norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis

European PSC norUDCA Study Group

Research output: Article

44 Citations (Scopus)

Abstract

Background & Aim 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 (500 mg/d, 1,000 mg/d or 1,500 mg/d) compared with placebo in patients with PSC. Methods 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. Results norUDCA reduced ALP levels by −12.3%, −17.3%, and −26.0% in the 500, 1,000, and 1,500 mg/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 500 mg/d, five patients in the 1,000 mg/d, two patients in the 1500 mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups. Conclusions 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.

Original languageEnglish
Pages (from-to)549-558
Number of pages10
JournalJournal of Hepatology
Volume67
Issue number3
DOIs
Publication statusPublished - szept. 1 2017

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Sclerosing Cholangitis
Cholestasis
Acids
Alkaline Phosphatase
Placebos
Therapeutics
Safety
Bile Duct Diseases
Ursodeoxycholic Acid
Pruritus
Serum
Anti-Inflammatory Agents
Randomized Controlled Trials

ASJC Scopus subject areas

  • Hepatology

Cite this

norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. / European PSC norUDCA Study Group.

In: Journal of Hepatology, Vol. 67, No. 3, 01.09.2017, p. 549-558.

Research output: Article

European PSC norUDCA Study Group. / norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. In: Journal of Hepatology. 2017 ; Vol. 67, No. 3. pp. 549-558.
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title = "norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis",
abstract = "Background & Aim 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 (500 mg/d, 1,000 mg/d or 1,500 mg/d) compared with placebo in patients with PSC. Methods 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. Results norUDCA reduced ALP levels by −12.3{\%}, −17.3{\%}, and −26.0{\%} in the 500, 1,000, and 1,500 mg/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 500 mg/d, five patients in the 1,000 mg/d, two patients in the 1500 mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups. Conclusions 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.",
keywords = "Alkaline phosphatase, Bile acid treatment, Cholehepatic shunting, Cholestasis, Sclerosing cholangitis, Side chain-shortened bile acids, Ursodeoxycholic acid",
author = "{European PSC norUDCA Study Group} and Peter Fickert and Hirschfield, {Gideon M.} and Gerald Denk and Marschall, {Hanns Ulrich} and I. Altorjay and Martti F{\"a}rkkil{\"a} and Christoph Schramm and Ulrich Spengler and Roger Chapman and Annika Bergquist and Erik Schrumpf and Frederik Nevens and Palak Trivedi and Reiter, {Florian P.} and Istvan Tornai and Emina Halilbasic and Roland Greinwald and Markus Pr{\"o}ls and Manns, {Michael P.} and Michael Trauner",
year = "2017",
month = "9",
day = "1",
doi = "10.1016/j.jhep.2017.05.009",
language = "English",
volume = "67",
pages = "549--558",
journal = "Journal of Hepatology",
issn = "0168-8278",
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TY - JOUR

T1 - norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis

AU - European PSC norUDCA Study Group

AU - Fickert, Peter

AU - Hirschfield, Gideon M.

AU - Denk, Gerald

AU - Marschall, Hanns Ulrich

AU - Altorjay, I.

AU - Färkkilä, Martti

AU - Schramm, Christoph

AU - Spengler, Ulrich

AU - Chapman, Roger

AU - Bergquist, Annika

AU - Schrumpf, Erik

AU - Nevens, Frederik

AU - Trivedi, Palak

AU - Reiter, Florian P.

AU - Tornai, Istvan

AU - Halilbasic, Emina

AU - Greinwald, Roland

AU - Pröls, Markus

AU - Manns, Michael P.

AU - Trauner, Michael

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Background & Aim 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 (500 mg/d, 1,000 mg/d or 1,500 mg/d) compared with placebo in patients with PSC. Methods 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. Results norUDCA reduced ALP levels by −12.3%, −17.3%, and −26.0% in the 500, 1,000, and 1,500 mg/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 500 mg/d, five patients in the 1,000 mg/d, two patients in the 1500 mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups. Conclusions 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.

AB - Background & Aim 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 (500 mg/d, 1,000 mg/d or 1,500 mg/d) compared with placebo in patients with PSC. Methods 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. Results norUDCA reduced ALP levels by −12.3%, −17.3%, and −26.0% in the 500, 1,000, and 1,500 mg/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 500 mg/d, five patients in the 1,000 mg/d, two patients in the 1500 mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups. Conclusions 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.

KW - Alkaline phosphatase

KW - Bile acid treatment

KW - Cholehepatic shunting

KW - Cholestasis

KW - Sclerosing cholangitis

KW - Side chain-shortened bile acids

KW - Ursodeoxycholic acid

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