Fibrates for the treatment of cholestatic itch (FITCH): study protocol for a randomized controlled trial

Ruth Bolier, Elsemieke S de Vries, Albert Parés, Jeltje Helder, E Marleen Kemper, Koos Zwinderman, Ronald P Oude Elferink, Ulrich Beuers, Netherlands Association for the Study of the Liver (NASL) Cholestatic Liver Diseases Study Group, Henk R van Buuren, Joost P Drenth, Karel J van Erpecum, Bart van Hoek, Peter L M Jansen, Karin M van Nieuwkerk, J Marleen de Vree, Ruth Bolier, Elsemieke S de Vries, Albert Parés, Jeltje Helder, E Marleen Kemper, Koos Zwinderman, Ronald P Oude Elferink, Ulrich Beuers, Netherlands Association for the Study of the Liver (NASL) Cholestatic Liver Diseases Study Group, Henk R van Buuren, Joost P Drenth, Karel J van Erpecum, Bart van Hoek, Peter L M Jansen, Karin M van Nieuwkerk, J Marleen de Vree

Abstract

Background: Pruritus (itch) is a frequent, burdensome and difficult-to-treat symptom in patients with cholestasis. Fibrates are currently under investigation for the treatment of primary biliary cholangitis in patients with a suboptimal response to ursodeoxycholic acid. Moreover, there is empirical evidence for a possible antipruritic effect. We aim to prove this in a randomized controlled trial, including patients with cholestatic liver diseases other than primary biliary cholangitis that are accompanied by pruritus.

Methods: A multicenter investigator-initiated, double-blind, randomized placebo-controlled trial to evaluate the effect of bezafibrate on cholestatic pruritus in 84 adult patients with primary biliary cholangitis or primary/secondary sclerosing cholangitis. Primary outcome is the proportion of patients with a reduction of itch intensity of 50% or more (measured on a Visual Analog Scale) after 21 days of treatment with bezafibrate 400 mg qid or placebo. Secondary outcomes include the effect of bezafibrate on a five-dimensional itch score, liver disease-specific quality of life, serum liver tests and autotaxin activity. Safety will be evaluated through serum parameters for kidney function and rhabdomyolysis as well as precise recording of (serious) adverse events. We provide a schematic overview of the study protocol and describe the methods used to recruit and randomize patients, collect and handle data and perform statistical analyses.

Discussion: Given its favorable safety profile and anticholestatic properties, bezafibrate may become the new first-line treatment option for treating cholestatic pruritus.

Trial registration: Netherlands Trial Register, ID: NCT02701166 . Registered on 2 March 2016; Netherlands Trial Register, ID: NTR5436 . Registered on 3 August 2015.

Keywords: Bezafibrate; Itch; Primary biliary cholangitis; Primary sclerosing cholangitis; Pruritus; Secondary sclerosing cholangitis.

Figures

Fig. 1
Fig. 1
Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) figure: schedule of enrollment, interventions and assessments. 5D five-dimensional, LDSI Liver Disease Symptom Index, VAS Visual Analog Scale

