageal or gastric varices, need for liver transplantation, and survival. Secondary endpoints will include measurements of the effects of urosodeoxycholic acid (28-30 mg/kd/d) on liver biochemistries, histologic stage, cholangiographic features, Mayo risk score, and quality of life, using validated questionnaires. This study will be the largest ever conducted in PSC and the follow-up will be the most extensive. This will provide an invaluable resource for studying the natural history of this disease and as part of this study we will also collect serum, cells for extraction of DNA, bile, and tissue from the liver and colon as a resource for future studies. The multi-centered nature of this trial will allow recruitment of patients into this study from a diverse patient population, representative of the gender and racial distribution of this disease. Chances of successful completion of this study are enhanced by the large PSC patient population that the participating centers currently manage, recognition of these sites as referral centers for new patients with PSC, as well as a longstanding track record in clinical trials in cholestatic liver disease.