Abstract

Background and aims: Pruritus may seriously impair quality of life in patients with cholestatic diseases such as primary or secondary sclerosing cholangitis (PSC, SSC) and primary biliary cholangitis (PBC). Pharmacological strategies show limited efficacy and can provoke serious side effects. We hypothesized that bezafibrate, a broad peroxisome proliferator-activated receptor (PPAR) agonist, relieves cholestasis-associated itch by alleviating hepatobiliary injury. The aim of this investigator-initiated FITCH trial ("Fibrates for cholestatic ITCH") was to assess effects of bezafibrate on pruritus in patients with PSC, PBC and SSC.

Methods: Patients with moderate to severe pruritus (>5 out of 10 on visual analogue scale (VAS)) due to PSC, PBC or SSC were recruited for this double-blind, randomized, placebo-controlled trial between 2016 and 2019. Patients received once-daily bezafibrate (400mg) or placebo for 21 days. The primary endpoint was >50% reduction of pruritus (VAS; intention-to-treat).

Results: 70 of 74 randomized patients completed the trial (95%; 44 PSC, 24 PBC, 2 SSC). For the primary endpoint, bezafibrate led in 45% (41% PSC, 55% PBC), placebo in 11% to >50% reduction of severe or moderate pruritus (p=0.003). For secondary endpoints, bezafibrate reduced morning (p=0.01 vs. placebo) and evening (p=0.007) intensity of pruritus (VAS) and improved the validated 5D-itch-questionnaire (p=0.002 vs. placebo). Bezafibrate also reduced serum alkaline phosphatase (-35%, p=0.03 vs. placebo) correlating with improved pruritus (VAS, p=0.01) suggesting reduced biliary damage. Serum bile acids and autotaxin activity remained unchanged. Serum creatinine levels tended to mildly increase (3% bezafibrate, 5% placebo, p=0.14).

Conclusion: Bezafibrate is superior to placebo in improving moderate to severe pruritus in patients with PSC and PBC.

Trial registration: Netherlands Trial Register, ID: NTR5436 (3 August 2015), ClinicalTrials.gov ID: NCT02701166 (2 March 2016).