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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Fickert, P; Hirschfield, GM; Denk, G; Marschall, HU; Altorjay, I; Färkkilä, M; Schramm, C; Spengler, U; Chapman, R; Bergquist, A; Schrumpf, E; Nevens, F; Trivedi, P; Reiter, FP; Tornai, I; Halilbasic, E; Greinwald, R; Pröls, M; Manns, MP; Trauner, M; European PSC norUDCA Study Group.
norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis.
J Hepatol. 2017; 67(3):549-558 Doi: 10.1016/j.jhep.2017.05.009 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Fickert Peter
Trauner Michael
Co-Autor*innen der Med Uni Graz
Halilbasic Emina
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Abstract:
Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease, currently lacking effective medical therapy. 24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C23 homologue of UDCA and has shown potent anti-cholestatic, anti-inflammatory and anti-fibrotic properties in a preclinical PSC mouse model. A randomized controlled trial, including 38 centers from 12 European countries, evaluated the safety and efficacy of three doses of oral norUDCA (500mg/d, 1,000mg/d or 1,500mg/d) compared with placebo in patients with PSC. One hundred sixty-one PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for a 12-week treatment followed by a 4-week follow-up. The primary efficacy endpoint was the mean relative change in ALP levels between baseline and end of treatment visit. norUDCA reduced ALP levels by -12.3%, -17.3%, and -26.0% in the 500, 1,000, and 1,500mg/d groups (p=0.029, p=0.003, and p<0.0001 when compared to placebo), respectively, while a +1.2% increase was observed in the placebo group. Similar dose-dependent results were found for secondary endpoints, such as ALT, AST, γ-GT, or the rate of patients achieving ALP levels <1.5× ULN. Serious adverse events occurred in seven patients in the 500mg/d, five patients in the 1,000mg/d, two patients in the 1500mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups. norUDCA significantly reduced ALP values dose-dependently in all treatment arms. The safety profile of norUDCA was excellent and comparable to placebo. Consequently, these results justify a phase III trial of norUDCA in PSC patients. Lay summary: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed. In this phase II clinical study in PSC patients, a side chain-shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA), significantly reduced serum alkaline phosphatase levels in a dose-dependent manner during a 12-week treatment. Importantly, norUDCA showed a favorable safety profile, which was similar to placebo. The use of norUDCA in PSC patients is promising and will be further evaluated in a phase III clinical study. ClinicalTrials.gov number: NCT01755507. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Find related publications in this database (using NLM MeSH Indexing)
Adult -
Alkaline Phosphatase - blood
Cholangitis, Sclerosing - drug therapy
Cholestasis - drug therapy
Dose-Response Relationship, Drug -
Double-Blind Method -
Female -
Humans -
Male -
Middle Aged -
Ursodeoxycholic Acid - adverse effects
Ursodeoxycholic Acid - analogs & derivatives
Ursodeoxycholic Acid - therapeutic use

Find related publications in this database (Keywords)
Alkaline phosphatase
Bile acid treatment
Cholestasis
Sclerosing cholangitis
Side chain-shortened bile acids
Cholehepatic shunting
Ursodeoxycholic acid
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