Gideon M Hirschfield1, Ulrich Beuers2, Limas Kupcinskas3, Peter Ott4, Annika Bergquist5, Martti Färkkilä6, Michael P Manns7, Albert Parés8, Ulrich Spengler9, Michael Stiess10, Roland Greinwald10, Markus Pröls10, Dominique Wendum11, Uta Drebber12, Raoul Poupon13. 1. Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada. Electronic address: gideon.hirschfield@uhn.ca. 2. Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. 3. Department of Gastroenterology & Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania. 4. Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark. 5. Department of Gastroenterology & Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. 6. Helsinki University and Helsinki University Hospital, Clinic of Gastroenterology, Helsinki, Finland. 7. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. 8. Liver Unit, Hospital Clínic, IDIBAPS, University of Barcelona, CIBERehd, Barcelona, Spain. 9. Department of Internal Medicine I, University of Bonn, Bonn, Germany. 10. Research and Development, Dr. Falk Pharma GmbH, Freiburg, Germany. 11. Service d'Anatomie et Cytologie Pathologiques Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75571 Paris cedex 12; Sorbonne Université, INSERM UMR_S938, Centre de Recherche Saint-Antoine(CRSA), 75012 Paris, France. 12. Institute of Pathology, University of Cologne, Cologne, Germany. 13. Service d'Hépatologie, Centre national de référence des maladies inflammatoires du foie et des voies biliaires, Hôpital Saint-Antoine, Paris, France.
Abstract
BACKGROUND & AIMS: In patients with primary biliary cholangitis (PBC), the efficacy of budesonide, a synthetic corticosteroid displaying high first-pass metabolism, is unresolved. In a placebo-controlled, double-blind trial, we evaluated the added-value of budesonide in those with PBC and ongoing risk of progressive disease despite ursodeoxycholic acid (UDCA) treatment. METHODS: We evaluated 62 patients with PBC who had histologically confirmed hepatic inflammatory activity, according to the Ishak score, and an alkaline phosphatase (ALP) >1.5× upper limit of normal (ULN), after at least 6 months of UDCA therapy. Participants were randomly assigned 2:1 to receive budesonide (9 mg/day) or placebo once daily, for 36 months, with UDCA treatment (12-16 mg/kg body weight/day) maintained. Primary efficacy was defined as improvement of liver histology with respect to inflammation and no progression of fibrosis. Secondary outcomes included changes in biochemical markers of liver injury. RESULTS: Recruitment challenges resulted in a study that was underpowered for the primary efficacy analysis. Comparing patients with paired biopsies only (n = 43), the primary histologic endpoint was not met (p >0.05). The proportion of patients with ALP <1.67×ULN, a ≥15% decrease in ALP and normal bilirubin was higher in the budesonide group than in the placebo group at 12, 24, and 36 months (p <0.05, each). In contrast to placebo, budesonide reduced mean ALP and 35% of budesonide-treated patients achieved normalisation of ALP (placebo 9%; p = 0.023). Serious adverse events occurred in 10 patients receiving budesonide and 7 patients receiving placebo. CONCLUSION: Budesonide add-on therapy was not associated with improved liver histology in patients with PBC and insufficient response to UDCA; however, improvements in biochemical markers of disease activity were demonstrated in secondary analyses. LAY SUMMARY: Around one-third of patients with primary biliary cholangitis (PBC) needs additional medical therapy alongside ursodeoxycholic acid (UDCA) treatment. In this clinical trial, the addition of the corticosteroid budesonide did not improve liver histology; there were however relevant improvements in liver blood tests. CLINICALTRIALS. GOV NUMBER: NCT00746486.
BACKGROUND & AIMS: In patients with primary biliary cholangitis (PBC), the efficacy of budesonide, a synthetic corticosteroid displaying high first-pass metabolism, is unresolved. In a placebo-controlled, double-blind trial, we evaluated the added-value of budesonide in those with PBC and ongoing risk of progressive disease despite ursodeoxycholic acid (UDCA) treatment. METHODS: We evaluated 62 patients with PBC who had histologically confirmed hepatic inflammatory activity, according to the Ishak score, and an alkaline phosphatase (ALP) >1.5× upper limit of normal (ULN), after at least 6 months of UDCA therapy. Participants were randomly assigned 2:1 to receive budesonide (9 mg/day) or placebo once daily, for 36 months, with UDCA treatment (12-16 mg/kg body weight/day) maintained. Primary efficacy was defined as improvement of liver histology with respect to inflammation and no progression of fibrosis. Secondary outcomes included changes in biochemical markers of liver injury. RESULTS: Recruitment challenges resulted in a study that was underpowered for the primary efficacy analysis. Comparing patients with paired biopsies only (n = 43), the primary histologic endpoint was not met (p >0.05). The proportion of patients with ALP <1.67×ULN, a ≥15% decrease in ALP and normal bilirubin was higher in the budesonide group than in the placebo group at 12, 24, and 36 months (p <0.05, each). In contrast to placebo, budesonide reduced mean ALP and 35% of budesonide-treated patients achieved normalisation of ALP (placebo 9%; p = 0.023). Serious adverse events occurred in 10 patients receiving budesonide and 7 patients receiving placebo. CONCLUSION: Budesonide add-on therapy was not associated with improved liver histology in patients with PBC and insufficient response to UDCA; however, improvements in biochemical markers of disease activity were demonstrated in secondary analyses. LAY SUMMARY: Around one-third of patients with primary biliary cholangitis (PBC) needs additional medical therapy alongside ursodeoxycholic acid (UDCA) treatment. In this clinical trial, the addition of the corticosteroid budesonide did not improve liver histology; there were however relevant improvements in liver blood tests. CLINICALTRIALS. GOV NUMBER: NCT00746486.
Authors: Xuan Guoyun; Ding Dawei; Liu Ning; Hu Yinan; Yang Fangfang; Tian Siyuan; Sun Hao; Yang Jiaqi; Xu Ang; Guo Guanya; Chen Xi; Shang Yulong; Han Ying Journal: Front Pharmacol Date: 2022-08-30 Impact factor: 5.988
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Authors: Joachim F Kuebler; Omid Madadi-Sanjani; Eva D Pfister; Ulrich Baumann; David Fortmann; Johannes Leonhardt; Benno M Ure; Michael P Manns; Richard Taubert; Claus Petersen Journal: J Clin Med Date: 2021-12-09 Impact factor: 4.241