Universität zu Köln

Traussnigg, Stefan, Schattenberg, Jorn M. ORCID: 0000-0002-4224-4703, Demir, Munevver, Wiegand, Johannes, Geier, Andreas, Teuber, Gerfinde, Hofmann, Wolf Peter, Kremer, Andreas E., Spreda, Frank, Kluwe, Johannes, Petersen, Jorg, Boettler, Tobias ORCID: 0000-0002-1195-055X, Rainer, Florian, Halilbasic, Emina, Greinwald, Roland, Prols, Markus, Manns, Michael P., Fickert, Peter and Trauner, Michael ORCID: 0000-0002-1275-6425 (2019). Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial. Lancet Gastroenterol. Hepatol., 4 (10). S. 781 - 794. SAN DIEGO: ELSEVIER INC. ISSN 2468-1253

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Abstract

Background Norursodeoxycholic acid is an orally administered side chain-shortened homologue of ursodeoxycholic acid that undergoes hepatic enrichment with hepatoprotective, anti-inflammatory, and antifibrotic activity. We assessed the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease. Methods We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial in tertiary referral hospitals and medical centres in Austria (n=6) and Germany (n=23) for patients with non-alcoholic fatty liver disease with or without diabetes. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and serum alanine aminotransferase (ALT) concentrations of more than 0.8 times the upper limit of normal were randomly assigned (1:1:1) using a computer-generated central randomisation. Patients were randomly assigned to receive either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks with a subsequent 4-week follow-up period. All individuals involved in the trial were masked to treatment allocation. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment assessed in the intention-to-treat population. This trial is registered with EudraCT, number 2013-004605-38. Findings Between March 30, 2015, and Sept 20, 2016, of 198 individuals included in the analysis, 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 ing group (mean change -27.8%, 95% repeated CI -34.7 to -14.4; p<0.0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. 112 treatment-emergent adverse events occurred in the 1500 mg group, 99 in the 500 mg group, and 103 in the placebo group. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis). Interpretation Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated encouraging further studies. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Traussnigg, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Schattenberg, Jorn M. UNSPECIFIED orcid.org/0000-0002-4224-4703 UNSPECIFIED Demir, Munevver UNSPECIFIED UNSPECIFIED UNSPECIFIED Wiegand, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Geier, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Teuber, Gerfinde UNSPECIFIED UNSPECIFIED UNSPECIFIED Hofmann, Wolf Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Kremer, Andreas E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Spreda, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Kluwe, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Petersen, Jorg UNSPECIFIED UNSPECIFIED UNSPECIFIED Boettler, Tobias UNSPECIFIED orcid.org/0000-0002-1195-055X UNSPECIFIED Rainer, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Halilbasic, Emina UNSPECIFIED UNSPECIFIED UNSPECIFIED Greinwald, Roland UNSPECIFIED UNSPECIFIED UNSPECIFIED Prols, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Manns, Michael P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fickert, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Trauner, Michael UNSPECIFIED orcid.org/0000-0002-1275-6425 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-133339
DOI:	10.1016/S2468-1253(19)30184-0
Journal or Publication Title:	Lancet Gastroenterol. Hepatol.
Volume:	4
Number:	10
Page Range:	S. 781 - 794
Date:	2019
Publisher:	ELSEVIER INC
Place of Publication:	SAN DIEGO
ISSN:	2468-1253
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language URSODEOXYCHOLIC ACID; BILE-ACIDS; STEATOHEPATITIS; EPIDEMIOLOGY Multiple languages Gastroenterology & Hepatology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13333