Multicentered Randomized Trial of High-dose Urso in PSC

高剂量 Urso 治疗 PSC 的多中心随机试验

• 批准号: 7904229
• 负责人: Keith D Lindor
• 金额: $ 67.67万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904229
• 关键词: Affect; Alanine Transaminase; Albumins; Alkaline Phosphatase; Aspartate Transaminase; Bile fluid; Biochemical; Biochemistry; Cells; Cessation of life; Cholangiocarcinoma; Cholangitis; Chronic; Cirrhosis; Clinical; Clinical Data; Clinical Trials; Colitis; Colon; DNA; Data; Development; Disease; Documentation; Dose; Enrollment; Esophageal; Etiology; Evaluation; Future; Gastric Varices; Gender; Genetic Materials; Histologic; Liver; Liver Failure; Liver diseases; Measurement; Medical; Nature; Outcome; Patient Recruitments; Patients; Placebos; Prothrombin time assay; Quality of life; Questionnaires; Research Personnel; Resources; Risk; Serum; Staging; Testing; Time; Tissues; Toxic effect; Ursodeoxycholic Acid; Varicosity; disease natural history; experience; follow-up; improved; liver transplantation; meetings; patient population; placebo controlled study; primary sclerosing cholangitis; randomized placebo controlled trial; randomized trial; total measurement Bilirubin

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.

描述（由申请人提供）： 原发性硬化性胆管炎（PSC）是一种逐渐与慢性结肠炎相关的无知病因的进行性慢性胆汁淤积性肝病。 PSC通常会导致晚期肝病和肝衰竭，因此是肝移植的重要迹象。不幸的是，PSC目前尚无有效的医疗疗法。 PSC患者的乌尔沙克氧胆酸（UDCA）的剂量为13-15 mg/kg/d导致了生化改善，但在我们进行的先前研究中不影响其他临床上重要的终点。我们进行的另一项研究的试验数据表明，更高剂量的UDCA（28-30 mg/kg/d）可能不仅对肝脏测试产生更大的影响，而且可能会改善临床结果。在一项小型随机试验中，来自另一组的数据支持了这些数据，该试验与安慰剂相比，与安慰剂相比，高剂量的ursexyoxycholic酸导致了生化，组织学和胆管造影改善。我们已经成功完成了对PSC的高剂量ursodoxycholic酸（28-30 mg/kg/d）的安慰剂对照试验的入学率。在此提交中，我们建议完成大规模的多中心安慰剂对照的随机试验，对150例原发性硬化性胆管炎患者进行五年的最低随访。我们的研究人员在胆汁淤积性肝病中的临床试验经验方面有很长的记录，似乎非常适合完成这项重要的研究。该研究的主要终点将包括组织学向肝硬化，食管或胃静脉曲张的文献，胆管癌的发展，对肝移植的需求以及死亡。次要终点将包括测量Ursdeoxycholic酸的影响（28-30 mg/kg/d） 在肝脏生物学，组织学阶段，胆管造影特征，蛋黄酱风险评分和使用经过验证的问卷的生活质量上。这项研究将是PSC有史以来最大的一项研究之一，随访将是最广泛的。这项研究将为研究这种疾病的自然史提供宝贵的资源。作为这项研究的一部分，我们还将继续收集血清，从肝脏和结肠中提取DNA，胆汁和组织的细胞，作为未来研究的资源。该试验的多中心性质允许从多样化的患者人群中招募患者进入这项研究，这是该疾病的性别和种族分布的代表。这项研究的成功完成取决于在该试验中持续出色的受试者的出色保留率，这将通过胆汁淤积性肝病的临床试验中的长期记录来增强这一研究人员。