A Placebo-controlled Trial of Bezafibrate in Primary Biliary Cholangitis
Trial Summarized by: Hajra Munawar, MBBS
Hasan Shafiq, MD
Contribution to literature
This trial revealed that the use of the Bezafibrate (PPAR-a agonist )add-on therapy with ursodeoxycholic acid (UDCA) in patients with primary biliary cholangitis, normalizes the serum levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, albumin, and prothrombin index at 24 months.
Description of the trail
The goal of this trial was to compare the Bezafibrate add-on therapy with placebo in patients with primary biliary cholangitis, who had an inadequate response to UDCA, at 24 months and assess the overall difference among complete biochemical markers (AST, ALT, ALP, PT, Total bilirubin and albumin).
It was a two-group, randomized, double-blinded, placebo-controlled trial from September 2012 to December 2014, that recruited patients from 21 centers throughout France. Patients were randomly assigned, in a 1:1 ratio, to receive either Bezafibrate 400mg (50 patients) or placebo (50 patients) once daily, patients in both groups received UDCA therapy for 6 months or more and had an inadequate response. Follow up performed every 3 months for 24 months and USG of liver and liver stiffness measurement were performed at baseline, at 12 months and at 24
Total number of patients: 100
Duration of follow up: 2 years
Percentage white female: 95%
Mean patient age: 53 years +/- 10
Clinically significant pruritus: 40%
Advanced stages of disease: 54%
18 years and older
Diagnosed cases of primary biliary cholangitis
All patients were treated with UDCA for 6 months or more
Inadequate biochemical response (ALP or AST >1.5 times of normal range and abnormal total bilirubin levels) to UDCA.
Patients with total bilirubin >3 mg/dl.
Patients with autoimmune hepatitis.
30 % of the patients with PBC, who had an inadequate response to UDCA, in the bezafibrate group had complete biochemical response ( normal serum levels of ALP, AST, total bilirubin, Albumin, and PT) and 1 % in the placebo group, for a difference of 29% (95% CI,16 to 43; P<0.001) at 24 months.
ALP Levels: At 24 months, 67% in the treatment group and 2 % in the placebo group had normal ALP levels with (95%CI ,47 to 79).
Total bilirubin levels: Total bilirubin decreased 14% in the treatment group and increased by 18% in the placebo group.
ALP and GGT: 60% median reduction in ALP and GGT in the treatment group at 3 moths.
Pruritus and fatigue: Changes in pruritus and fatigue were consistent with the primary outcome
Quality of life: No significant change in the quality of life scores.
Liver fibrosis: Liver stiffness/fibrosis decreased 15 % in the treatment group and increased by 22% in the placebo group (95% CI, -64 to -8)
Histologic data: Histologic data was limited to only 28 patients and no significant difference between the 2 groups.
Portal HTN and liver complications: No significant difference in developing Portal HTN and liver complications in 2 groups.
Post hoc outcomes:
Total and endogenous bile acids, UDCA and C4 (a marker of bile acid synthesis): no significant difference between the groups
IgM, IgG levels, CRP, TNF a, IL12: no significant difference between the groups.
The Trial demonstrated that among the patients with primary biliary cholangitis who had an inadequate response to UDCA, approximately one-third of the patients in the bezafibrate group, as compared with no patients in the placebo group, reached the normal levels of biochemical markers at 24 months. Parallel changes with respect to pruritus, fatigue and noninvasive liver fibrosis were
consistent with this result.
Though this trial has some limitations as well. The trial was not large enough or long enough to assess the effect of bezafibrate on hard outcomes, such as liver transplantation and death. Advanced cirrhosis and severe cholestasis should be considered as potential limiting factors for add-on therapy with bezafibrate. Bezafibrate was associated with a 5% increase in the serum creatinine. Stage 3 CKD developed during treatment with bezafibrate in one patient in this trial, who had diabetes and HTN. As a precaution, bezafibrate should be used carefully in patients with diabetes, HTN, or any known kidney disease.
In conclusion, in patients with primary biliary cholangitis, who had an inadequate response to UDCA, add-on therapy with bezafibrate for 24 months resulted in a higher rate of complete biochemical response than UDCA therapy plus placebo. Parallel changes in fatigue, pruritus and liver fibrosis were consistent with this effect. Bezafibrate was associated with an increase in creatinine levels. Longer and larger studies are needed to assess the effects of Bezafibrate on clinical outcome.
Christophe Corpechot, M.D., Olivier Chazouillères, M.D., Alexandra Rousseau, Ph.D., Antonia Le Gruyer, M.D., François Habersetzer, M.D., Ph.D., Philippe Mathurin, M.D., Ph.D., Odile Goria, M.D., Pascal Potier, M.D., Anne Minello, M.D., Ph.D., Christine Silvain, M.D., Armand Abergel, M.D., Ph.D., Maryline Debette-Gratien, M.D., Ph.D., NEJM june 7,2018. Vol. 378 .no.23