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Abstract Details
A placebo-controlled randomised trial of budesonide for primary biliary cholangitis following an insufficient response to UDCA
J Hepatol. 2020 Sep 17;S0168-8278(20)33623-0. doi: 10.1016/j.jhep.2020.09.011.Online ahead of print.
G M Hirschfield1, U Beuers2, L Kupcinskas3, P Ott4, A Bergquist5, M Färkkilä6, M P Manns7, A Parés8, U Spengler9, M Stiess10, R Greinwald10, M Pröls10, D Wendum11, U Drebber12, R Poupon13
Author information
1Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada. Electronic address: gideon.hirschfield@uhn.ca.
2Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
3Department of Gastroenterology & Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
4Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
5Department of Gastroenterology & Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
6Helsinki University and Helsinki University Hospital, Clinic of Gastroenterology, Helsinki Finland.
7Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
8Liver Unit, Hospital Clínic, IDIBAPS, University of Barcelona, CIBERehd, Barcelona, Spain.
9Department of Internal Medicine I, University of Bonn, Bonn, Germany.
10Research and Development, Dr. Falk Pharma GmbH, Freiburg, Germany.
11Service 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.
12Institute of Pathology, University of Cologne, Cologne, Germany.
13Service 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 utility 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).
Methods: We evaluated 62 patients with PBC who had histologically confirmed hepatic inflammatory activity, according to the Ishak-score, and an alkaline phosphatase (ALP) >1.5x 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 underpowered compared to original intent. The primary histologic endpoint, comparing patients with paired biopsies only (n= 43), was not met (p>0.05). The proportion of patients with ALP <1.67xULN, ≥15% decrease 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 had 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 in patients with PBC, and insufficient response to UDCA, did not associate with improvement in liver histology; improvements in biochemical markers of disease activity were demonstrated in secondary analyses.