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

四硫代钼酸盐 (TM) 治疗原发性胆汁性肝硬化的 III 期试验

基本信息

批准号：
7603793
负责人：
GEORGE J BREWER
金额：
$ 1.56万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-01 至 2007-09-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7603793
关键词：
Adult Adverse effects Affect Anemia Angiogenesis Inhibitors Animals Antiinflammatory Effect Biological Biological Preservation Bleomycin Blinded Carbon Tetrachloride Ceruloplasmin Computer Retrieval of Information on Scientific Projects Database Computers Concanavalin A Copper Databases Disease Dose Double-Blind Method End Point Female Funding Grant Hepatolenticular Degeneration Human Informed Consent Institution Leukopenia Liver Liver diseases Lung Malignant Neoplasms Modeling Monitor Oral Patients Pharmaceutical Preparations Phase Placebos Primary biliary cirrhosis Randomized Records Research Research Personnel Resources Source Specimen Testing Toxic effect United States Food and Drug Administration United States National Institutes of Health Upper arm Ursodeoxycholic Acid Visit Writing day improved liver biopsy liver function mouse model outcome forecast research study stem tetrathiomolybdate tumor

项目摘要

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.'

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目及研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是对于中心来说，它不一定是研究者的机构。原发性胆汁性肝硬化 (PBC) 是一种严重的肝脏疾病，通常呈进展性，并且通常在 5-10 年内致命。 PBC 预后较差，通常影响成人，且多见于女性。目前只有一种治疗方法，熊二醇，可以提供一些改善，但通常只是部分改善。通常，尽管进行了熊二醇治疗，但疾病仍会进展。在已经接受熊二醇治疗的 PBC 患者中，我们建议测试一种新的实验性治疗（使用一种名为四硫代钼酸盐 (TM) 的研究药物）是否可以阻止 PBC 的进一步进展，并稳定或改善肝功能。除此类实验研究外，TM 尚未获得 FDA 批准用于人体。博莱霉素小鼠模型研究证明了四硫代钼酸盐 (TM) 疗法在肺部具有抗纤维化和抗炎作用。刀豆球蛋白 A 和四氯化碳小鼠模型研究证明了肝脏的抗纤维化和抗炎作用。 TM是一种针对威尔逊氏病开发的抗铜药物。 TM 还通过降低全身铜水平，在非威尔逊氏病癌症患者和动物肿瘤模型中产生抗血管生成作用。在 PBC 中进行 TM 试验的基本原理源于其在小鼠模型中的抗纤维化和抗炎作用。这项针对 PBC 的双盲试验将以四个月的间隔对患者进行为期两年的跟踪。患者已经在服用熊二醇，该药已在这种疾病中显示出一些益处。患者将被随机分到两组中的一组。一只手臂的患者将接受当前最好的治疗，包括熊二醇，加上 TM 安慰剂。第二组患者将接受当前最佳治疗，包括熊二醇和 TM 治疗。每次访视时都会进行肝功能和其他研究。将在基线和两年后进行肝脏活检。口服TM的剂量将逐渐调整，以将铜蓝蛋白（Cp）保持在5-15mg/天，即发挥功效且无毒性所需的水平。将酌情监测患者的 Cp 水平、贫血/白细胞减少症和其他副作用。 Brewer 博士和 Marrero 博士将被揭盲，以便他们可以进行 TM 治疗。 Askari 博士和 Conjeevaram 博士将担任盲法评估员。主要终点是肝功能的保存。研究记录将保存在受密码保护的数据库中。获得的生物样本的可链接信息将保存在该计算机中。书面文件将保存在上锁的研究办公室中。将使用书面知情同意书。