Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design
Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design
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DOI：
10.1016/j.cct.2016.02.012
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发表时间：
2016-03-01
影响因子：
2.2
通讯作者：
Ratziu, Vlad
中科院分区：
文献类型：
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作者：
Friedman, Scott;Sanyal, Arun;Ratziu, Vlad
背景：非酒精性脂肪性肝炎（NASH）常伴有肝纤维化，可进展为肝硬化； C-C 趋化因子受体 2 型和 5 型 (CCR2/CCR5) 介导驱动炎症和纤维化的相互作用，是有希望的治疗靶点。 Cenicriviroc (CVC) 是一种 CCR2/CCR5 双重拮抗剂，在动物模型中具有有效的抗炎和抗纤维化活性；在 HIV 阳性受试者中，它降低了可溶性 CD14 水平、天冬氨酸转氨酶与血小板计数比值指数以及非侵入性肝纤维化风险评分；在 600 名受试者中证明了良好的耐受性。 CVC 150 mg 治疗 NASH 伴肝纤维化的疗效和安全性正在进行 2 年多的评估（主要终点为第 1 年 [Y1]）。设计：2b 期、随机、双盲、安慰剂对照、跨国研究（CENTAUR；NCT02217475）。具有 NASH 组织学证据、非酒精性脂肪肝疾病活动评分 (NAS) >= 4 和肝纤维化（NASH 临床研究网络系统 1-3 阶段）的成人入组。由于以下特征，受试者进展为肝硬化的风险增加：2 型糖尿病；体重指数 > 25 kg/m(2)，且具有 >= 1 种代谢综合征特征；桥接纤维化和/或 NAS >= 5。在筛选、第 1 年和第 2 年 (Y2) 时进行肝活检评估。 目的：评估组织学改善（NAS 中 >= 2 点，>1 类别中 >= 1 点改善），第 1 年（初级）纤维化没有恶化；评估 NASH 的完全缓解，而不会在第 2 年（关键次要的）纤维化恶化。讨论：CENTAUR 是第一项评估口服药物的前瞻性研究，专门招募患有 NASH 和肝纤维化的受试者，且罹患肝硬化的风险增加。它将比较较短与较长的 CVC 治疗，并评估炎症减少和纤维化之间的相关性。 (C) 2016 年作者。由 Elsevier Inc. 出版。这是一篇遵循 CC BY-NC-ND 许可的开放获取文章。
Background: Non-alcoholic steatohepatitis (NASH) is often accompanied by liver fibrosis, which can progress to cirrhosis; C-C chemokine receptors type 2 and 5 (CCR2/CCR5), which mediate interactions driving inflammation and fibrosis, are promising treatment targets. Cenicriviroc (CVC), a dual-CCR2/CCR5 antagonist, has potent antiinflammatory and antifibrotic activity in animal models; in HIV-positive subjects it reduced soluble CD14 levels, aspartate aminotransferase-to-platelet count ratio index, and non-invasive hepatic fibrosis risk scores; favorable tolerability was demonstrated in similar to 600 subjects. Efficacy and safety of CVC 150 mg for treating NASH with liver fibrosis are being evaluated over 2 years (primary endpoint at Year 1 [Y1]).Design: Phase 2b, randomized, double-blind, placebo-controlled, multinational study (CENTAUR; NCT02217475). Adults with histological evidence of NASH, non-alcoholic fatty liver disease activity score (NAS) >= 4, and liver fibrosis (stages 1-3 NASH clinical research network system) enrolled. Subjects have increased risk of progression to cirrhosis due to characteristic: type 2 diabetes; body mass index > 25 kg/m(2) with >= 1 feature of metabolic syndrome; bridging fibrosis and/or NAS >= 5. Liver biopsy evaluation at Screening, Yl, and Year 2 (Y2).Objectives: Assess histologic improvement (>= 2-point in NAS with >= 1-point improvement in >1 category) without worsening of fibrosis at Y1 (primary); evaluate complete NASH resolution without worsening of fibrosis at Y2 (key secondary).Discussion: CENTAUR is the first prospective study evaluating an oral agent exclusively enrolling subjects with NASH and liver fibrosis, with increased risk of developing cirrhosis. It will compare shorter versus longer CVC treatment and assess correlations between decreased inflammation and fibrosis. (C) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.