Efficacy of Lubiprostone in Patients with Non-Alcoholic Fatty Liver Disease: A Randomized, Double-Blind, Placebo-Controlled, Phase 2A Trial

Abstract

Background: The laxative drug lubiprostone (LUB) was previously shown to improve intestinal permeability in healthy volunteers. We aimed to evaluate the efficacy and safety of LUB in patients with non-alcoholic fatty liver disease (NAFLD) via attenuation of intestinal permeability. Methods: In this randomized, double-blind, placebo-controlled, phase 2a study, NAFLD patients were randomly assigned to receive oral LUB doses (24 μg or 12 μg, once a day) or placebo for 12 weeks. All participants and investigators were blinded to the treatment groups. The primary and key secondary endpoints were the absolute changes in alanine aminotransferase (ALT) levels and lactulose-mannitol ratio (LMR), which was indicator for intestinal permeability, after 12 weeks. LMR responders and non-responders were defined as LMR 0. Findings: In total, 150 patients were randomly assigned to receive 24 μg of LUB (LUB24, n=55), 12 μg of LUB (LUB12, n=50), or placebo (n=45). We observed a significant decrease in absolute ALT levels in the LUB24 (−13 vs. 1 IU/L, p=0·0007) and LUB12 groups (−12 vs. −1 IU/L, p=0·002) compared to those in the placebo group. Compared to the non-responders, the LMR responders showed a significant reduction in absolute ALT levels in the LUB24 (−21 vs. 2 IU/L, p=0·002) and LUB12 groups (−21 vs. 6 IU/L, p=0·0007). Adverse events were more frequently reported in the LUB24 group than in the LUB12 and placebo groups. Interpretation: LUB was well tolerated and significantly reduced the levels of liver enzymes as well as intestinal permeability in NAFLD patients. The greater reduction in LMR responders suggested that manipulation of intestinal permeability may be a promising novel treatment approach for NAFLD. Nevertheless, further studies are necessary to better define the efficacy and tolerability of LUB in NAFLD patients. Trial Registration: This trial is registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMI26635). Funding Statement: This investigator-initiated clinical trial was conducted by the Yokohama City University - as the sponsor - and funded by Mylan EPD G.K. Declaration of Interests: AN reports grant and research support from Gilead, Mylan EPD, EA Pharma, Kowa, Taisho, and Biofermine and is a consulting adviser for Gilead, Boehringer Ingelheim, BMS, Kowa, Asteras, EA Pharma, and Mylan EPD. Other authors declare no competing interests. Ethics Approval Statement: The study protocol complied with both the Declaration of Helsinki and the Ethics Guidelines for Clinical Research published by the Ministry of Health, Labour and Welfare of Japan. The study protocol and relevant supporting data were approved by local ethics committees on November 21, 2016, prior to the initiation of the study.