Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN)

描述（由申请人提供）：非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）是美国慢性肝病最重要的原因之一，每3名成人中就有1名受影响，每5名儿童中就有1名受影响。NAFLD，特别是NASH，与肝脏，心血管和癌症相关死亡率增加有关。NASH临床研究网络（NASH CRN）成立于2002年，旨在开展与儿童和成人的临床特征，风险因素，发病机制，自然史和治疗相关的研究。在上一个资助周期中，CRN已经招募了3，021名患者（截至2013年9月）进入两项临床试验（FLINT和CyNCh）和纵向NAFLD患者数据库的组合。在CRN取得的进展的鼓舞下，NIDDK发布了RFA-DK-08-505，目的是将NASH CRN再延长5年。NASH CRN在下一个资助期内的目标是：（a）成功完成上一个资助期内启动的3项全网络研究。这是一项成人和儿童NAFLD观察性纵向队列研究（NAFLD数据库2研究，n= 1，874）、一项INT-747治疗NASH的随机双盲对照治疗试验（FLINT，n=283）和一项半胱胺治疗儿童NAFLD的随机对照治疗试验（CYNCH，n=160）。NAFLD数据库可能会进行修改，以满足下一个供资期间的其他成果目标。这些修改可包括延长入选者的随访时间，考虑在患者亚组中进行随访肝活检，扩展以包括心血管和糖尿病相关结局，以及入选精心选择的无NAFLD的对照;（B）在当前资助期间成功完成NASH CRN批准和启动的大量辅助和先导/可行性研究;（c）在患有NASH的成人和儿童中进行额外的新型治疗研究，包括2a期机制验证试验和2b期临床试验。将建立额外的公私合作伙伴关系来进行这些试验;（d）根据NASH CRN先前资助期间收集的临床材料，成像/弹性测量和生物标本（300，000+）进行新的转化研究。这些研究将利用与具有特定专业知识（例如遗传学，脂质组学，代谢组学）的团体的合作，开发NAFLD/NASH的综合模型，该模型将允许识别处于风险中的成人和儿童，对肝脏和非肝脏发病率和死亡率的风险进行分层，并建立针对NASH的有效预防和治疗策略。这个庞大且高度特征化的队列，加上NASH CRN在利用公私合作伙伴关系进行创新治疗试验方面的专业知识，在满足这些重要的临床需求方面具有独特的优势。在满足这些需求的过程中，NASH CRN将对该领域产生重大影响，并直接推进美国国立卫生研究院改善公众健康的使命。

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) ranks as one of the most important causes of chronic liver disease in the United States, with 1 of every 3 adults and 1 of every 5 children affected. NAFLD, especially NASH, is associated with increased liver, cardiovascular and cancer-related mortality. The NASH Clinical Research Network (NASH CRN) was established in 2002 to conduct research related to its clinical features, risk factors, pathogenesis, natural history and treatmen in children and adults. Over the last funding cycle, the CRN has enrolled 3,021 patients (as of September, 2013) into a combination of two clinical trials (FLINT and CyNCh) and a longitudinal NAFLD patient database. Encouraged by the advances made by the CRN, the NIDDK has issued RFA-DK-08-505 with the objectives of continue the NASH CRN for an additional 5 years. The objectives of the NASH CRN during this next funding period are: (a) to successfully complete the 3 network-wide studies initiated during the last funding period. These are an observational longitudinal cohort study of NAFLD in adults and children (NAFLD Database 2 study, n=1,874), a randomized double blind controlled therapeutic trial of INT-747 for NASH (FLINT, n=283) and a randomized controlled therapeutic trial of cysteamine for NAFLD in children (CYNCH, n=160). The NAFLD database may be amended to meet additional outcome goals during the next funding period. These modifications may include extending the length of follow-up of those enrolled, consideration of a follow-up liver biopsy in a subset of patients, expansion to include cardiovascular and diabetes-related outcomes, and enrollment of carefully selected controls without NAFLD; (b) to successfully complete a large number of ancillary and pilot/feasibility studies that were approved and initiated by the NASH CRN during the current funding; (c) to conduct additional novel therapeutic studies in adults and children with NASH, including phase 2a proof of mechanism trials and phase 2b clinical trials. Additional public-private partnerships will be established to perform these trials; (d) to conduct new translational studies based on the clinical material, imaging/elastometry and biospecimens (300,000+) collected during previous funding periods of the NASH CRN. These studies will leverage collaborations with groups with specific expertise (e.g. genetics, lipidomics, metabolomics) to develop a comprehensive model of NAFLD/NASH which will allow identification of adults and children at risk, stratification of risk of liver and non-liver morbidity and mortality, and establishment of effective preventive and treatment strategies against NASH. This large and highly characterized cohort, together with the NASH CRN expertise in leveraging public-private partnerships to perform innovative therapeutic trials, is uniquely positioned to address these important clinical needs. In meeting those needs, the NASH CRN will have a major impact on the field and directly advance the mission of the National Institutes of Health to improve the health of the public.