Stefan Traussnigg1, Jörn M Schattenberg2, Münevver Demir3, Johannes Wiegand4, Andreas Geier5, Gerlinde Teuber6, Wolf Peter Hofmann7, Andreas E Kremer8, Frank Spreda9, Johannes Kluwe10, Jörg Petersen11, Tobias Boettler12, Florian Rainer13, Emina Halilbasic1, Roland Greinwald14, Markus Pröls14, Michael P Manns15, Peter Fickert13, Michael Trauner16. 1. Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University Vienna, Vienna, Austria. 2. Department of Internal Medicine I, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany. 3. Clinic for Gastroenterology and Hepatology, University Hospital of Cologne, Cologne, Germany. 4. Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Leipzig, Leipzig, Germany. 5. Department of Medicine II, Division of Hepatology, University Hospital Würzburg, Würzburg, Germany. 6. Teuber Consulting & Research UG, Frankfurt, Germany. 7. Practice for Gastroenterology, Berlin, Germany. 8. Department of Medicine I, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. 9. Practice of Hadem/Spreda, Daaden, Germany. 10. Department of Internal Medicine, Division of Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 11. Ifi-Studies and Projects at the Asklepios Clinic St Georg, Hamburg, Germany. 12. Department of Medicine II, Medical CenterFaculty of Medicine, University of Freiburg, Freiburg, Germany. 13. Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria. 14. Dr Falk Pharma GmbH, Freiburg, Germany. 15. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. 16. Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University Vienna, Vienna, Austria. Electronic address: michael.trauner@meduniwien.ac.at.
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 mg 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. FUNDING: Dr Falk Pharma GmbH.
RCT Entities:
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 mg 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. FUNDING: Dr Falk Pharma GmbH.
Authors: Han Ah Lee; Young Chang; Pil Soo Sung; Eileen L Yoon; Hye Won Lee; Jeong-Ju Yoo; Young-Sun Lee; Jihyun An; Do Seon Song; Young Youn Cho; Seung Up Kim; Yoon Jun Kim Journal: Clin Mol Hepatol Date: 2022-07-01