A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis
Frederik Nevens, Pietro Andreone, Giuseppe Mazzella, Simone I Strasser, Christopher Bowlus, Pietro Invernizzi, Joost P H Drenth, Paul J Pockros, Jaroslaw Regula, Ulrich Beuers, Michael Trauner, David E Jones, Annarosa Floreani, Simon Hohenester, Velimir Luketic, Mitchell Shiffman, Karel J van Erpecum, Victor Vargas, Catherine Vincent, Gideon M Hirschfield, Hemant Shah, Bettina Hansen, Keith D Lindor, Hanns-Ulrich Marschall, Kris V Kowdley, Roya Hooshmand-Rad, Tonya Marmon, Shawn Sheeron, Richard Pencek, Leigh MacConell, Mark Pruzanski, David Shapiro, POISE Study Group, Peter Angus, Stuart Roberts, Simone I Strasser, Michael Trauner, Wolfgang Vogel, Ivo Graziadei, Frederik Nevens, Hemant Shah, Catherine Vincent, Victor de Lédinghen, Thomas Berg, Daniel Gotthardt, Heinz Hartmann, Simon D Hohenester, Andreas E Kremer, Frank Lammert, Michael P Manns, Christian Rust, Christoph Schramm, Christian Trautwein, Stefan Zeuzem, Pietro Andreone, Annarosa Floreani, Pietro Invernizzi, Marco Carbone, Giuseppe Mazzella, Ulrich Beuers, Joost P H Drenth, Bettina Hansen, Karel J van Erpecum, Carin C M J van Nieuwkerk, Krzysztof Celinski, Maciej Gonciarz, Marek Hartleb, Piotr Milkiewicz, Jaroslaw Regula, Albert Parés, Victor Vargas, Hanns-Ulrich Marschall, Peter Bramley, Douglas Thorburn, Rajeshwar P Mookerjee, Andrew Burroughs, Roger Chapman, John F Dillon, John A Greer, Gideon M Hirschfield, Dhiraj Tripathi, David E Jones, Anne McCune, Stephen Ryder, Bruce R Bacon, Jahnavi Naik, Lan Sun Wang, Henry C Bodenheimer, Christopher L Bowlus, Naga Chalasani, Lisa M Forman, Stuart C Gordon, Kris V Kowdley, Keith D Lindor, Velimir A Luketic, Marlyn Mayo, Andrew J Muir, Paul J Pockros, K Gautham Reddy, Mitchell Shiffman, Jayant T Talwalker, John M Vierling, Frederik Nevens, Pietro Andreone, Giuseppe Mazzella, Simone I Strasser, Christopher Bowlus, Pietro Invernizzi, Joost P H Drenth, Paul J Pockros, Jaroslaw Regula, Ulrich Beuers, Michael Trauner, David E Jones, Annarosa Floreani, Simon Hohenester, Velimir Luketic, Mitchell Shiffman, Karel J van Erpecum, Victor Vargas, Catherine Vincent, Gideon M Hirschfield, Hemant Shah, Bettina Hansen, Keith D Lindor, Hanns-Ulrich Marschall, Kris V Kowdley, Roya Hooshmand-Rad, Tonya Marmon, Shawn Sheeron, Richard Pencek, Leigh MacConell, Mark Pruzanski, David Shapiro, POISE Study Group, Peter Angus, Stuart Roberts, Simone I Strasser, Michael Trauner, Wolfgang Vogel, Ivo Graziadei, Frederik Nevens, Hemant Shah, Catherine Vincent, Victor de Lédinghen, Thomas Berg, Daniel Gotthardt, Heinz Hartmann, Simon D Hohenester, Andreas E Kremer, Frank Lammert, Michael P Manns, Christian Rust, Christoph Schramm, Christian Trautwein, Stefan Zeuzem, Pietro Andreone, Annarosa Floreani, Pietro Invernizzi, Marco Carbone, Giuseppe Mazzella, Ulrich Beuers, Joost P H Drenth, Bettina Hansen, Karel J van Erpecum, Carin C M J van Nieuwkerk, Krzysztof Celinski, Maciej Gonciarz, Marek Hartleb, Piotr Milkiewicz, Jaroslaw Regula, Albert Parés, Victor Vargas, Hanns-Ulrich Marschall, Peter Bramley, Douglas Thorburn, Rajeshwar P Mookerjee, Andrew Burroughs, Roger Chapman, John F Dillon, John A Greer, Gideon M Hirschfield, Dhiraj Tripathi, David E Jones, Anne McCune, Stephen Ryder, Bruce R Bacon, Jahnavi Naik, Lan Sun Wang, Henry C Bodenheimer, Christopher L Bowlus, Naga Chalasani, Lisa M Forman, Stuart C Gordon, Kris V Kowdley, Keith D Lindor, Velimir A Luketic, Marlyn Mayo, Andrew J Muir, Paul J Pockros, K Gautham Reddy, Mitchell Shiffman, Jayant T Talwalker, John M Vierling
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. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524; Current Controlled Trials number, ISRCTN89514817.).
Source: PubMed