Utility and variability of three non-invasive liver fibrosis imaging modalities to evaluate efficacy of GR-MD-02 in subjects with NASH and bridging fibrosis during a phase-2 randomized clinical trial

BackgroundGiven the worldwide prevalence of NAFLD and NASH, there is a need to develop treatments to slow or reverse disease progression. GR-MD-02 (galactoarabino-rhamnogalaturonate) has been shown to reduce hepatic fibrosis in animal studies, and lower serum biomarkers of NASH fibrogenesis in humans. The primary aim of this study was to determine the difference between four-months of treatment with GR-MD-02 or placebo in liver inflammation and fibrosis as measured by iron-corrected T1 (cT1) mapping, a non-invasive magnetic resonance imaging (MRI) biomarker that correlates with the extent of hepatic fibro-inflammatory disease. The secondary aims were to determine change in liver stiffness as measured by magnetic resonance elastography (MRE) and shear-wave ultrasonic elastography (LSM), and to explore test-retest repeatability of the three biomarkers.Materials and methodsThirty subjects (13 females, 46–71 years) with NASH and advanced fibrosis were recruited. Subjects were randomized to receive 8 mg.kg-1 GR-MD-02 (via IV infusion) or placebo, administered biweekly over a 16-week period. Therapeutic efficacy was examined using cT1, MRE, and LSM. Statistical analyses on group differences in the biomarkers were performed using robust ANCOVA models adjusting for baseline measurement and additional covariates.ResultsThere was no significant difference in cT1 (p = 0.16) between GR-MD-02 and placebo groups following a 16-week intervention. There was also no significant difference in liver stiffness, measured by MRE (p = 0.80) or LSM (p = 0.63), between groups. Examination of repeatability of the cT1, MRE and LSM revealed coefficient of variations of 3.1%, 11% and 40% respectively.Conclusions8 mg.kg-1 of GR-MD-02 had no significant effect on non-invasive biomarkers of liver inflammation or fibrosis over a 4-month period. Histological confirmation was not available in this study. The high reproducibility of the primary outcome measure suggests that cT1 could be utilized for monitoring longitudinal change in patients with NASH.

研究背景：鉴于非酒精性脂肪性肝病（non-alcoholic fatty liver disease, NAFLD）与非酒精性脂肪性肝炎（non-alcoholic steatohepatitis, NASH）在全球范围内的高患病率，亟需开发能够延缓甚至逆转疾病进展的治疗手段。GR-MD-02（galactoarabino-rhamnogalaturonate，半乳阿拉伯糖-鼠李糖半乳糖醛酸聚糖）已在动物实验中被证实可减轻肝脏纤维化，在人体研究中也能降低NASH相关肝纤维化的血清生物标志物水平。本研究的主要目的为：通过铁校正T1成像（iron-corrected T1, cT1）——一种与肝脏纤维炎症性疾病负荷相关的非侵入性磁共振成像（magnetic resonance imaging, MRI）生物标志物——对比GR-MD-02与安慰剂治疗4个月后，对肝脏炎症及纤维化的影响差异。次要研究目的包括：评估磁共振弹性成像（magnetic resonance elastography, MRE）与剪切波超声弹性成像（shear-wave ultrasonic elastography, LSM）所测得的肝脏硬度变化，并探索上述三种生物标志物的重测重复性。
材料与方法：本研究共招募30名经确诊为NASH且伴有进展期肝纤维化的受试者（13名女性，年龄46~71岁）。将受试者随机分配至8mg·kg⁻¹ GR-MD-02静脉输注组或安慰剂组，给药方案为每两周一次给药，持续16周。采用cT1成像、MRE及LSM评估治疗疗效。针对生物标志物的组间差异，采用校正了基线测量值及其他协变量的稳健协方差分析（analysis of covariance, ANCOVA）模型进行统计学分析。
研究结果：16周干预结束后，GR-MD-02组与安慰剂组的cT1值无显著统计学差异（p=0.16）。两组间通过MRE测得的肝脏硬度（p=0.80）及LSM测得的肝脏硬度（p=0.63）同样无显著差异。对cT1成像、MRE及LSM的重复性分析结果显示，三者的变异系数分别为3.1%、11%及40%。
研究结论：在4个月的治疗周期内，8mg·kg⁻¹的GR-MD-02对肝脏炎症及纤维化的非侵入性生物标志物无显著改善作用。本研究未进行组织学验证。作为主要结局指标的cT1成像具有良好的重复性，提示其可用于监测NASH患者的纵向病情变化。