Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid

Gideon M. Hirschfield, Andrew Mason, Velimir Luketic, Keith Lindor, Stuart C. Gordon, Marlyn Mayo, Kris V. Kowdley, Catherine Vincent, Henry C. Bodhenheimer, Albert Parés, Michael Trauner, Hanns Ulrich Marschall, Luciano Adorini, Cathi Sciacca, Tessa Beecher-Jones, Erin Castelloe, Olaf Böhm, David Shapiro

Research output: Contribution to journalArticle

254 Citations (Scopus)

Abstract

Background Aims We evaluated the efficacy and safety of obeticholic acid (OCA, α-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid therapy. Methods We performed a double-blind study of 165 patients with primary biliary cirrhosis (95% women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year. Results OCA was superior to placebo in achieving the primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study (P <.0001 all OCA groups vs placebo). Levels of ALP decreased 21%-25% on average from baseline in the OCA groups and 3% in the placebo group. Sixty-nine percent (68 of 99) of patients given OCA had at least a 20% reduction in ALP compared with 8% (3 of 37) of patients given placebo (P <.0003). Among secondary end points, levels of γ-glutamyl transpeptidase decreased 48%-63%, on average, among subjects given OCA, vs a 7% decrease in the group given placebo; levels of alanine aminotransferase decreased 21%-35% on average among subjects given OCA vs none of the patients given placebo. Pruritus was the principal adverse event; incidence values in the OCA 10 mg, 25 mg, and 50 mg groups were 47% (not significantly different), 87% (P <.0003), and 80% (P <.006), respectively, vs 50% in the placebo group. In the extension study, levels of ALP continued to decrease to a mean level of 202 ± 11 U/L after 12 months vs 285 ± 15 U/L at baseline. Conclusions Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, γ-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial.

Original languageEnglish (US)
Pages (from-to)751-761.e8
JournalGastroenterology
Volume148
Issue number4
DOIs
StatePublished - Apr 1 2015

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Ursodeoxycholic Acid
Biliary Liver Cirrhosis
Placebos
Alkaline Phosphatase
gamma-Glutamyltransferase
Pruritus
Alanine Transaminase
6-ethylchenodeoxycholic acid
Incidence
Double-Blind Method
Randomized Controlled Trials
Safety

Keywords

  • Acids
  • Bile
  • Cholestasis
  • Dose
  • FXR
  • Study

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. / Hirschfield, Gideon M.; Mason, Andrew; Luketic, Velimir; Lindor, Keith; Gordon, Stuart C.; Mayo, Marlyn; Kowdley, Kris V.; Vincent, Catherine; Bodhenheimer, Henry C.; Parés, Albert; Trauner, Michael; Marschall, Hanns Ulrich; Adorini, Luciano; Sciacca, Cathi; Beecher-Jones, Tessa; Castelloe, Erin; Böhm, Olaf; Shapiro, David.

In: Gastroenterology, Vol. 148, No. 4, 01.04.2015, p. 751-761.e8.

Research output: Contribution to journalArticle

Hirschfield, GM, Mason, A, Luketic, V, Lindor, K, Gordon, SC, Mayo, M, Kowdley, KV, Vincent, C, Bodhenheimer, HC, Parés, A, Trauner, M, Marschall, HU, Adorini, L, Sciacca, C, Beecher-Jones, T, Castelloe, E, Böhm, O & Shapiro, D 2015, 'Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid', Gastroenterology, vol. 148, no. 4, pp. 751-761.e8. https://doi.org/10.1053/j.gastro.2014.12.005
Hirschfield, Gideon M. ; Mason, Andrew ; Luketic, Velimir ; Lindor, Keith ; Gordon, Stuart C. ; Mayo, Marlyn ; Kowdley, Kris V. ; Vincent, Catherine ; Bodhenheimer, Henry C. ; Parés, Albert ; Trauner, Michael ; Marschall, Hanns Ulrich ; Adorini, Luciano ; Sciacca, Cathi ; Beecher-Jones, Tessa ; Castelloe, Erin ; Böhm, Olaf ; Shapiro, David. / Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. In: Gastroenterology. 2015 ; Vol. 148, No. 4. pp. 751-761.e8.
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abstract = "Background Aims We evaluated the efficacy and safety of obeticholic acid (OCA, α-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid therapy. Methods We performed a double-blind study of 165 patients with primary biliary cirrhosis (95{\%} women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year. Results OCA was superior to placebo in achieving the primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study (P <.0001 all OCA groups vs placebo). Levels of ALP decreased 21{\%}-25{\%} on average from baseline in the OCA groups and 3{\%} in the placebo group. Sixty-nine percent (68 of 99) of patients given OCA had at least a 20{\%} reduction in ALP compared with 8{\%} (3 of 37) of patients given placebo (P <.0003). Among secondary end points, levels of γ-glutamyl transpeptidase decreased 48{\%}-63{\%}, on average, among subjects given OCA, vs a 7{\%} decrease in the group given placebo; levels of alanine aminotransferase decreased 21{\%}-35{\%} on average among subjects given OCA vs none of the patients given placebo. Pruritus was the principal adverse event; incidence values in the OCA 10 mg, 25 mg, and 50 mg groups were 47{\%} (not significantly different), 87{\%} (P <.0003), and 80{\%} (P <.006), respectively, vs 50{\%} in the placebo group. In the extension study, levels of ALP continued to decrease to a mean level of 202 ± 11 U/L after 12 months vs 285 ± 15 U/L at baseline. Conclusions Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, γ-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial.",
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TY - JOUR