References

    1. Beuers U, Gershwin ME, Gish RG, Invernizzi P, Jones DE, Lindor K, et al. Changing nomenclature for PBC: from ‘cirrhosis’ to ‘cholangitis’. Hepatology. 2015;62:1620–2. doi: 10.1002/hep.28140.
    1. Beuers U, Kremer AE, Bolier AR, Oude Elferink RPJ. Pruritus in cholestasis: facts and fiction. Hepatology. 2014;60:399–407. doi: 10.1002/hep.26909.
    1. Kuiper EM, Hansen BE, Metselaar HJ, de Man RA, Haagsma EB, van Hoek B, et al. Trends in liver transplantation for primary biliary cirrhosis in the Netherlands 1988–2008. BMC Gastroenterol. 2010;10:144. doi: 10.1186/1471-230X-10-144.
    1. Beuers U, Boberg K, Chapman R, Chazouillères OIP, Jones D, Lammert F, et al. EASL clinical practice guidelines: management of cholestatic liver diseases. J Hepatology. 2009;51:237–67. doi: 10.1016/j.jhep.2009.09.018.
    1. Miyaguchi S, Ebinuma H, Imaeda H, Nitta Y, Watanabe T, Saito H, et al. A novel treatment for refractory primary biliary cirrhosis? Hepatogastroenterology. 2000;47:1518–21.
    1. Nakai S, Masaki T, Kurokohchi K, Deguchi A, Nishioka M. Combination therapy of bezafibrate and ursodeoxycholic acid in primary biliary cirrhosis: a preliminary study. Am J Gastroenterol. 2000;95:326–7. doi: 10.1111/j.1572-0241.2000.01667.x.
    1. Kurihara T, Maeda A, Shigemoto M, Yamashita K, Hashimoto E. Investigation into the efficacy of bezafibrate against primary biliary cirrhosis, with histological references from cases receiving long term monotherapy. Am J Gastroenterol. 2002;97:212–4. doi: 10.1111/j.1572-0241.2002.05413.x.
    1. Yano K, Kato H, Morita S, Takahara O, Ishibashi H, Furukawa R. Is bezafibrate histologically effective for primary biliary cirrhosis? Am J Gastroenterol. 2002;97:1075–7. doi: 10.1111/j.1572-0241.2002.05645.x.
    1. Kanda T, Yokosuka O, Imazeki F, Saisho H. Bezafibrate treatment: a new medical approach for PBC patients? J Gastroenterol. 2003;38:573–8.
    1. Itakura J, Izumi N, Nishimura Y, Inoue K, Ueda K, Nakanishi H, et al. Prospective randomized crossover trial of combination therapy with bezafibrate and UDCA for primary biliary cirrhosis. Hepatol Res. 2004;29:216–22. doi: 10.1016/j.hepres.2004.04.001.
    1. Akbar SM, Furukawa S, Nakanishi S, Abe M, Horiike N, Onji M. Therapeutic efficacy of decreased nitrite production by bezafibrate in patients with primary biliary cirrhosis. J Gastroenterol. 2005;40:157–63. doi: 10.1007/s00535-004-1518-3.
    1. Nakamuta M, Enjoji M, Kotoh K, Shimohashi N, Tanabe Y. Long-term fibrate treatment for PBC. J Gastroenterol. 2005;40:546–7. doi: 10.1007/s00535-004-1583-7.
    1. Kita R, Takamatsu S, Kimura T, Kokuryu H, Osaki Y, Tomono N. Bezafibrate may attenuate biliary damage associated with chronic liver diseases accompanied by high serum biliary enzyme levels. J Gastroenterol. 2006;41:686–92. doi: 10.1007/s00535-006-1831-0.
    1. Ohmoto K, Yoshioka N, Yamamoto S. Long-term effect of bezafibrate on parameters of hepatic fibrosis in primary biliary cirrhosis. J Gastroenterol. 2006;41:502–3. doi: 10.1007/s00535-006-1778-1.
    1. Hazzan R, Tur-Kaspa R. Bezafibrate treatment of primary biliary cirrhosis following incomplete response to ursodeoxycholic acid. J Clin Gastroenterol. 2010;44:371–3.
    1. Takeuchi Y, Ikeda F, Fujioka S, Takaki T, Osawa T, Yasunaka T, et al. Additive improvement induced by bezafibrate in patients with primary biliary cirrhosis showing refractory response to ursodeoxycholic acid. J Gastroenterol Hepatol. 2011;26:1395–401.
