Systematic Analysis and Threshold Synthesis for |G*| as a Diagnostic Biomarker for NAFLD and NASH Clinical Trials - DDT-BMQ-000099

|G*| 的系统分析和阈值合成

• 批准号: 10410011
• 负责人: Kay Marie Pepin
• 金额: $ 25万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410011
• 关键词: Systematic; Analysis; Threshold; Synthesis; Diagnostic

Higher incidence of metabolic disease and obesity have fueled a rise in non-alcoholic fatty liver disease (NAFLD), which has in turn contributed to increased prevalence of non-alcoholic steatohepatitis (NASH). Despite the increasing prevalence of NAFLD and NASH, drug development in this area has faced several challenges – notably the lack of validated, noninvasive biomarkers to enroll patients based on the stage of fibrosis. This is a critical enrollment step, as regulatory bodies have identified two specific cohorts of NASH patients for clinical study: NASH with fibrosis (F2-F3) and NASH with cirrhosis (F4). A validated diagnostic biomarker for enrolling subjects in the correct cohort of interest in a timely and cost-effective way would replace the need for liver biopsy and greatly propel the field forward. The overall goal of this work is to document an evidence base to support the use of an MR elastography-based measurement of the magnitude of the complex shear modulus (|G*|) as a diagnostic pre-screening biomarker. |G*| is proposed for use to screen for subjects with NAFLD/NASH with high risk of having histopathologic findings of significant fibrosis. This biomarker has an accepted Letter of Intent (DDTBMQ000099). While |G*| and its corresponding measurement method, magnetic resonance elastography (MRE), is recognized as a reliable and established biomarker of liver fibrosis in the clinical radiology and hepatology communities, there are minor gaps that must be filled for this diagnostic Context of Use. The objective for this proposal is to conduct a retrospective analysis of the diagnostic performance of this biomarker for staging liver fibrosis and to establish standardized thresholds for |G*| for use as a diagnostic screening drug development tool. Aim 1: Establish cutoffs for |G*| for the diagnosis of significant (≥F2), advanced fibrosis (≥F3) or cirrhosis (F4) for subjects with NAFLD and determine evidence-based diagnostic performance summaries of |G*| compared with the reference standard of liver biopsy for a pre-screening context of use. Aim 2: Validate optimal cutoffs in a test cohort of subjects with NAFLD and biopsy determine the diagnostic performance (sensitivity, specificity, PPV, NVP, and AUROC). The completion of Aim 1 and Aim 2 will provide critical evidence to further the development of |G*| as a pre-screening biomarker for fibrotic NAFLD/NASH, fulfilling an unmet need in NAFLD drug development. Completion of this work will inform our Qualification Plan for |G*| as a pre- screening biomarker to the FDA’s Biomarker Qualification Program.

代谢性疾病和肥胖症的发病率较高，助长了非酒精性脂肪肝的上升 非酒精性脂肪肝（NAFLD），这反过来又导致非酒精性脂肪肝的患病率增加。 脂肪性肝炎（NASH）。尽管NAFLD和NASH的患病率不断增加，但药物 这一领域的发展面临着一些挑战-特别是缺乏经过验证的， 非侵入性生物标志物，以根据纤维化阶段招募患者。这是一个关键 由于监管机构已经确定了两个特定的NASH患者队列， 临床研究：NASH伴纤维化（F2-F3）和NASH伴肝硬化（F4）。经过验证的诊断 生物标志物，以便及时且具有成本效益地将受试者招募到正确的感兴趣队列中 这种方法将取代肝活检的需要，并大大推动该领域的发展。 这项工作的总体目标是记录证据基础，以支持使用MR 复合剪切模量的大小的基于弹性成像的测量（|G级 *|）作为 诊断性预筛选生物标志物。|G级 *| 拟用于筛查受试者， 具有显著纤维化组织病理学结果的高风险的NAFLD/NASH。这 生物标志物具有可接受的意向书（DDTBMQ 000099）。 而|G级 *| 及其相应的测量方法，磁共振弹性成像 (MRE)在临床上被认为是肝纤维化的可靠和确定的生物标志物。 放射学和肝病学社区，有一些小的差距，必须为此填补 诊断使用环境。本提案的目的是进行回顾性分析 这种生物标志物对肝纤维化分期的诊断性能， 标准化阈值|G级 *| 用作诊断筛选药物开发工具。 目标1：确定以下方面的截止值|G级 *| 用于诊断严重（≥F2）、晚期纤维化（≥F3）或 NAFLD受试者的肝硬化（F4），并确定循证诊断性能 摘要|G级 *| 与预筛选肝活检参考标准进行比较 使用上下文。 目的2：确定NAFLD和活检受试者测试队列的最佳截止值 诊断性能（灵敏度、特异性、PPV、NVP和AUROC）。 目标1和目标2的完成将为进一步发展 |G级 *| 作为纤维化NAFLD/NASH的预筛选生物标志物，满足NAFLD中未满足的需求 药物开发这项工作的完成将通知我们的资格计划，|G级 *| 作为一个前- 筛选生物标志物的FDA的生物标志物资格计划。