Gideon M Hirschfield1, Andrew Mason2, Velimir Luketic3, Keith Lindor4, Stuart C Gordon5, Marlyn Mayo6, Kris V Kowdley7, Catherine Vincent8, Henry C Bodhenheimer9, Albert Parés10, Michael Trauner11, Hanns-Ulrich Marschall12, Luciano Adorini13, Cathi Sciacca13, Tessa Beecher-Jones13, Erin Castelloe13, Olaf Böhm14, David Shapiro13. 1. Centre for Liver Research, NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK. Electronic address: g.hirschfield@bham.ac.uk. 2. Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada. 3. Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, Virginia; McGuire Research Institute, McGuire VA Medical Center, Richmond, VA. 4. Division of Gastroenterology and Hepatology, Mayo Medical School, Rochester, Minnesota; School for the Science of Health Care Delivery, Arizona State University, Phoenix, Arizona. 5. Division of Hepatology, Henry Ford Health Systems, Detroit, Michigan. 6. Division of Digestive and Liver Diseases, University of Texas, Southwestern Medical Center, Dallas, Texas. 7. Digestive Disease Institute, Virginia Mason Medical Center, Seattle, Washington. 8. Department of Hepatology, Hopital Saint-Luc/CHUM Montreal, Canada. 9. Department of Medicine, Mount Sinai School of Medicine, New York, New York; Division of Digestive Diseases, Beth Israel Medical Center, New York, New York. 10. Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain. 11. Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Austria. 12. Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 13. Intercept Pharmaceuticals, San Diego, California. 14. FGK Clinical Research, Munich, Germany.
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. ClinicalTrials.gov ID: NCT00550862.
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. ClinicalTrials.gov ID: NCT00550862.
Authors: Jessica K Dyson; Gideon M Hirschfield; David H Adams; Ulrich Beuers; Derek A Mann; Keith D Lindor; David E J Jones Journal: Nat Rev Gastroenterol Hepatol Date: 2015-02-03 Impact factor: 46.802
Authors: Ryan E Feaver; Banumathi K Cole; Mark J Lawson; Stephen A Hoang; Svetlana Marukian; Brett R Blackman; Robert A Figler; Arun J Sanyal; Brian R Wamhoff; Ajit Dash Journal: JCI Insight Date: 2016-12-08