    1. Lens S, Leoz M, Nazal L, Bruguera M, Pares A. Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid. Liver Int. 2014;34:197–203. doi: 10.1111/liv.12290.
    1. Iwasaki S, Akisawa N, Saibara T, Onishi S. Fibrate for treatment of primary biliary cirrhosis. Hepatol Res. 2007;37:S515–7. doi: 10.1111/j.1872-034X.2007.00232.x.
    1. Iwasaki S, Ohira H, Nishiguchi S, Zeniya M, Kaneko S, Onji M, et al. The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: a prospective, multicenter study. Hepatol Res. 2008;38:557–64. doi: 10.1111/j.1872-034X.2007.00305.x.
    1. Honda A, Ikegami T, Nakamuta M, Miyazaki T, Iwamoto J, Hirayama T, et al. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology. 2013;57:1931–41. doi: 10.1002/hep.26018.
    1. Reig A, Sese P, Pares A. Bezafibrate: a novel and effective alternative for relieving pruritus in patients with primary biliary cirrhosis. Hepatology. 2015;62:508A. doi: 10.1002/hep.27881.
    1. Pares A. Advances in treatment of pruritus and osteoporosis. Abstract book EASL Monothematic Conference: Primary Biliary Cirrhosis, Milan, Italy 2014. J Hepatology. 2014;60:54.
    1. Iwasaki S, Tsuda K, Ueta H, Aono R, Ono M, Saibara T, et al. Bezafibrate may have a beneficial effect in precirrhotic primary biliary cirrhosis. Hepatol Res. 1999;16:12–8. doi: 10.1016/S1386-6346(99)00033-9.
    1. Tandon P, Rowe BH, Vandermeer B, Bain VG. The efficacy and safety of bile acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritus. Am J Gastroenterol. 2007;102:1528–36. doi: 10.1111/j.1572-0241.2007.01200.x.
    1. Siemens W, Xander C, Meerpohl JJ, Buroh S, Antes G, Schwarzer G, Becker G. Pharmacological interventions for pruritus in adult palliative care patients. Cochrane Database Syst Rev. 2016;11:CD008320.
    1. Bachs L, Pares A, Elena M, Piera C, Rodes J. Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis. Lancet. 1989;1:574–6. doi: 10.1016/S0140-6736(89)91608-5.
    1. Bachs L, Pares A, Elena M, Piera C, Rodes J. Effects of long-term rifampicin administration in primary biliary cirrhosis. Gastroenterology. 1992;102:2077–80. doi: 10.1016/0016-5085(92)90335-V.
    1. Podesta A, Lopez P, Terg R, Villamil F, Flores D, Mastai R, et al. Treatment of pruritus of primary biliary cirrhosis with rifampin. Dig Dis Sci. 1991;36:216–20. doi: 10.1007/BF01300759.
    1. Ghent CN, Carruthers SG. Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial. Gastroenterology. 1988;94:488–93. doi: 10.1016/0016-5085(88)90442-8.
    1. Woolf GM, Reynolds TB. Failure of rifampin to relieve pruritus in chronic liver disease. J Clin Gastroenterol. 1990;12:174–7. doi: 10.1097/00004836-199004000-00012.
    1. Loginov AS, Reshetniak VI, Petrakov AV. The treatment of primary biliary liver cirrhosis with rifampicin. Ter Arkh. 1993;65:57–62.
    1. Prince MI, Burt AD, Jones DE. Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis. Gut. 2002;50:436–9. doi: 10.1136/gut.50.3.436.
    1. Phan NQ, Blome C, Fritz F, Gerss J, Reich A, Ebata T, et al. Assessment of pruritus intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus. Acta Derm Venereol. 2012;92:502–7. doi: 10.2340/00015555-1246.
    1. Stander S, Blome C, Breil B, Bruland P, Darsow U, Dugas M, et al. Assessment of pruritus—current standards and implications for clinical practice: consensus paper of the Action Group Pruritus Parameter of the International Working Group on Pruritus Research (AGP) Hautarzt. 2012;63:521–2. doi: 10.1007/s00105-011-2318-3.
