Efficacy, safety, and tolerability of lubiprostone for the treatment of non-alcoholic fatty liver disease in adult patients with constipation: The LUBIPRONE, double-blind, randomised, placebo-controlled study design
Section snippets
List of abbreviations
NAFLD non-alcoholic fatty liver disease NASH non-alcoholic steatohepatitis LUB lubiprostone ALT alanine aminotransferase
Background
Fatty liver disease in individuals who consume little to no alcohol is known as non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis (NASH). NASH is an increasingly common cause of chronic liver disease worldwide and is associated with increased liver-related mortality and hepatocellular carcinoma [1]. It progresses to cirrhosis in 15%–20% of affected individuals and is a rising indication for liver transplantation that has become a health concern in Europe
Trial design
The LUBIPRONE trial was designed as a randomised, double-blind, allocation-concealed, placebo-controlled, investigator-initiated clinical study to test the efficacy, safety, and tolerability of LUB 12 μg (LUB12) or 24 μg (LUB24) once daily per oral vs. placebo for 16 weeks in NAFLD with constipation (Fig. 2). The primary endpoint will be assessed at 12 weeks. The study planned to recruit 150 adults from the Yokohama City University Hospital cohort. Randomised allocation will be performed by
Discussion
This is the first study proposed to explore the effect of LUB in NAFLD patients with constipation. The primary endpoint of previous NASH clinical trials, such as PIVENS, FLINT, and GOLDEN, was liver histology evaluated by liver biopsy [[20], [21], [22], [23]]. Liver histology endpoints, such as the complete resolution of NASH, are considered surrogates for preventing cirrhosis in that they are thought to predict clinical benefit but are not direct measurements of it. However, invasive liver
Conclusions
This is the first study for the assessment of the safety and tolerability of LUB in improving gut permeability in a large population of NAFLD patients with constipation. The findings of this study will also allow an evaluation of NAFLD progression by using non-invasive imaging methods instead of liver biopsy.
Consent for publication
Written informed consent for publication will be obtained from all participating patients.
Availability of data and material
Not applicable.
Competing interests
The authors declare that they have competing interests. This study is funded by Mylan EPD G.K., which is the distributor of lubiprostone in Japan.
Funding
This study received funding from Mylan EPD G.K. (Tokyo, Japan). The funder had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all of the data and had final responsibility for the decision to submit for publication.
Authors' contributions
T. Kessoku and AN conceived the study. T. Kessoku conducted feasibility phase work. Recruitment of participants and follow-up will be performed by T. Kato, YH, SK and TH. Analysis and interpretation of data will be conducted by T. Kobayashi, KK, MT, and TY. HK and SS will perform bioinformatic analysis. FibroScan will be measured by YO and WT. Reading of MRI will be done by KI and MY. UH and KW will measure lactulose mannitol ratio. All authors read and approved the final manuscript.
Acknowledgements
We would like to thank the patients, their families, the study coordinators and investigators, as well as the LUBIPRONE study team. The skilful technical assistance of Ayaka Miura, Kaori Suzuki and Machiko Hiraga is gratefully acknowledged. The administrative assistance of Kyoko Koike and Ayako Ujiie is gratefully acknowledged. We thank Sarah Williams, PhD, from Edanz Group (www.edanzediting.com) for editing a draft of this manuscript and helping to draft the abstract.
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Lubiprostone in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled, phase 2a trial
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Amelioration of non-alcoholic steatohepatitis by Qushi Huayu decoction is associated with inhibition of the intestinal mitogen-activated protein kinase pathway
2020, PhytomedicineCitation Excerpt :The protection of colonic tight junctions is probably the identified cause of the inhibitory effect of QHD on endotoxaemia in NASH, a function that was predominantly mediated by the MAPK pathway. On the other hand, our finding is consistent with the positive results of a recently completed phase II clinical trial on the treatment of NAFLD with lubiprostone, which suppressed gut permeability (Kessoku et al., 2018). Inhibition of metabolic endotoxaemia by QHD is associated with downregulation of the intestinal MAPK pathway, which contributes to the therapeutic effects of QHD on NASH.
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