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.

抽象的 非酒精性脂肪性肝病 (NAFLD) 是一种影响 8300 万美国人的慢性肝脏疾病， 其特征是肝脏脂肪变性（脂肪变性）。 25% 的 NAFLD 患者也与 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 会导致肝纤维化、肝硬化，需要肝脏 移植，死亡率增加。目前尚无批准治疗 NASH 的药物，但其疗效显着 与肥胖的关联支持优先考虑减肥作为治疗。生活方式干预 (LI) 产生体重减轻，特别是当体重减轻接近10%时，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 背景，强调替代疗法的必要性。最常见的减肥手术是 垂直袖状胃切除术 (VSG) 可靠地实现了 20% 的总体体重减轻。 VSG 不仅提供 显着持久的减肥效果，但也会影响微生物组和代谢调节剂，例如胆汁酸 可能会影响 NASH 的进展。使用肝活检进行评估的单中心非对照研究 NASH 表现出 NASH 和纤维化的改善。然而，没有1级证据表明 建议采用减肥手术治疗 NASH。对照研究至关重要，因为 NASH 和 在药物试验的安慰剂组中观察到纤维化的改善。来自最终的试验 与 LI 相比，VSG 的安全性和对 NASH 的中期影响的重要信息 纤维化改善以及长期减少有临床意义的事件，例如肝硬化和 死亡。我们还将了解谁将对 VSG 做出反应以及哪些生物标志物可能会优先预测 VSG 或 LI 结果支持 NASH 治疗的个性化方法。目前尚无治疗方法 已知可改善 T2DM 和 NASH 患者的临床结果。在进行这种性质的审判之前 启动后，我们计划启动一项为期 12 个月的 VSG 与 LI 对比试验和可行性随机对照试验 (RCT) 用于治疗糖尿病前期或 T2DM 患者的 NASH，其 3 个目标是 (1) 确定相对 VSG 对 NASH 组成部分（脂肪变性、炎症、细胞 损伤和纤维化）为最终试验提供样本量计算信息。 (2) 证明我们可以 迅速招募、确保遵守方案并保留将接受 12 个月肝脏活检的参与者。 (3) 证明我们可以可靠地收集和分析潜在的生物标志物样本，优先考虑微生物组， 预测组织学结果并与之相关。我们利用两个拥有不同人群的网站来 提高我们研究结果的普遍性。这项解释性治疗试验随机对照试验的提议是为了响应 PAS-20-160 将为 VSG 的大规模假设驱动 RCT 提供所需的信息 NASH 和 T2DM 的明确管理。