A Placebo-controlled trial of obeticholic acid in primary biliary cholangitis

F. Nevens, P. Andreone, G. Mazzella, S. I. Strasser, C. Bowlus, P. Invernizzi, J. P H Drenth, P. J. Pockros, J. Regula, U. Beuers, M. Trauner, D. E. Jones, A. Floreani, S. Hohenester, V. Luketic, M. Shiffman, K. J. Van Erpecum, V. Vargas, C. Vincent, G. M. HirschfieldH. Shah, B. Hansen, Keith Lindor, H. U. Marschall, K. V. Kowdley, R. Hooshmand-Rad, T. Marmon, S. Sheeron, R. Pencek, L. MacConell, M. Pruzanski, D. Shapiro

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281 Citations (Scopus)

Abstract

BACKGROUND Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. METHODS In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. RESULTS Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5-10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, -113 and -130 U per liter, respectively, vs. -14 U per liter; P<0.001 for both comparisons) and total bilirubin level (-0.02 and -0.05 mg per deciliter [-0.3 and -0.9 μmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 μmol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5-10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5-10-mg group, 11% in the 10-mg group, and 4% in the placebo group. CONCLUSIONS Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid.

Original languageEnglish (US)
Pages (from-to)631-643
Number of pages13
JournalNew England Journal of Medicine
Volume375
Issue number7
DOIs
StatePublished - Aug 18 2016

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Cholangitis
Placebos
Ursodeoxycholic Acid
Bilirubin
Alkaline Phosphatase
6-ethylchenodeoxycholic acid
Biliary Liver Cirrhosis
Pruritus
Random Allocation
Least-Squares Analysis
Liver Cirrhosis
Liver Transplantation
Reference Values
Fibrosis
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Nevens, F., Andreone, P., Mazzella, G., Strasser, S. I., Bowlus, C., Invernizzi, P., ... Shapiro, D. (2016). A Placebo-controlled trial of obeticholic acid in primary biliary cholangitis. New England Journal of Medicine, 375(7), 631-643. https://doi.org/10.1056/NEJMoa1509840

A Placebo-controlled trial of obeticholic acid in primary biliary cholangitis. / Nevens, F.; Andreone, P.; Mazzella, G.; Strasser, S. I.; Bowlus, C.; Invernizzi, P.; Drenth, J. P H; Pockros, P. J.; Regula, J.; Beuers, U.; Trauner, M.; Jones, D. E.; Floreani, A.; Hohenester, S.; Luketic, V.; Shiffman, M.; Van Erpecum, K. J.; Vargas, V.; Vincent, C.; Hirschfield, G. M.; Shah, H.; Hansen, B.; Lindor, Keith; Marschall, H. U.; Kowdley, K. V.; Hooshmand-Rad, R.; Marmon, T.; Sheeron, S.; Pencek, R.; MacConell, L.; Pruzanski, M.; Shapiro, D.

In: New England Journal of Medicine, Vol. 375, No. 7, 18.08.2016, p. 631-643.

