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

https://doi.org/10.1016/j.cct.2018.04.002Get rights and content

Abstract

Background

This paper reports the protocol of a randomised, double-blind, placebo-controlled study to test the efficacy, safety, and tolerability of lubiprostone (LUB) vs. placebo on suppressing gut permeability in non-alcoholic fatty liver disease (NAFLD) patients with constipation. NAFLD, including non-alcoholic steatohepatitis (NASH), is a common chronic liver disorder. Progression is associated with increased gut permeability and gut-derived endotoxins. Most NAFLD/NASH clinical trial drugs aim to improve liver function or systemic metabolism. LUB is a type 2 chloride channel activator used as a laxative for the treatment of patients with constipation. LUB suppresses gut permeability induced by non-steroidal anti-inflammatory drugs in healthy volunteers and lowers blood endotoxin levels. There have been no clinical studies of LUB for NAFLD/NASH patients.

Methods

The study plans to enrol adult patients (20–85 years, planned enrolment, n = 150; planned sample size, n = 120) with NAFLD and constipation, alanine aminotransferase ≥40 IU/L, equivalent steatosis grade ≥1, and equivalent fibrosis stage <4 measured using non-invasive vibration-controlled transient elastography and magnetic resonance imaging. Participants will be randomly allocated into three groups: LUB 12 μg, LUB 24 μg, and a placebo group.

Results

The primary endpoint will be changes in alanine aminotransferase from baseline at 12 weeks. The main secondary endpoint will be changes in intestinal permeability from baseline at 12 weeks using the lactulose mannitol ratio.

Conclusions

This study will determine whether LUB improves gut permeability in NAFLD patients with constipation.

Trial registration

This trial is registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000026635).

Section snippets

List of abbreviations

NAFLDnon-alcoholic fatty liver disease
NASHnon-alcoholic steatohepatitis
LUBlubiprostone
ALTalanine 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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