Cholestasis Reversal (Phase ll): Efficacy of lV Fish Oil

描述(由申请人提供)： 肠外营养(PN)溶液是外科胃肠道疾病患者的救命良方。然而，在儿童人群中使用PN，特别是早产儿，经常与肝脏损伤有关，这种损伤最终可能导致肝功能衰竭，从而导致移植和/或死亡。研究表明，含有静脉脂肪乳剂(IFE)的大豆油可能是一个主要的致病因素。最近的经验表明，停止使用大豆为基础的IFE，改用从鱼油中提取的omega-3脂肪酸组成的产品(Omeaven)，可能通过一系列因素，包括改善甘油三酯清除和抗炎特性，有效地逆转先前存在的PN相关性肝病。2002年，美国国家糖尿病、消化和肾脏疾病研究所(NIDDK)表示，美国有2万人因肠道衰竭而接受PN支持，其中约30%-60%的儿童在接受长期PN治疗后出现肝功能障碍。该项目计划在3年内研究30名因使用PN而既往存在肝病的儿科患者。主要目的是评估鱼油脂肪乳剂逆转由于使用PN引起的胆汁淤积的效果。使用开放标签研究设计，PN胆汁淤积症患者将停用传统的大豆油脂乳剂，并接受以鱼油为基础的IFE治疗。用鱼油治疗的受试者的胆汁淤积逆转时间将与60名相似的受试者(当代历史对照)进行比较，这些受试者在发生胆汁淤积后继续接受基于大豆的IFE。其他肝脏、生长和安全性结果也将得到评估。根据初步结果，很难对这些患者进行前瞻性随机试验。尽管这项拟议的研究不是随机试验，但人们认为可以产生足够的证据，导致FDA批准Omeaven等LFE。

DESCRIPTION (provided by applicant): Parenteral nutrition (PN) solutions are life saving in patients with surgical gastrointestinal diseases. However, the use of PN in pediatric populations, especially premature infants, is frequently associated with liver injury that may ultimately result in liver failure that can lead to transplantation and/or death. Studies suggest that soybean oil containing intravenous fat emulsions (IFE) may be a major contributing factor. Recent experience suggests that discontinuing soybean based IFE and switching to a product comprised of omega-3 fatty acids derived from fish oils (Omegaven) may be effective in reversing preexisting PN associated liver disease through a combination of factors, including improved triglyceride clearance coupled with anti-inflammatory properties. In 2002, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) stated that 20,000 individuals in the US were supported by PN for intestinal failure and of these, approximately 30-60% of children develop hepatic dysfunction after receiving prolonged courses of PN. This project plans to study 30 such pediatric patients over a 3 year period with preexisting liver disease due to PN use. The primary aim is to assess the efficacy of the fish oil fat emulsion in reversing cholestasis due to PN use. Using an open label study design, patients with PN cholestasis will have the conventional soybean oil lipid emulsion stopped and be treated with the fish oil based IFE. Time to reversal of cholestasis of subjects treated with the fish oil will be compared to 60 similar subjects (contemporary historical controls) who continued to receive soybean based IFE after developing cholestasis. Other hepatic, growth, and safety outcomes will be also assessed. Based on preliminary results, it would be difficult to perform a prospective randomized trial with these patients. Although the proposed study is not a randomized trial, it is thought that sufficient evidence could be generated that would result in FDA approval of an lFE such as Omegaven.