A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis.
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A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis. / Nevens, Frederik; Andreone, Pietro; Mazzella, Giuseppe; Strasser, Simone I; Bowlus, Christopher; Invernizzi, Pietro; Drenth, Joost P H; Pockros, Paul J; Regula, Jaroslaw; Beuers, Ulrich; Trauner, Michael; Jones, David E; Floreani, Annarosa; Hohenester, Simon; Luketic, Velimir; Shiffman, Mitchell; van Erpecum, Karel J; Vargas, Victor; Vincent, Catherine; Hirschfield, Gideon M; Shah, Hemant; Hansen, Bettina; Lindor, Keith D; Marschall, Hanns-Ulrich; Kowdley, Kris V; Hooshmand-Rad, Roya; Marmon, Tonya; Sheeron, Shawn; Pencek, Richard; MacConell, Leigh; Pruzanski, Mark; Shapiro, David; POISE Study Group.
In: NEW ENGL J MED, Vol. 375, No. 7, 18.08.2016, p. 631-43.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis.
AU - Nevens, Frederik
AU - Andreone, Pietro
AU - Mazzella, Giuseppe
AU - Strasser, Simone I
AU - Bowlus, Christopher
AU - Invernizzi, Pietro
AU - Drenth, Joost P H
AU - Pockros, Paul J
AU - Regula, Jaroslaw
AU - Beuers, Ulrich
AU - Trauner, Michael
AU - Jones, David E
AU - Floreani, Annarosa
AU - Hohenester, Simon
AU - Luketic, Velimir
AU - Shiffman, Mitchell
AU - van Erpecum, Karel J
AU - Vargas, Victor
AU - Vincent, Catherine
AU - Hirschfield, Gideon M
AU - Shah, Hemant
AU - Hansen, Bettina
AU - Lindor, Keith D
AU - Marschall, Hanns-Ulrich
AU - Kowdley, Kris V
AU - Hooshmand-Rad, Roya
AU - Marmon, Tonya
AU - Sheeron, Shawn
AU - Pencek, Richard
AU - MacConell, Leigh
AU - Pruzanski, Mark
AU - Shapiro, David
AU - POISE Study Group
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. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524; Current Controlled Trials number, ISRCTN89514817.).
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. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524; Current Controlled Trials number, ISRCTN89514817.).
KW - Adult
KW - Aged
KW - Alkaline Phosphatase
KW - Bile Acids and Salts
KW - Bone Density
KW - Chenodeoxycholic Acid
KW - Double-Blind Method
KW - Female
KW - Fibroblast Growth Factors
KW - Humans
KW - Liver Cirrhosis
KW - Liver Cirrhosis, Biliary
KW - Male
KW - Middle Aged
KW - Pruritus
KW - Clinical Trial, Phase III
KW - Journal Article
KW - Multicenter Study
KW - Randomized Controlled Trial
KW - Research Support, Non-U.S. Gov't
U2 - 10.1056/NEJMoa1509840
DO - 10.1056/NEJMoa1509840
M3 - SCORING: Journal article
C2 - 27532829
VL - 375
SP - 631
EP - 643
JO - NEW ENGL J MED
JF - NEW ENGL J MED
SN - 0028-4793
IS - 7
ER -