T1 - Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid

AU - Hirschfield, Gideon M.

AU - Mason, Andrew

AU - Luketic, Velimir

AU - Lindor, Keith

AU - Gordon, Stuart C.

AU - Mayo, Marlyn

AU - Kowdley, Kris V.

AU - Vincent, Catherine

AU - Bodhenheimer, Henry C.

AU - Parés, Albert

AU - Trauner, Michael

AU - Marschall, Hanns Ulrich

AU - Adorini, Luciano

AU - Sciacca, Cathi

AU - Beecher-Jones, Tessa

AU - Castelloe, Erin

AU - Böhm, Olaf

AU - Shapiro, David

PY - 2015/4/1

Y1 - 2015/4/1

N2 - Background Aims We evaluated the efficacy and safety of obeticholic acid (OCA, α-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid therapy. Methods We performed a double-blind study of 165 patients with primary biliary cirrhosis (95% women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year. Results OCA was superior to placebo in achieving the primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study (P <.0001 all OCA groups vs placebo). Levels of ALP decreased 21%-25% on average from baseline in the OCA groups and 3% in the placebo group. Sixty-nine percent (68 of 99) of patients given OCA had at least a 20% reduction in ALP compared with 8% (3 of 37) of patients given placebo (P <.0003). Among secondary end points, levels of γ-glutamyl transpeptidase decreased 48%-63%, on average, among subjects given OCA, vs a 7% decrease in the group given placebo; levels of alanine aminotransferase decreased 21%-35% on average among subjects given OCA vs none of the patients given placebo. Pruritus was the principal adverse event; incidence values in the OCA 10 mg, 25 mg, and 50 mg groups were 47% (not significantly different), 87% (P <.0003), and 80% (P <.006), respectively, vs 50% in the placebo group. In the extension study, levels of ALP continued to decrease to a mean level of 202 ± 11 U/L after 12 months vs 285 ± 15 U/L at baseline. Conclusions Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, γ-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial.

AB - Background Aims We evaluated the efficacy and safety of obeticholic acid (OCA, α-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid therapy. Methods We performed a double-blind study of 165 patients with primary biliary cirrhosis (95% women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year. Results OCA was superior to placebo in achieving the primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study (P <.0001 all OCA groups vs placebo). Levels of ALP decreased 21%-25% on average from baseline in the OCA groups and 3% in the placebo group. Sixty-nine percent (68 of 99) of patients given OCA had at least a 20% reduction in ALP compared with 8% (3 of 37) of patients given placebo (P <.0003). Among secondary end points, levels of γ-glutamyl transpeptidase decreased 48%-63%, on average, among subjects given OCA, vs a 7% decrease in the group given placebo; levels of alanine aminotransferase decreased 21%-35% on average among subjects given OCA vs none of the patients given placebo. Pruritus was the principal adverse event; incidence values in the OCA 10 mg, 25 mg, and 50 mg groups were 47% (not significantly different), 87% (P <.0003), and 80% (P <.006), respectively, vs 50% in the placebo group. In the extension study, levels of ALP continued to decrease to a mean level of 202 ± 11 U/L after 12 months vs 285 ± 15 U/L at baseline. Conclusions Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, γ-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial.

KW - Acids

KW - Bile

KW - Cholestasis

KW - Dose

KW - FXR

KW - Study

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