Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN)

描述(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)是美国慢性肝病的最重要原因之一，每3个成年人中就有1个受到影响，每5个儿童中就有1个受到影响。NAFLD，尤其是NASH，与肝脏、心血管和癌症相关死亡率的增加有关。NASH临床研究网络(NASH CRN)成立于2002年，旨在开展与NASH的临床特征、危险因素、发病机制、自然病史以及儿童和成人治疗相关的研究。在上一个资助周期中，CRN已经招募了3021名患者(截至2013年9月)，参加了两项临床试验(Flint和CyNCH)和一个纵向NAFLD患者数据库。在CRN取得的进展的鼓舞下，NIDDK发布了RFA-DK-08-505，目标是将NASH CRN再延续5年。NASH CRN在下一个资助期的目标是：(A)圆满完成上一个资助期启动的3项全网研究。这些是成人和儿童NAFLD的观察性纵向队列研究(NAFLD数据库2研究，n=1874)，INT-747治疗NASH的随机双盲对照试验(Flint，n=283)，以及半胱胺治疗儿童NAFLD的随机对照试验(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。这些修改可能包括延长入选患者的随访时间，考虑在部分患者中进行后续肝活检，扩大到包括心血管和糖尿病相关结果，以及在没有非酒精性脂肪肝的情况下招募精心挑选的对照；(B)成功完成NASH CRN在当前资金期间批准和启动的大量辅助和试点/可行性研究；(C)对患有NASH的成人和儿童进行更多新颖的治疗研究，包括2a阶段机制验证试验和2b阶段临床试验。将建立更多的公私伙伴关系来进行这些试验；(D)根据NASH CRN以前供资期间收集的临床材料、成像/弹性测量和生物显微镜(300,000+)进行新的翻译研究。这些研究将利用与具有特定专业知识(如遗传学、脂质组学、代谢组学)的小组的合作，开发一个全面的NAFLD/NASH模型，该模型将能够识别处于风险中的成人和儿童，对肝脏和非肝脏的发病率和死亡率风险进行分层，并建立有效的NASH预防和治疗策略。这一庞大且高度个性化的队列，再加上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处于独特的地位。在满足这些需求方面，NASH CRN将对这一领域产生重大影响，并直接推动国家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.