A 2-year multicenter, double-blind, randomized, placebo-controlled study of bezafibrate for the treatment of primary biliary cholangitis in patients with inadequate biochemical response to ursodeoxycholic acid therapy (Bezurso)

Abstract

Background and Aims: 30‐40% of patients with primary biliary cholangitis (PBC) have inadequate biochemical response to ursodeoxycholic acid (UDCA) therapy. These patients are at high risk of liver complications and therefore are candidates for additional treatments. Recently, obeticholic acid has been approved for such patients in combination with UDCA. Combination of fibrates with UDCA may be an alternative option, but evidence supporting this combination in PBC remains limited to small‐sized, non‐blinded controlled studies with limited follow‐up. We report here the first large double‐blind, randomized, placebo‐controlled trial of fibrates (bezafibrate, BZF) in patients with PBC who did not respond adequately to UDCA (NCT01654731). Methods: Patients with an inadequate biochemical response to UDCA based on the Paris‐2 criteria were randomized 1:1 to a 2‐year treatment period with either BZF 400 mg/d or placebo (PLB) in combination with UDCA 13‐15 mg/kg/d. Clinical and biochemical parameters were monitored every 3 months. Pruritus was assessed using a visual analog scale. Liver stiffness measurement (LSM) was assessed by transient elastography. Primary endpoint was normal serum levels of total bilirubin (TB), alkaline phosphatase (ALP), transaminases (AST, ALT), albuminand prothrombintime atmonth24. Results: 100 patients (95% female; mean age: 53 years; 23% cirrhosis; mean LSM: 12.1 kPa; mean TB: 0.8 mg/dL; mean ALP: 2.5 xULN) were randomized. Groups were similar at baseline. Early study discontinuation was observed in 2 BZF and 6 PLB patients (NS). Primary endpointwas reached in 15 (30%) BZFand 0 (0%) PLB patients (p < 0.0001). ALP normalization occurred in 67% and 0% of patients, respectively (p < 0.0001). Relative changes in TB, ALP, AST, ALT, albumin, IgM, cholesterol, itch score, and LSM are shown in Table. The rates of end‐stage liver complications did not differ between groups. Relative changes (%) from baseline to month 24: median [interquartile]. Conclusions: BZF in combination with UDCA is well tolerated, normalizes biochemical prognostic markers, improves pruritus and prevents progression of liver stiffness in PBC patients with inadequate response to UDCA.