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 investigatorinitiated 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, placebocontrolled 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 ¼ .003). For secondary end points, bezafibrate reduced morning (P ¼ .01 vs placebo) and evening (P ¼ .007) intensity of pruritus (VAS) and improved the validated 5D-Itch questionnaire (P ¼ .002 vs placebo). Bezafibrate also reduced serum alkaline phosphatase (À35%, P ¼ .03 vs placebo) correlating with improved pruritus (VAS, P ¼ .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 ¼ .14). CONCLUSIONS: Bezafibrate is superior to placebo in improving moderate to severe pruritus in patients with PSC and PBC.

Combination of fibrates with obeticholic acid is able to normalise biochemical liver tests in patients with difficult‐to‐treat primary biliary cholangitis

“…Another important finding from our study is that fibrates, when added to OCA and UDCA (Group OCA‐Fibrate), led to a significant improvement of pruritus with a 10 times increased probability of having no itch than with OCA and UDCA. This result is in accordance with the known beneficial effect of fibrates on PBC‐associated pruritus 14,15,22 . It suggests that the association of fibrates with OCA, irrespective of its long‐term potentiating effects on PBC, could be particularly relevant in order to mitigate the side effects of OCA 17 …”

“…This result is in accordance with the known beneficial effect of fibrates on PBC-associated pruritus. 14,15,22 It suggests that the association of fibrates with OCA, irrespective of its long-term potentiating effects on PBC, could be particularly relevant in order to mitigate the side effects of OCA. 17 The comparison of therapeutic sequences between OCA and fibrates (Group OCA-Fibrate vs Group Fibrate-OCA) revealed differences in biochemical responses that could reflect drug-specific mechanisms.…”

“…Bezafibrate (BZF), a pan-PPAR agonist, has shown beneficial effects on both symptoms and biochemical features of high-risk PBC patients, while fenofibrate (FNF), a selective PPARα agonist, has comparable effects. [13][14][15][16] Most frequent side effects of fibrates are myalgia and increased creatinine level.…”

Specific considerations for the management of primary biliary cholangitis: are the drug treatment options good enough?

“…Intractable pruritus remains an indication for liver transplantation [1]. Paradoxically, UDCA [18] and OCA can make pruritus worse although there is emerging evidence to suggest fibrates may help control pruritus [13,19]. A number of clinical trials targeting pruritus suggest promise, including the use of ileal bile acid transporter inhibitors [20].…”

<p>Experimental Pharmacological Agents for the Treatment of Primary Biliary Cholangitis</p>

“…Interestingly, a double blind, randomized, placebo-controlled trial with the aim to assess the effects of bezafibrate on pruritus (FITCH) has been conducted in 70 patients with PBC, PSC and secondary sclerosing cholangitis with moderate to severe pruritus. 32 The primary endpoint was ≥50% reduction of pruritus (scored on visual analogue scale). Bezafibrate (400 mg/day) led 45%, placebo 11% to the primary endpoint (P=0.003).…”