From the Department of Radiology (H.J., K.J.L., M.R.B.), Center for Advanced MR Development (M.R.B.), Division of Gastroenterology, Department of Medicine (M.R.B.), and Department of Radiation Oncology (K.J.L.), Duke University Medical Center, School of Medicine, and Department of Electrical and Computer Engineering, Pratt School of Engineering (K.J.L.), Duke University, Box 3808, Durham, NC 27710; Department of Radiology, West China Hospital, Sichuan University, Chengdu, China (H.J.); and Metacrine, San Diego, Calif (H.C.C.).
Radiology. 2021 Aug;300(2):361-368. doi: 10.1148/radiol.2021204325. Epub 2021 Jun 1.
Background Pharmacologic treatment of nonalcoholic steatohepatitis (NASH) is long term in nature; thus, early noninvasive treatment response assessment is important for therapeutic decision making. Purpose To investigate potential early predictors of the 12-week treatment response estimated by using the MRI-based proton-density fat fraction (PDFF). Materials and Methods In this secondary analysis of a prospective phase Ib clinical trial evaluating a candidate treatment (MET409, a farnesoid X receptor agonist) for NASH, participants were analyzed at baseline and at 4 and 12 weeks after either active treatment with MET409 or placebo treatment between June 2019 and January 2020. Correlation and multiple linear regression analyses were used to identify clinical, laboratory, and imaging predictors of the relative PDFF change at week 12 (W12). Multivariate logistic regression analysis was used to develop predictive models for an at least 30% relative PDFF reduction at W12, a well-validated indicator of histologic improvement. Model performance was characterized by using area under the receiver operating characteristic curve (AUC) analysis, sensitivity, and specificity. Results A total of 48 participants were analyzed (median age, 57 years; age range, 40-62 years; 32 women), among whom 30 received MET409 and 18 received a placebo. The week 4 (W4) relative changes in PDFF (regression coefficient = 1.24, < .001) and the serum alkaline phosphatase (ALP) level (regression coefficient = -0.29, = .03) were predictors of the W12 relative PDFF change. An at least 19.3% relative PDFF reduction at W4 yielded an AUC of 0.98 (sensitivity, 89%; specificity, 95%) for predicting an at least 30% relative PDFF reduction at W12. The addition of ALP to the predictive model did not improve model performance. Conclusion In participants with nonalcoholic steatohepatitis enrolled in a phase Ib treatment trial, the relative change in the MRI-based proton-density fat fraction (PDFF) at week 4 was highly predictive of the treatment response estimated by using the week 12 MRI-based PDFF. © RSNA, 2021
背景 非酒精性脂肪性肝炎（NASH）的药物治疗需要长期进行；因此，早期的非侵入性治疗反应评估对于治疗决策非常重要。目的 利用基于 MRI 的质子密度脂肪分数（PDFF）来评估 12 周治疗反应，探讨其潜在的早期预测因素。材料与方法 本研究为一项评估候选治疗药物（MET409，法尼酯 X 受体激动剂）治疗 NASH 的前瞻性 Ib 期临床试验的二次分析，2019 年 6 月至 2020 年 1 月，参与者接受 MET409 或安慰剂治疗后，分别在基线、4 周和 12 周进行分析。采用相关性和多元线性回归分析，确定 12 周时相对 PDFF 变化的临床、实验室和影像学预测因素。采用多元逻辑回归分析，建立 12 周时相对 PDFF 减少至少 30%的预测模型，这是组织学改善的一个有效验证指标。采用受试者工作特征曲线（ROC）下面积（AUC）分析、灵敏度和特异性来评估模型性能。结果 共纳入 48 名参与者（中位年龄 57 岁；年龄范围 40-62 岁；32 名女性），其中 30 名接受 MET409 治疗，18 名接受安慰剂治疗。第 4 周（W4）时 PDFF 的相对变化（回归系数=1.24， <.001）和血清碱性磷酸酶（ALP）水平（回归系数=-0.29， =.03）是 12 周时相对 PDFF 变化的预测因素。W4 时 PDFF 减少至少 19.3%，预测 12 周时 PDFF 减少至少 30%的 AUC 为 0.98（灵敏度为 89%，特异性为 95%）。将 ALP 添加到预测模型中并不能提高模型性能。结论 在参加 Ib 期治疗试验的 NASH 患者中，基于 MRI 的 PDFF 的相对变化在第 4 周时高度预测了 12 周时基于 MRI 的 PDFF 所估计的治疗反应。
