TY - JOUR
T1 - A placebo-controlled randomised trial of budesonide for PBC following an insufficient response to UDCA
AU - Hirschfield, Gideon M.
AU - Beuers, Ulrich
AU - Kupcinskas, Limas
AU - Ott, Peter
AU - Bergquist, Annika
AU - Färkkilä, Martti
AU - Manns, Michael P.
AU - Parés, Albert
AU - Spengler, Ulrich
AU - Stiess, Michael
AU - Greinwald, Roland
AU - Pröls, Markus
AU - Wendum, Dominique
AU - Drebber, Uta
AU - Poupon, Raoul
N1 - Funding Information: G Hirschfield: personal fees and advisory board fees from Dr Falk Pharma GmbH, Cymabay, Gilead, Intercept, GSK, Roche, Pliant and Genfit. U Beuers: support for investigator-initiated studies by Dr.Falk and Intercept. No lecture fees in 2019 and 2020 (current member EASL Clinical Practice Guideline Committees). A Pares: received grant funding, personal fees and advisory board fees from Intercept Pharmaceuticals; advisory board fees and personal fees from Novartis; and personal fees from CymaBay Therapeutics and Inova Diagnostics. M Manns: grants, personal fees and non-financial support from Gilead; grants, personal fees and non-financial support from Intercept; grants, personal fees and non-financial support from Falk; grants, personal fees and non-financial support from Novartis, outside the submitted work. R. Greinwald, M. Pröls and M. Stiess: employees of Dr Falk Pharma GmbH. All other authors had no relevant conflicts of interest to declare. Funding Information: This study was funded by Dr. Falk Pharma GmbH . With the input of key investigators and regulators, Dr. Falk Pharma GmbH designed the protocol, and supported the analysis of the data. Publisher Copyright: © 2020 European Association for the Study of the Liver Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
KW - Autoimmune liver disease
KW - Clinical trial
KW - Corticosteroids
KW - Treatment non-responder
UR - http://www.scopus.com/inward/record.url?scp=85096558683&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jhep.2020.09.011
DO - https://doi.org/10.1016/j.jhep.2020.09.011
M3 - Article
C2 - 32950590
SN - 0168-8278
VL - 74
SP - 321
EP - 329
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 2
ER -