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.
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).
['Kessoku|Takaomi|T|', 'Imajo|Kento|K|', 'Kobayashi|Takashi|T|', 'Honda|Yasushi|Y|', 'Kato|Takayuki|T|', 'Ogawa|Yuji|Y|', 'Tomeno|Wataru|W|', 'Kato|Shingo|S|', 'Higurashi|Takuma|T|', 'Yoneda|Masato|M|', 'Kirikoshi|Hiroyuki|H|', 'Kubota|Kazumi|K|', 'Taguri|Masataka|M|', 'Yamanaka|Takeharu|T|', 'Usuda|Haruki|H|', 'Wada|Koichiro|K|', 'Saito|Satoru|S|', 'Nakajima|Atsushi|A|']
D000410:Alanine Transaminase D065101:Chloride Channel Agonists D003248:Constipation D004311:Double-Blind Method D054459:Elasticity Imaging Techniques D005260:Female D041981:Gastrointestinal Tract D006801:Humans D007564:Japan D000068238:Lubiprostone D008279:Magnetic Resonance Imaging D008297:Male D008875:Middle Aged D065626:Non-alcoholic Fatty Liver Disease D017063:Outcome Assessment, Health Care D010539:Permeability
Lubiprostone Non-alcoholic fatty liver disease Randomised Gut permeability Non-alcoholic steatohepatitis Endotoxin Double blind Placebo controlled