Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Palliative Medicine, Yokohama City University Hospital, Yokohama, Japan.
Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Lancet Gastroenterol Hepatol. 2020 Nov;5(11):996-1007. doi: 10.1016/S2468-1253(20)30216-8. Epub 2020 Aug 15.
The laxative drug lubiprostone improves intestinal permeability in healthy volunteers. We aimed to assess efficacy and safety of lubiprostone in patients with non-alcoholic fatty liver disease (NAFLD) with constipation via attenuation of intestinal permeability.
This randomised, double-blind, placebo-controlled, phase 2a study in Yokohama City University Hospital, Japan, recruited patients (aged 20-85 years) with NAFLD and constipation, alanine aminotransferase (ALT) at least 40 U/L, liver stiffness (≤6·7 kPa), and hepatic fat fraction at least 5·2% when assessed by MRI-proton density fat fraction. Eligible patients were randomly assigned (11:10:9) by a computer-based system and stratified by age and sex to receive 24 μg lubiprostone, 12 μg lubiprostone, or placebo, orally, once per day for 12 weeks. The primary endpoint was the absolute changes in ALT at 12 weeks. Efficacy analysis was done by intention to treat. Safety was assessed in all treated patients. This trial was registered with University Hospital Medical Information Network Clinical Trials Registry (UMIN000026635).
Between March 24, 2017, and April 3, 2018, we screened 288 patients, of whom 150 (52%) were randomly assigned to treatment: 55 patients were assigned to receive 24 μg lubiprostone, 50 to receive 12 μg lubiprostone, and 45 to receive placebo. A greater decrease in the absolute ALT levels from baseline to 12 weeks was seen in the 24 μg lubiprostone group (mean -13 U/L [SD 19]) than in the placebo group (1 U/L [24]; mean difference -15 U/L [95% CI -23 to -6], p=0·0007) and in the 12 μg lubiprostone group (-12 U/L [21]) than in the placebo group (mean difference -13 U/L [-22 to -5], p=0·0023). 18 (33%) of 55 patients in the 24 μg group had at least one adverse event, as did three (6%) of 47 patients in the 12 μg group and three (7%) of 43 in the placebo group. The most common adverse event was diarrhoea (17 [31%] of patients in the 24 μg group, three [6%] in the 12 μg group, none in the placebo group). No life-threatening events or treatment-related deaths occurred.
Lubiprostone was well tolerated and reduced the levels of liver enzymes in patients with NAFLD and constipation. Further studies are necessary to better define the efficacy and tolerability of lubiprostone in patients with NAFLD without constipation.
Mylan EPD G.K.
通便药物鲁比前列酮可改善健康志愿者的肠道通透性。我们旨在通过降低肠道通透性来评估鲁比前列酮在伴有便秘的非酒精性脂肪性肝病（NAFLD）患者中的疗效和安全性。
这是一项在日本横滨市立大学医院进行的随机、双盲、安慰剂对照、2a 期研究，招募了患有 NAFLD 和便秘的患者（年龄 20-85 岁），其丙氨酸氨基转移酶（ALT）至少为 40 U/L，肝硬度（≤6.7kPa）和肝脂肪分数（MRI 质子密度脂肪分数评估）至少为 5.2%。符合条件的患者通过基于计算机的系统以 11:10:9 的比例随机分配，并按年龄和性别分层，接受 24μg 鲁比前列酮、12μg 鲁比前列酮或安慰剂，每天口服一次，持续 12 周。主要终点为 12 周时 ALT 的绝对变化。通过意向治疗进行疗效分析。在所有接受治疗的患者中评估安全性。该试验在大学医院医疗信息网临床试验注册处（UMIN000026635）进行了注册。
在 2017 年 3 月 24 日至 2018 年 4 月 3 日期间，我们筛选了 288 名患者，其中 150 名（52%）被随机分配接受治疗：55 名患者接受 24μg 鲁比前列酮，50 名患者接受 12μg 鲁比前列酮，45 名患者接受安慰剂。与安慰剂组（1 U/L [24]；平均差值-15 U/L [95%CI -23 至-6]，p=0·0007）和 12μg 鲁比前列酮组（-12 U/L [21]）相比，24μg 鲁比前列酮组从基线到 12 周时的 ALT 水平绝对下降更大（平均-13 U/L [SD 19]）（平均差值-13 U/L [-22 至-5]，p=0·0023）。24μg 组 55 名患者中有 18 名（33%）至少发生了一次不良事件，12μg 组 47 名患者中有 3 名（6%），安慰剂组 43 名患者中有 3 名（7%）。最常见的不良事件是腹泻（24μg 组 17 [31%]名患者，12μg 组 3 [6%]名患者，安慰剂组无患者）。没有发生危及生命的事件或与治疗相关的死亡。
鲁比前列酮耐受性良好，可降低伴有便秘的 NAFLD 患者的肝酶水平。需要进一步的研究来更好地确定鲁比前列酮在没有便秘的 NAFLD 患者中的疗效和耐受性。
Mylan EPD G.K.
