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A placebo-controlled randomised trial of budesonide for PBC following an insufficient response to UDCA

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  • Gideon M Hirschfield, University Health Network
  • ,
  • Ulrich Beuers, University of Amsterdam
  • ,
  • Limas Kupcinskas, Lithuanian University of Health Sciences
  • ,
  • Peter Ott
  • Annika Bergquist, Karolinska Univ Hosp, Karolinska Institutet, Karolinska University Hospital
  • ,
  • Martti Färkkilä, University of Helsinki and Helsinki University Hospital
  • ,
  • Michael P Manns, Hannover Medical School
  • ,
  • Albert Parés, University of Barcelona
  • ,
  • Ulrich Spengler, University of Bonn
  • ,
  • Michael Stiess, Dr Falk Pharma GmbH, Freiburg, Germany.
  • ,
  • Roland Greinwald, Dr Falk Pharma GmbH, Freiburg, Germany.
  • ,
  • Markus Pröls, Dr Falk Pharma GmbH, Freiburg, Germany.
  • ,
  • Dominique Wendum, Service d'Anatomie et Cytologie Pathologiques Hôpital Saint-Antoine, Sorbonne Université
  • ,
  • Uta Drebber, University of Cologne
  • ,
  • Raoul Poupon, Service d'Hépatologie, Hôpital Saint-Antoine, Université Pierre & Marie Curie, Paris, France.

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.

Original languageEnglish
Book seriesJournal of Hepatology
Pages (from-to)321-329
Number of pages9
Publication statusPublished - Feb 2021

    Research areas

  • Autoimmune liver disease, Clinical trial, Corticosteroids, Treatment non-responder

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