Elsemieke de Vries1, Ruth Bolier1, Jorn Goet2, Albert Parés3, Jef Verbeek4, Marleen de Vree5, Joost Drenth6, Karel van Erpecum7, Karin van Nieuwkerk8, Frans van der Heide5, Nahid Mostafavi1, Jeltje Helder1, Cyriel Ponsioen1, Ronald Oude Elferink1, Henk van Buuren2, Ulrich Beuers9. 1. Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands. 2. Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands. 3. Liver Unit, Hospital Clinic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d'Investigacion Biomediques August Pi-Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain. 4. Department of Gastroenterology & Hepatology, Maastricht University Medical Center, Maastricht, the Netherlands. 5. Department of Gastroenterology & Hepatology, University Medical Center Groningen, Groningen, the Netherlands. 6. Department of Gastroenterology & Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands. 7. Department of Gastroenterology & Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands. 8. Department of Gastroenterology & Hepatology, Amsterdam University Medical Centers, location Vrije Universiteit Medisch Centrum (VUmc), Amsterdam, the Netherlands. 9. Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands. Electronic address: u.h.beuers@amsterdamumc.nl.
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). Pharmacologic 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 of 10 on visual analog 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 (400 mg) or placebo for 21 days. The primary end point was ≥50% reduction of pruritus (VAS; intention-to-treat). RESULTS:Of 74 randomized patients, 70 completed the trial (95%; 44 PSC, 24 PBC, 2 SSC). For the primary end point, bezafibrate led in 45% (41% PSC, 55% PBC) and placebo in 11% to ≥50% reduction of severe or moderate pruritus (P = .003). For secondary end points, bezafibrate reduced morning (P = .01 vs placebo) and evening (P = .007) intensity of pruritus (VAS) and improved the validated 5D-Itch questionnaire (P = .002 vs placebo). Bezafibrate also reduced serum alkaline phosphatase (-35%, P = .03 vs placebo) correlating with improved pruritus (VAS, P = .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 = .14). CONCLUSIONS:Bezafibrate is superior to placebo in improving moderate to severe pruritus in patients with PSC and PBC. TRIAL REGISTRATION: Netherlands Trial Register, ID: NTR5436 (August 3, 2015), ClinicalTrials.gov ID: NCT02701166 (March 2, 2016).
RCT Entities:
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). Pharmacologic 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 of 10 on visual analog 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 (400 mg) or placebo for 21 days. The primary end point was ≥50% reduction of pruritus (VAS; intention-to-treat). RESULTS: Of 74 randomized patients, 70 completed the trial (95%; 44 PSC, 24 PBC, 2 SSC). For the primary end point, bezafibrate led in 45% (41% PSC, 55% PBC) and placebo in 11% to ≥50% reduction of severe or moderate pruritus (P = .003). For secondary end points, bezafibrate reduced morning (P = .01 vs placebo) and evening (P = .007) intensity of pruritus (VAS) and improved the validated 5D-Itch questionnaire (P = .002 vs placebo). Bezafibrate also reduced serum alkaline phosphatase (-35%, P = .03 vs placebo) correlating with improved pruritus (VAS, P = .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 = .14). CONCLUSIONS:Bezafibrate is superior to placebo in improving moderate to severe pruritus in patients with PSC and PBC. TRIAL REGISTRATION: Netherlands Trial Register, ID: NTR5436 (August 3, 2015), ClinicalTrials.gov ID: NCT02701166 (March 2, 2016).