Vertical Sleeve Gastrectomy for Treatment of NASH: a pilot randomized control

垂直袖状胃切除术治疗 NASH：试点随机对照

• 批准号: 10185737
• 负责人: Bilal Hameed
• 金额: $ 33.01万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-14 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10185737
• 关键词: Address; Adherence; Adverse effects; Adverse event; Agreement; Alternative Therapies; American; Bacteria; Benefits and Risks; Bile Acids; Biological; Biological Markers; Body Weight decreased; Body mass index; Cell Death; Chronic; Cirrhosis; Clinical; Clinical Trials; Clinical Trials Design; Control Groups; Controlled Study; Data; Development; Disease; Disease remission; Dissection; Ensure; Event; Fatty acid glycerol esters; Feasibility Studies; Fibrosis; Gastrectomy; Goals; Hepatic; Hepatocyte; Histologic; Histology; Individual; Infiltration; Inflammation; Intervention; Intestines; Lead; Learning; Link; Liver; Liver Fibrosis; Metabolic; Minnesota; Mission; Multicenter Trials; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Outcome; Participant; Pathogenesis; Pathologist; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pilot Projects; Placebos; Population; Population Heterogeneity; Positioning Attribute; Prediabetes syndrome; Prevalence; Primary carcinoma of the liver cells; Protocols documentation; Randomized; Randomized Controlled Trials; Research; Resolution; Ribosomal RNA; Risk; Risk Factors; Role; Safety; Sample Size; Sampling; Severities; Site; Standardization; Testing; Therapeutic; Therapeutic Effect; Uncontrolled Study; United States; Whole-Genome Shotgun Sequencing; arm; bariatric surgery; cardiovascular disorder risk; cell injury; cost; design; experience; feasibility trial; fecal microbiome; gut microbiome; improved; inflammatory marker; intervention program; lifestyle intervention; liver biopsy; liver transplantation; microbiome; mortality; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; personalized approach; pilot trial; potential biomarker; randomized trial; recruit; relative effectiveness; response; secondary endpoint; success; treatment effect; trial design; visit adherence

Abstract Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition that impacts 83 million Americans and is characterized by fat (steatosis) of the liver. Twenty-five percent of individuals with NAFLD also have associated liver cell inflammation and cell damage in a condition known as nonalcoholic steatohepatitis (NASH). Particularly in the presence of type 2 diabetes (T2DM), NASH leads to liver fibrosis, cirrhosis, the need for liver transplant, and an increase in mortality. There are no approved medications to treat NASH but its strong association with obesity supports prioritization of weight loss as therapy. Lifestyle interventions (LI) that produce weight loss, especially when close to 10% total body weight loss, can reduce the core components of NASH and fibrosis. There are significant challenges with adherence to LI programs outside of the research setting, highlighting the need for alternative therapies. The most common weight loss surgical procedure, the vertical sleeve gastrectomy (VSG), reliably achieves 20% total body weight loss. The VSG not only offers significant durable weight loss but also impacts the microbiome and metabolic regulators such as bile acids that can influence the progression of NASH. Single-site uncontrolled studies using the liver biopsy to evaluate NASH demonstrate improvement in both NASH and fibrosis. However, there is no level 1 evidence to recommend the use of bariatric surgery for NASH. Controlled studies are essential as significant NASH and fibrosis improvement have been observed in the placebo arms of pharmaceutical trials. From a definitive trial of VSG compared to LI, we will gain important information on the safety and medium-term effect on NASH and fibrosis improvements as well as longer term reduction in clinically meaningful events such as cirrhosis and mortality. We will also learn who will respond to the VSG and what biomarkers might be prioritized to predict VSG or LI outcomes to support personalized approaches for NASH therapy. At present, there is no therapy known to improve clinical outcomes in patients with T2DM and NASH. Before a trial of this nature can be initiated, we plan to initiate a 12 month pilot and feasibility randomized controlled trial (RCT) of VSG versus LI for treatment of NASH in patients with prediabetes or T2DM with 3 aims to (1) Determine the relative effectiveness of VSG on histologic improvements of the components NASH (steatosis, inflammation, cellular damage, and fibrosis) to inform sample size calculations for a definitive trial. (2) Demonstrate that we can recruit briskly, ensure protocol adherence, and retain participants who will undergo 12-month liver biopsies. (3) Demonstrate that we can reliably collect and analyze potential biomarker samples, prioritizing the microbiome, to predict and correlate with histologic outcomes. We leverage two sites with diverse populations in order to increase generalizability of our findings. This proposal of an explanatory therapeutic pilot RCT in response to PAS-20-160 will provide the information needed for a large-scale hypothesis-driven RCT of VSG for the definitive management of NASH and T2DM.

摘要 非酒精性脂肪肝（NAFLD）是一种慢性肝病，影响8300万美国人， 以肝脏脂肪（脂肪变性）为特征。25%的NAFLD患者也有相关的 在称为非酒精性脂肪性肝炎（NASH）的病症中的肝细胞炎症和细胞损伤。 特别是在存在2型糖尿病（T2 DM）的情况下，NASH导致肝纤维化、肝硬化，需要肝脏移植。 移植和死亡率的增加。目前还没有批准的药物治疗NASH，但其强大的 与肥胖症的关联支持将体重减轻作为治疗的优先次序。生活方式干预措施， 产生体重减轻，特别是当接近10%的总体重减轻，可以减少核心成分， NASH和纤维化。在研究之外坚持LI计划存在重大挑战 环境，强调替代疗法的必要性。最常见的减肥手术， 垂直袖状胃切除术（VSG），可靠地实现20%的总体重减轻。VSG不仅提供 显著持久的体重减轻，但也会影响微生物组和代谢调节剂，如胆汁酸 可以影响NASH的进展。使用肝活检评价的单中心非对照研究 NASH显示NASH和纤维化的改善。然而，没有一级证据表明， 建议使用减肥手术治疗NASH。对照研究是重要的NASH， 在药物试验的安慰剂组中已经观察到纤维化改善。从最终的审判中 与LI相比，我们将获得关于安全性和对NASH的中期影响的重要信息， 纤维化改善以及临床上有意义的事件（如肝硬化和 mortality.我们还将了解谁将对VSG作出反应，以及哪些生物标志物可能优先预测 VSG或LI结局支持NASH治疗的个性化方法。目前还没有治疗方法 已知可改善T2 DM和NASH患者的临床结局。在这种性质的审判之前 我们计划启动一项为期12个月的VSG与LI的试点和可行性随机对照试验（RCT） 用于治疗糖尿病前期或T2 DM患者的NASH，目的有3个：（1）确定与糖尿病前期或T2 DM相关的 VSG对NASH组分（脂肪变性、炎症、细胞浸润）的组织学改善的有效性 损伤和纤维化），以告知确定性试验的样本量计算。(2)证明我们能够 迅速招募，确保方案遵守，并保留将接受12个月肝活检的参与者。（三） 证明我们可以可靠地收集和分析潜在的生物标志物样本，优先考虑微生物组， 预测并与组织学结果相关联。我们利用两个不同人口的地点， 增加我们发现的普遍性。这一解释性治疗试点RCT的提议是为了应对 PAS-20-160将提供VSG大规模假设驱动RCT所需的信息， NASH和T2 DM的明确管理。