Aprepitant in Anti-histamine-refractory Chronic Nodular Prurigo: A Multicentre, Randomized, Double-blind, Placebo-controlled, Cross-over, Phase-II trial (APREPRU)

Abstract

Chronic nodular prurigo is characterized by multiple highly pruritic cutaneous nodules and a high impact on quality of life. The molecule substance P appears to play a significant role in the pathway of chronic pruritus. This randomized, double-blind, placebo-controlled, cross-over trial aimed to find out if using the drug aprepitant to block the substance P pathway could influence chronic pruritus in chronic nodular prurigo. However, the results showed no significant difference between aprepitant and placebo. The aim of this multicentre, randomized, double-blind, placebo-controlled, cross-over, phase-II study was to determine the antipruritic effect of aprepitant vs. placebo in 58 patients with anti-histamine-refractory chronic pruritus in chronic nodular prurigo. Patients were randomized to receive either first oral aprepitant 80 mg/day or placebo for 4 weeks. Following a 2-week wash-out phase, the patients were crossedover to receive the other treatment for 4 weeks. Primary efficacy criterion was the intra-individual difference between mean itch intensity (visual analogue scale) at baseline compared with the end of treatment period. Prurigo lesions, pruritus course, quality of life, patient benefits, and safety were secondary parameters. No significant differences were found between aprepitant treatment and placebo for any of the parameters investigated. Under the experimental conditions of the study, aprepitant, 80 mg daily for 4 weeks, did not have an antipruritic effect in patients with chronic prurigo. (DRKS00005594; EudraCT Number: 2013-001601-85).

Neurokinin‐1 and cytokine receptors as targets for therapy of chronic prurigo

“…Scratching is known to preserve prurigo nodules, and pruritus has to be greatly reduced in order enable prurigo lesions to heal. The modest antipruritic effect observed in the present investigation is in accordance with a recent multicenter, randomized, double‐blind study of aprepitant on chronic prurigo where both aprepitant‐ and placebo‐treated patients showed improvement, no significant difference in efficacy between the groups being shown …”

264 Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK1/2 activation

“…28,29 But, both, topical and systemic application, have been also reported to be insufficient for successful treatment in other studies. 19,[30][31][32] On the other hand, NK1R antagonism with serlopitant revealed high antipruritic effects in PN patients in a recent clinical trial 21. Within our study, we aimed to identify putative cutaneous effects of NK1R antagonists in PN patients and in vitro in a cell culture model.…”

“…13,16 Blocking the binding of SP by systemic application of the NK1R antagonist aprepitant showed a marked reduction of itch in large series of patients with chronic pruritus including PN, 17,18 but failed in a recent randomized placebocontrolled clinical trial. 19 However, another clinical trial with the novel NK1R antagonist serlopitant demonstrated high antipruritic effects in PN patients. 20,21 Up to now it is unclear if the antipruritic effects of NK1R antagonists result from receptor binding in the skin or the central nervous system.…”

Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK1/2 activation

“…Aprepitant was frequently supposed to mediate effects in the skin . But, both, topical and systemic application, have been also reported to be insufficient for successful treatment in other studies …”

“…Furthermore, NK1R may activate the MAP kinase signal pathway member ERK1/2, a known inducer of pro‐inflammatory ILs . Blocking the binding of SP by systemic application of the NK1R antagonist aprepitant showed a marked reduction of itch in large series of patients with chronic pruritus including PN, but failed in a recent randomized placebo‐controlled clinical trial . However, another clinical trial with the novel NK1R antagonist serlopitant demonstrated high antipruritic effects in PN patients .…”