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

Gideon M Hirschfield; Ulrich Beuers; Limas Kupcinskas; Peter Ott; Annika Bergquist; Martti Färkkilä; Michael P Manns; Albert Parés; Ulrich Spengler; Michael Stiess; Roland Greinwald; Markus Pröls; Dominique Wendum; Uta Drebber; Raoul Poupon

doi:10.1016/j.jhep.2020.09.011

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

Gideon M Hirschfield^*, Ulrich Beuers, Limas Kupcinskas, Peter Ott, Annika Bergquist, Martti Färkkilä, Michael P Manns, Albert Parés, Ulrich Spengler, Michael Stiess, Roland Greinwald, Markus Pröls, Dominique Wendum, Uta Drebber, Raoul Poupon

^*Corresponding author for this work

Department of Clinical Medicine - Hepatology and Gastroenterology

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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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.

Original language	English
Book series	Journal of Hepatology
Volume	74
Issue	2
Pages (from-to)	321-329
Number of pages	9
ISSN	0169-5185
DOIs	https://doi.org/10.1016/j.jhep.2020.09.011
Publication status	Published - Feb 2021

Keywords

Autoimmune liver disease
Clinical trial
Corticosteroids
Treatment non-responder

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10.1016/j.jhep.2020.09.011

1-s2.0-S0168827820336230-mainFinal published version, 758 KBLicence: CC BY-NC-ND

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Hirschfield, G. M., Beuers, U., Kupcinskas, L., Ott, P., Bergquist, A., Färkkilä, M., Manns, M. P., Parés, A., Spengler, U., Stiess, M., Greinwald, R., Pröls, M., Wendum, D., Drebber, U., & Poupon, R. (2021). A placebo-controlled randomised trial of budesonide for PBC following an insufficient response to UDCA. Journal of Hepatology, 74(2), 321-329. https://doi.org/10.1016/j.jhep.2020.09.011

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

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.",

keywords = "Autoimmune liver disease, Clinical trial, Corticosteroids, Treatment non-responder",

author = "Hirschfield, {Gideon M} and Ulrich Beuers and Limas Kupcinskas and Peter Ott and Annika Bergquist and Martti F{\"a}rkkil{\"a} and Manns, {Michael P} and Albert Par{\'e}s and Ulrich Spengler and Michael Stiess and Roland Greinwald and Markus Pr{\"o}ls and Dominique Wendum and Uta Drebber and Raoul Poupon",

year = "2021",

month = feb,

doi = "10.1016/j.jhep.2020.09.011",

language = "English",

volume = "74",

pages = "321--329",

journal = "Journal of Hepatology",

issn = "0169-5185",

publisher = "Elsevier B.V.",

number = "2",

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Hirschfield, GM, Beuers, U, Kupcinskas, L, Ott, P, Bergquist, A, Färkkilä, M, Manns, MP, Parés, A, Spengler, U, Stiess, M, Greinwald, R, Pröls, M, Wendum, D, Drebber, U & Poupon, R 2021, 'A placebo-controlled randomised trial of budesonide for PBC following an insufficient response to UDCA', Journal of Hepatology, vol. 74, no. 2, pp. 321-329. https://doi.org/10.1016/j.jhep.2020.09.011

A placebo-controlled randomised trial of budesonide for PBC following an insufficient response to UDCA. / Hirschfield, Gideon M; Beuers, Ulrich; Kupcinskas, Limas et al.
In: Journal of Hepatology, Vol. 74, No. 2, 02.2021, p. 321-329.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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

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

U2 - 10.1016/j.jhep.2020.09.011

DO - 10.1016/j.jhep.2020.09.011

M3 - Journal article

C2 - 32950590

SN - 0169-5185

VL - 74

SP - 321

EP - 329

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 2

ER -

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

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