Research output: Contribution to journalArticle

Nevens, F, Andreone, P, Mazzella, G, Strasser, SI, Bowlus, C, Invernizzi, P, Drenth, JPH, Pockros, PJ, Regula, J, Beuers, U, Trauner, M, Jones, DE, Floreani, A, Hohenester, S, Luketic, V, Shiffman, M, Van Erpecum, KJ, Vargas, V, Vincent, C, Hirschfield, GM, Shah, H, Hansen, B, Lindor, K, Marschall, HU, Kowdley, KV, Hooshmand-Rad, R, Marmon, T, Sheeron, S, Pencek, R, MacConell, L, Pruzanski, M & Shapiro, D 2016, 'A Placebo-controlled trial of obeticholic acid in primary biliary cholangitis', New England Journal of Medicine, vol. 375, no. 7, pp. 631-643. https://doi.org/10.1056/NEJMoa1509840
Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P et al. A Placebo-controlled trial of obeticholic acid in primary biliary cholangitis. New England Journal of Medicine. 2016 Aug 18;375(7):631-643. https://doi.org/10.1056/NEJMoa1509840
Nevens, F. ; Andreone, P. ; Mazzella, G. ; Strasser, S. I. ; Bowlus, C. ; Invernizzi, P. ; Drenth, J. P H ; Pockros, P. J. ; Regula, J. ; Beuers, U. ; Trauner, M. ; Jones, D. E. ; Floreani, A. ; Hohenester, S. ; Luketic, V. ; Shiffman, M. ; Van Erpecum, K. J. ; Vargas, V. ; Vincent, C. ; Hirschfield, G. M. ; Shah, H. ; Hansen, B. ; Lindor, Keith ; Marschall, H. U. ; Kowdley, K. V. ; Hooshmand-Rad, R. ; Marmon, T. ; Sheeron, S. ; Pencek, R. ; MacConell, L. ; Pruzanski, M. ; Shapiro, D. / A Placebo-controlled trial of obeticholic acid in primary biliary cholangitis. In: New England Journal of Medicine. 2016 ; Vol. 375, No. 7. pp. 631-643.
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abstract = "BACKGROUND Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. METHODS In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15{\%} from baseline, and a normal total bilirubin level. RESULTS Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93{\%} received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46{\%}) and the 10-mg group (47{\%}) than in the placebo group (10{\%}; P<0.001 for both comparisons). Patients in the 5-10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, -113 and -130 U per liter, respectively, vs. -14 U per liter; P<0.001 for both comparisons) and total bilirubin level (-0.02 and -0.05 mg per deciliter [-0.3 and -0.9 μmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 μmol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56{\%} of patients in the 5-10-mg group and 68{\%} of those in the 10-mg group vs. 38{\%} in the placebo group). The rate of serious adverse events was 16{\%} in the 5-10-mg group, 11{\%} in the 10-mg group, and 4{\%} in the placebo group. CONCLUSIONS Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid.",
author = "F. Nevens and P. Andreone and G. Mazzella and Strasser, {S. I.} and C. Bowlus and P. Invernizzi and Drenth, {J. P H} and Pockros, {P. J.} and J. Regula and U. Beuers and M. Trauner and Jones, {D. E.} and A. Floreani and S. Hohenester and V. Luketic and M. Shiffman and {Van Erpecum}, {K. J.} and V. Vargas and C. Vincent and Hirschfield, {G. M.} and H. Shah and B. Hansen and Keith Lindor and Marschall, {H. U.} and Kowdley, {K. V.} and R. Hooshmand-Rad and T. Marmon and S. Sheeron and R. Pencek and L. MacConell and M. Pruzanski and D. Shapiro",
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TY - JOUR

T1 - A Placebo-controlled trial of obeticholic acid in primary biliary cholangitis

AU - Nevens, F.

AU - Andreone, P.

AU - Mazzella, G.

AU - Strasser, S. I.

AU - Bowlus, C.

AU - Invernizzi, P.

AU - Drenth, J. P H

AU - Pockros, P. J.

AU - Regula, J.

AU - Beuers, U.

AU - Trauner, M.

AU - Jones, D. E.

AU - Floreani, A.

AU - Hohenester, S.

AU - Luketic, V.

AU - Shiffman, M.

AU - Van Erpecum, K. J.

AU - Vargas, V.

AU - Vincent, C.

AU - Hirschfield, G. M.

AU - Shah, H.

AU - Hansen, B.

AU - Lindor, Keith

AU - Marschall, H. U.

AU - Kowdley, K. V.

AU - Hooshmand-Rad, R.

AU - Marmon, T.

AU - Sheeron, S.

AU - Pencek, R.

AU - MacConell, L.

AU - Pruzanski, M.

AU - Shapiro, D.

PY - 2016/8/18

Y1 - 2016/8/18

N2 - BACKGROUND Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. METHODS In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. RESULTS Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5-10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, -113 and -130 U per liter, respectively, vs. -14 U per liter; P<0.001 for both comparisons) and total bilirubin level (-0.02 and -0.05 mg per deciliter [-0.3 and -0.9 μmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 μmol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5-10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5-10-mg group, 11% in the 10-mg group, and 4% in the placebo group. CONCLUSIONS Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid.

AB - BACKGROUND Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. METHODS In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. RESULTS Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5-10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, -113 and -130 U per liter, respectively, vs. -14 U per liter; P<0.001 for both comparisons) and total bilirubin level (-0.02 and -0.05 mg per deciliter [-0.3 and -0.9 μmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 μmol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5-10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5-10-mg group, 11% in the 10-mg group, and 4% in the placebo group. CONCLUSIONS Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid.

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