    1. Kuiper EM, van Erpecum KJ, Beuers U, Hansen BE, Thio HB, de Man RA, et al. The potent bile acid sequestrant colesevelam is not effective in cholestatic pruritus: results of a double-blind, randomized, placebo-controlled trial. Hepatology. 2010;52:1334–40. doi: 10.1002/hep.23821.
    1. Delerive P, Gervois P, Fruchart JC, Staels B. Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J Biol Chem. 2000;275:36703–7. doi: 10.1074/jbc.M004045200.
    1. Lee JE, Park JH, Jang SJ, Koh HC. Rosiglitazone inhibits chlorpyrifos-induced apoptosis via modulation of the oxidative stress and inflammatory response in SH-SY5Y cells. Toxicol Appl Pharmacol. 2014;278:159–71. doi: 10.1016/j.taap.2014.04.021.
    1. Xu Y, Yang X, Wang Z, Li M, Ning Y, Chen S, et al. Estrogen sulfotransferase (SULT1E1) regulates inflammatory response and lipid metabolism of human endothelial cells via PPARgamma. Mol Cell Endocrinol. 2013;369:140–9. doi: 10.1016/j.mce.2013.01.020.
    1. Ghonem NS, Ananthanarayanan M, Soroka CJ. PPAR alpha activates human MDR3/ABCB4 transcription and increases rat biliary phosphatidylcholine secretion. Hepatology. 2014;59:1030–42. doi: 10.1002/hep.26894.
    1. Kok T, Bloks VW, Wolters H, Havinga R, Jansen PL, Staels B, et al. Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice. Biochem J. 2003;369:539–47. doi: 10.1042/bj20020981.
    1. Matsumoto T, Miyazaki H, Nakahashi Y, Hirohara J, Seki T, Inoue K, et al. Multidrug resistance3 is in situ detected in the liver of patients with primary biliary cirrhosis, and induced in human hepatoma cells by bezafibrate. Hepatol Res. 2004;30:125–36. doi: 10.1016/j.hepres.2004.08.015.
    1. Shoda J, Inada Y, Tsuji A, Kusama H, Ueda T, Ikegami T, et al. Bezafibrate stimulates canalicular localization of NBD-labeled PC in HepG2 cells by PPARalpha-mediated redistribution of ABCB4. J Lipid Res. 2004;45:1813–25. doi: 10.1194/jlr.M400132-JLR200.
    1. Miyahara T, Schrum L, Rippe R, Xiong S, Yee HFJ, Motomura K, et al. Peroxisome proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem. 2000;275:35715–22. doi: 10.1074/jbc.M006577200.
    1. Kremer AE, Martens JJ, Kulik W, Rueff F, Kuiper EM, van Buuren HR, et al. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology. 2010;139:1008–18. doi: 10.1053/j.gastro.2010.05.009.
    1. Kremer AE, van Dijk R, Leckie P, Schaap FG, Kuiper EM, Mettang T, et al. Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions. Hepatology. 2012;56:1391–400. doi: 10.1002/hep.25748.
    1. Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new measure of pruritus. Br J Dermatol. 2010;162:587–93. doi: 10.1111/j.1365-2133.2009.09586.x.
    1. Waslen GD. Management of outpatient burns. Can Fam Physician. 1986;32:805–8.
    1. Van der Plas SM, Hansen BE, de Boer JB, Stijnen T, Passchier J, de Man RA, et al. The Liver Disease Symptom Index 2.0; validation of a disease-specific questionnaire. Qual Life Res. 2004;13:1469–81. doi: 10.1023/B:QURE.0000040797.17449.c0.
    1. Mayo MJ, Handem I, Saldana S, Jacobe H, Getachew Y, Rush AJ. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology. 2007;45:666–74. doi: 10.1002/hep.21553.
    1. Terg R, Coronel E, Sorda J, Munoz AE, Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study. J Hepatol. 2002;37:717–22. doi: 10.1016/S0168-8278(02)00318-5.
    1. Wolfhagen FH, Sternieri E, Hop WC, Vitale G, Bertolotti M, van Buuren HR. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology. 1997;113:1264–9. doi: 10.1053/gast.1997.v113.pm9322521.
    1. Bergasa NV. The itch of liver disease. Semin Cutan Med Surg. 2011;30:93–8. doi: 10.1016/j.sder.2011.04.009.

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