Department of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States.
Department of Hepatology/Gastroenterology, Charité University Medical Center, Berlin, Germany.
J Hepatol. 2019 Oct;71(4):823-833. doi: 10.1016/j.jhep.2019.04.019. Epub 2019 Jul 9.
Non-alcoholic fatty liver disease (NAFLD) is a global public health concern. Its natural history, the development of non-alcoholic steatohepatitis (NASH) and fibrosis, is highly variable, prone to endogenous (e.g., genetics, microbiota) and exogenous (e.g., nutrition, alcohol, physical activity) disease modifiers, and can fluctuate over time. The complexity of its pathophysiology is reflected by the multitude of pharmacological targets in development. NASH clinical trials have provided valuable insight that is applicable to future trial design. Endpoints for NASH have evolved over the past decade and will continue to be refined. Currently accepted endpoints for conditional approval include resolution of NASH without worsening of fibrosis and/or improvement in fibrosis without worsening of NASH by standardized evaluation of paired liver histology. In pediatric NASH, practical obstacles, pubertal hormonal changes, and stringent safety requirements mandate adaptations in trial design. In adult patients with NASH-related cirrhosis, decrease in portal pressure as well as clinical events (e.g. decompensation, hepatocellular carcinoma, transplantation, death) are more prevalent and thereby are viable primary endpoints for clinical trials. Consideration of the natural fluctuation of disease, the clinical implication of the chosen primary endpoint, and factors that may affect placebo response will facilitate an accurate determination of efficacy of emerging therapeutics for NASH. Conclusion: The June 2018 American Association for the Study of Liver Diseases and European Association for the Study of the Liver joint workshop on NAFLD endpoints summarized important findings from ongoing and completed trials, defined the scientific evidence supporting distinct endpoints, and provided guidance for future trial design.
非酒精性脂肪性肝病（NAFLD）是一个全球性的公共卫生关注点。其自然病史，即非酒精性脂肪性肝炎（NASH）和纤维化的发展，具有高度的可变性，容易受到内源性（如遗传、微生物组）和外源性（如营养、酒精、体力活动）疾病修饰因素的影响，并且可能随时间而波动。其病理生理学的复杂性反映在众多正在开发的药理学靶点上。NASH 的临床试验提供了宝贵的见解，这些见解适用于未来的试验设计。过去十年中，NASH 的终点已经发展，并且将继续得到完善。目前，NASH 的有条件批准的终点包括在不加重纤维化的情况下缓解 NASH，和/或在不加重 NASH 的情况下改善纤维化，这是通过对肝组织学进行标准化评估来实现的。在儿科 NASH 中，实际障碍、青春期激素变化和严格的安全性要求需要对试验设计进行调整。在患有 NASH 相关肝硬化的成年患者中，门静脉压力下降以及临床事件（如失代偿、肝细胞癌、移植、死亡）更为常见，因此它们是临床试验的可行主要终点。考虑到疾病的自然波动、所选主要终点的临床意义以及可能影响安慰剂反应的因素，将有助于准确确定新兴 NASH 治疗方法的疗效。结论：2018 年 6 月美国肝病研究协会和欧洲肝病研究协会联合工作组就 NAFLD 终点问题进行了讨论，总结了正在进行和已完成试验的重要发现，确定了支持不同终点的科学证据，并为未来的试验设计提供了指导。
