Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies: A Double-Blind, Randomized, Placebo-Controlled Trial

E de Vries; R Bolier; Jorn Goet; A Parés; J Verbeek; M de Vree; J Drenth; K van Erpecum; K van Nieuwkerk; F van der Heide; N Mostafavi; J Helder; C Ponsioen; R Oude Elferink; Henk van Buuren; U Beuers

doi:10.1053/j.gastro.2020.10.001

Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies: A Double-Blind, Randomized, Placebo-Controlled Trial

E de Vries, R Bolier, Jorn Goet, A Parés, J Verbeek, M de Vree, J Drenth, K van Erpecum, K van Nieuwkerk, F van der Heide, N Mostafavi, J Helder, C Ponsioen, R Oude Elferink, Henk van Buuren, U Beuers

Gastroenterology & Hepatology

Research output: Contribution to journal › Article › Academic › peer-review

121 Citations (Scopus)

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).

Original language	English
Pages (from-to)	734-743.e6
Journal	Gastroenterology
Volume	160
Issue number	3
DOIs	https://doi.org/10.1053/j.gastro.2020.10.001
Publication status	Published - Feb 2021

Bibliographical note

Funding Information:
Funding The trial was funded by a South African PSC patient foundation (to U.B.), a Netherlands patient donation (to U.B.), a “Gastrostart” grant of the Netherlands Society of Gastroenterology covering 50% of drug manufacturing (to U.B.), and for management of patient inclusion in Barcelona grant PI15/797 from the Instituto de Salud Carlos III (to A.P.).

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© 2021 AGA Institute

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de Vries, E., Bolier, R., Goet, J., Parés, A., Verbeek, J., de Vree, M., Drenth, J., van Erpecum, K., van Nieuwkerk, K., van der Heide, F., Mostafavi, N., Helder, J., Ponsioen, C., Oude Elferink, R., van Buuren, H., & Beuers, U. (2021). Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies: A Double-Blind, Randomized, Placebo-Controlled Trial. Gastroenterology, 160(3), 734-743.e6. https://doi.org/10.1053/j.gastro.2020.10.001

@article{a09056ad558b43efbfbe6ff01025f610,

title = "Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies: A Double-Blind, Randomized, Placebo-Controlled Trial",

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).",

author = "{de Vries}, E and R Bolier and Jorn Goet and A Par{\'e}s and J Verbeek and {de Vree}, M and J Drenth and {van Erpecum}, K and {van Nieuwkerk}, K and {van der Heide}, F and N Mostafavi and J Helder and C Ponsioen and {Oude Elferink}, R and {van Buuren}, Henk and U Beuers",

note = "Funding Information: Funding The trial was funded by a South African PSC patient foundation (to U.B.), a Netherlands patient donation (to U.B.), a “Gastrostart” grant of the Netherlands Society of Gastroenterology covering 50% of drug manufacturing (to U.B.), and for management of patient inclusion in Barcelona grant PI15/797 from the Instituto de Salud Carlos III (to A.P.). Publisher Copyright: {\textcopyright} 2021 AGA Institute",

year = "2021",

month = feb,

doi = "10.1053/j.gastro.2020.10.001",

language = "English",

volume = "160",

pages = "734--743.e6",

journal = "Gastroenterology",

issn = "0016-5085",

number = "3",

}

de Vries, E, Bolier, R, Goet, J, Parés, A, Verbeek, J, de Vree, M, Drenth, J, van Erpecum, K, van Nieuwkerk, K, van der Heide, F, Mostafavi, N, Helder, J, Ponsioen, C, Oude Elferink, R, van Buuren, H & Beuers, U 2021, 'Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies: A Double-Blind, Randomized, Placebo-Controlled Trial', Gastroenterology, vol. 160, no. 3, pp. 734-743.e6. https://doi.org/10.1053/j.gastro.2020.10.001

TY - JOUR

T1 - Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies: A Double-Blind, Randomized, Placebo-Controlled Trial

AU - de Vries, E

AU - Bolier, R

AU - Goet, Jorn

AU - Parés, A

AU - Verbeek, J

AU - de Vree, M

AU - Drenth, J

AU - van Erpecum, K

AU - van Nieuwkerk, K

AU - van der Heide, F

AU - Mostafavi, N

AU - Helder, J

AU - Ponsioen, C

AU - Oude Elferink, R

AU - van Buuren, Henk

AU - Beuers, U

N1 - Funding Information: Funding The trial was funded by a South African PSC patient foundation (to U.B.), a Netherlands patient donation (to U.B.), a “Gastrostart” grant of the Netherlands Society of Gastroenterology covering 50% of drug manufacturing (to U.B.), and for management of patient inclusion in Barcelona grant PI15/797 from the Instituto de Salud Carlos III (to A.P.). Publisher Copyright: © 2021 AGA Institute

PY - 2021/2

Y1 - 2021/2

N2 - 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).

AB - 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).

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U2 - 10.1053/j.gastro.2020.10.001

DO - 10.1053/j.gastro.2020.10.001

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C2 - 33031833

SN - 0016-5085

VL - 160

SP - 734-743.e6

JO - Gastroenterology

JF - Gastroenterology

IS - 3

ER -

Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies: A Double-Blind, Randomized, Placebo-Controlled Trial

Abstract

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