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: 10631958
• 负责人: Bilal Hameed
• 金额: $ 30.69万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631958
• 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; Recommendation; 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; participant retention; personalized approach; pilot trial; potential biomarker; randomized trial; recruit; relative effectiveness; response; secondary endpoint; simple steatosis; success; treatment effect; trial design; visit adherence; 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; Recommendation; 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; participant retention; personalized approach; pilot trial; potential biomarker; randomized trial; recruit; relative effectiveness; response; secondary endpoint; simple steatosis; 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.

抽象的 非酒精性脂肪肝病（NAFLD）是一种慢性肝病，影响了8300万美国人，并且是 以肝脏的脂肪（脂肪变性）为特征。 25％的NAFLD个人也有关联 肝细胞炎症和细胞损伤，称为非酒精性脂肪性肝炎（NASH）。 特别是在存在2型糖尿病（T2DM）的情况下，NASH导致肝纤维化，肝硬化，需要肝脏 移植和死亡率增加。没有批准的药物可以治疗纳什，但它很强 与肥胖相关联支持减肥作为治疗的优先级。生活方式干预（li） 减肥，尤其是当近10％的总体重减轻时，可以减少 纳什和纤维化。在研究之外遵守LI计划存在重大挑战 设置，突出了对替代疗法的需求。最常见的减肥手术程序， 垂直套筒胃切除术（VSG）可靠地达到20％的总体重减轻。 VSG不仅提供 大量耐用的体重减轻，但也影响微生物组和代谢调节剂，例如胆汁酸 这会影响纳什的进展。使用肝活检评估的单位点不受控制的研究 NASH表现出NASH和纤维化的改善。但是，没有1级证据 建议将减肥手术用于NASH。对照研究至关重要，因为纳什和 在药物试验的安慰剂组中，已经观察到了纤维化的改善。从确定的审判中 VSG与LI相比，我们将获得有关纳什和中期影响的重要信息 纤维化的改善以及临床上有意义的事件（例如肝硬化和）的长期减少 死亡。我们还将学习谁将对VSG做出回应，以及可以优先考虑哪些生物标志物以预测 VSG或LI结果支持NASH治疗的个性化方法。目前，没有治疗 已知可以改善T2DM和NASH患者的临床结果。在对这种性质进行试验之前 启动时，我们计划启动12个月的飞行员和可行性随机对照试验（RCT）VSG与Li 用于治疗糖尿病前期或T2DM患者的NASH，目的是（1）确定相对 VSG对组件纳什组件组织学改善的有效性（脂肪变性，炎症，细胞 损坏和纤维化）为确定试验的样本计算提供了信息。 （2）证明我们可以 轻快地招募，确保协议依从性，并保留将进行12个月肝活检的参与者。 （3） 证明我们可以可靠地收集和分析潜在的生物标志物样品，优先考虑微生物组， 预测并与组织学结果相关。我们利用两个人口不同的网站来 提高我们发现的普遍性。这项关于解释性治疗试验RCT的建议 PAS-20-160将为大规模假设驱动的VSG的RCT提供所需的信息 NASH和T2DM的权威管理。