Non Alcoholic Steatohepatitis Clinical Research Network

摘要 本申请是克利夫兰诊所临床站点及其子站点的延续 脂肪性肝炎临床研究网络(NASH CRN)。非酒精性脂肪性肝病(NAFLD)影响近 在北美有三分之一的成年人和五分之一的儿童，这是美国的一个主要公共卫生问题。 非酒精性脂肪肝和更严重的非酒精性脂肪性肝炎(NASH)会导致肝硬变和原发性肝 癌症，以及与肝脏、心血管和癌症相关的发病率和死亡率，导致大幅增加 在医疗负担和成本方面。纳什CRN的定位是理想和独特的，可以影响持续的 NASH的公共卫生负担只能通过这个大型研究联盟与 证明了在前几个周期中取得成功的记录。NASH CRN的主要目标是执行 成人和儿童NASH和NAFLD的高质量、可重复性临床研究 这将为更好地认识自然历史和发展手段提供基础 诊断、治疗和临床管理。在NASH CRN的这一筹资周期中，成人和儿童 在前一个供资周期启动的治疗试验将完成，新的治疗试验， 包括阶段2a的机制证明和阶段2b的临床试验将启动，以发展循证的 安全、有效、廉价的治疗方案。具体地说，我们建议改变维生素D3的用途 (胆钙化醇)作为NASH的治疗方法，建议进行一项全网络研究，比较每天5000国际单位与1000国际单位 已经24个月了。成人和儿童NAFLD的纵向队列将扩大，这将 前瞻性地定义疾病的自然病史、心血管和代谢危险因素，并将有助于 在生物标记物的发现和验证以及非侵入性技术的开发和验证方面 评估和识别NASH/NAFLD患者、干预反应人员并确定患病率 进步。我们将把正在接受评估和接受减肥手术的患者纳入这一队列。最后， 我们将使用反向翻译方法来开发新的生物标记物并确定潜在的治疗方法 纳什的目标。具体地说，我们将评估一种新的高密度胆固醇功能分析方法和一种 使用前几个资金周期的生物库样本和资源进行NAFLD的microRNA签名 以补充目前的研究以达到这一目的。克利夫兰工厂在临床和医疗服务方面发挥了关键作用。 自NASH CRN成立以来，翻译研究取得了成功。我们一直是全球领先的招生网站 成人的Pivens和Flint试验以及儿童的Quiton和Cynch试验。克利夫兰现场调查员 在提高对系统性异常的理解方面具有独特的地位，包括心血管和 非酒精性脂肪肝的代谢紊乱。考虑到我们网站和数据的高招聘、高保留和高质量 我们继续致力于合作的成功，Nash CRN准备继续其主要 对实地产生影响，推进美国国立卫生研究院改善公众健康的使命。

ABSTRACT This application is for the continuation of the Cleveland Clinic clinical site and its subsites of the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Nonalcoholic fatty liver disease (NAFLD) affects nearly a third of adults and a fifth of children in North America and is a major public health issue in the United States. NAFLD, and the more severe form, nonalcoholic steatohepatitis (NASH), lead to cirrhosis and primary liver cancer, as well as liver-, cardiovascular-, and cancer-related morbidity and mortality, resulting in major increases in health care burdens and costs. The NASH CRN is ideally and uniquely positioned to impact the continuing public health burden of NASH that can only be addressed through this large research consortium with a demonstrated track record of success in previous cycles. The primary objective of the NASH CRN is to perform high quality, reproducible clinical research on NASH and NAFLD in adults and children focusing on the pathogenesis that will provide the basis for understanding the natural history and developing means of better diagnosis, treatment, and clinical management. In this funding cycle of the NASH CRN, the adult and pediatric therapeutic trials initiated during the previous funding cycle will be completed, and new therapeutic trials, including phase 2a proof of mechanism and phase 2b clinical trials will be initiated to develop evidence-based treatment options that are safe, effective, and inexpensive. Specifically, we propose to repurpose vitamin D3 (cholecalciferol) as a treatment for NASH by proposing a network wide study comparing 5000 IU to 1000 IU daily for 24 months. The longitudinal cohort of adults and children with NAFLD will be extended, which will prospectively define the natural history of the disease, the cardiovascular and metabolic risk factors, and will aid in biomarker discovery and validation, and the development and validation of non-invasive techniques to evaluate and identify patients with NASH/NAFLD, responders to interventions and determine the rate of disease progression. We will include patients being evaluated for and undergoing bariatric surgery to this cohort. Finally, we will use a reverse translational approach to develop novel biomarkers and identify potential therapeutic targets in NASH. Specifically, we will evaluate a novel functional assay for high density cholesterol and a microRNA signature for NAFLD using the biorepository samples and resources from the previous funding cycles to complement the current studies for this aim. The Cleveland site has played a key role in both the clinical and translational research success of the NASH CRN since its inception. We have been a leading enrolling site in the PIVENS and FLINT trials in adults and TONIC and CynCh trials in children. The Cleveland site investigators are uniquely placed in improving the understanding of systemic abnormalities including cardiovascular and metabolic perturbations in NAFLD. Given the high recruitment, retention and quality of data from our site and our continued commitment to the success of the collaboration, the NASH CRN is poised to continue its major impact on the field and advance the mission of the NIH to improve the health of the public.