PHASE III TRIAL OF TETRATHIOMOLYBDATE (TM) IN PRIMARY BILIARY CIRRHOSIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 原发性胆汁性肝硬变(PBC)是一种严重的肝脏疾病，通常是进行性的，通常在5-10年内致命。PBC预后较差，通常影响成人，在女性中更常见。目前只有一种治疗方法--乌索地尔能有所改善，而且通常只是部分改善。通常情况下，尽管接受乌索地尔治疗，疾病仍会继续发展。在已经接受乌索地尔治疗的PBC患者中，我们建议测试一种新的实验性治疗方法，即一种名为四硫钼酸(TM)的研究药物，是否可以阻止PBC的进一步发展，并稳定或改善肝功能。除了像这样的实验研究外，TM还没有被FDA批准用于人类。博莱霉素小鼠模型研究证实了四硫钼酸盐(TM)治疗肺部的抗纤维化和抗炎作用。刀豆蛋白A和四氯化碳的小鼠模型研究表明，在肝脏有抗纤维化和抗炎作用。TM是一种针对威尔逊病开发的抗铜药物。TM还通过降低全身铜水平，在患有癌症的非威尔逊病患者以及动物肿瘤模型中产生抗血管生成作用。TM在PBC中试验的理论基础来自于它在小鼠模型中的抗纤维化和抗炎作用。这项在PBC进行的双盲试验将对患者进行为期两年的跟踪试验，每隔四个月一次。患者将已经在服用乌索地尔，它已经显示出对这种疾病的一些好处。患者将被随机分配到两组中的一组。在一只手臂上，患者将接受目前最好的治疗，包括乌索地尔，外加TM安慰剂。在第二个手臂中，患者将接受最好的当前疗法，包括乌索地尔，加上TM疗法。每次就诊时，将进行肝功能和其他研究。肝活检将在基线和两年后进行。口服TM的剂量将被滴定以保持铜蓝蛋白(CP)在5-15毫克/天，这是无毒性疗效所需的水平。将适当监测患者的CP水平、贫血/白细胞减少症和其他副作用。布鲁尔医生和马雷罗医生将不会失明，这样他们就可以进行TM治疗。Askari博士和Conjeevaram博士将是盲目的评估者。主要终点是保存肝功能。研究记录将保存在一个受密码保护的数据库中。获得的生物标本的可链接信息将保存在这台计算机中。书面文件将保存在上了锁的自习室里。将使用书面知情同意。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Primary biliary cirrhosis (PBC) is a serious disease of the liver that is usually progressive, and often fatal within 5-10 years. PBC has a poor prognosis, usually affects adults, and is more common in females. Currently only one treatment, ursodiol, offers some improvement, and that is usually only partial. Usually the disease progresses in spite of ursodiol therapy. In PBC patients already on ursodiol therapy, we propose to test whether a new experimental treatment, with a study drug called tetrathiomolybdate (TM), can halt further progression of PBC, and stabilize or improve liver function. TM is not yet approved by the FDA for use in humans, except for experimental studies such as this. Bleomycin mouse model studies demonstrated an antifibrotic and antiinflammatory effect of tetrathiomolybdate (TM) therapy in the lung. Concanavalin A and carbon tetrachloride mouse model studies demonstrate antifibrotic and antiinflammatory effects in the liver. TM is an anticopper drug developed for Wilson's disease. TM also produces an antiangiogenic effect in non-Wilson's disease patients with cancer, and in animal tumor models, by lowering systemic copper levels. The rationale for a trial of TM in PBC stems from its antifibrotic, and antiinflammatory effects in mouse models. This double blind trial in PBC will follow patients for two years at four-month intervals. Patients will already be on ursodiol, which has shown some benefit in this disease. Patients will be randomized to one of two arms. In one arm patients will receive best current therapy, including ursodiol, plus a TM placebo. In the second arm patients will receive best current therapy, including ursodiol, plus TM therapy. At each visit liver function and other studies will be performed. Liver biopsies will be performed at baseline and at two years. The dose of oral TM will be titrated to keep ceruloplasmin (Cp) at 5-15mg/day, the level required for efficacy without toxicity. Patients will be monitored as appropriate for Cp levels, anemia/leukopenia, and other side effects. Dr. Brewer and Dr. Marrero will be unblinded so they he can manage TM therapy. Dr. Askari and Dr. Conjeevaram will be blinded evaluators. The primary endpoint is preservation of liver function. Research records will be kept in a password protected database. Linkable information for biological specimens obtained will be kept in this computer. Written documents will be kept in a locked study office. Written informed consent will be utilized.'