Acta Dermato-Venereologica 99-4CompleteContent | Page 9

CLINICAL REPORT 379 Aprepitant in Anti-histamine-refractory Chronic Nodular Prurigo: A Multicentre, Randomized, Double-blind, Placebo-controlled, Cross-over, Phase-II trial (APREPRU) Athanasios TSIANAKAS 1,2# , Claudia ZEIDLER 1# , Claudia RIEPE 1 , Matthias BOROWSKI 3 , Caroline FORNER 1 , Joachim GERSS 3 , Martin METZ 4 , Petra STAUBACH 5 , Ulrike RAAP 6,7 , Martin KAATZ 8 , Marc URBAN 9 , Thomas A. LUGER 1 and Sonja STÄNDER 1 1 Center for Chronic Pruritus, Department of Dermatology, University Hospital Münster, Münster, 2 Fachklinik Bad Bentheim, Department of Dermatology, Bad Bentheim, 3 Institute of Biostatistics and Clinical Research, University of Münster, Münster, 4 Department of Dermatology and Allergy, Charité –Universitätsmedizin Berlin, 5 Clinical Research Center, Department of Dermatology, University Medical Center, Mainz, 6 Hannover Medical University, Department of Dermatology, Allergology, and Venereology, Hannover, 7 Clinics of Dermatology, Allergy Faculty of Medicine and Health Science, University of Oldenburg, Klinikum Oldenburg AöR, Oldenburg, 8 Department of Dermatology, Jena University Hospital, and Department of Dermatology, SRH Wald-Klinikum Gera, Jena, and 9 Centre for Clinical Trials, Medical Faculty of the University of Münster, Münster, Germany # Both authors contributed equally to this paper. 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 aprepi- tant 80 mg/day or placebo for 4 weeks. Following a 2-week wash-out phase, the patients were crossed- over to receive the other treatment for 4 weeks. Pri- mary efficacy criterion was the intra-individual diffe- rence 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 parame- ters. No significant differences were found between aprepitant treatment and placebo for any of the pa- rameters investigated. Under the experimental condi- tions 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). Key words: pruritus; itch; chronic nodular prurigo; substance P; neurokinin receptor 1; NK1 antagonist. Accepted Jan 16, 2019; E-published Jan 17, 2019 Acta Derm Venereol 2019; 99: 379–385. Corr: Sonja Ständer, Center for Chronic Pruritus, Department of Der- matology, University Hospital Münster, Von-Esmarch-Str. 58, DE-48149 Münster, Germany. E-mail: [email protected] C hronic pruritus (CP) (of over 6 weeks’ duration) has a lifetime prevalence of up to 25.5% (1) and considerably impairs quality of life; thus it represents a worldwide burden (2, 3). Although the medical care of patients with CP has improved over recent years, through establishment of specialized itch clinics, a classifica- tion system, and well-defined treatment guidelines (4, 5), the currently available treatment modalities are not sufficiently efficacious in many patients with CP (6, 7). In addition, many of the recommended therapies exhibit adverse effects and cannot be used on a long-term basis. SIGNIFICANCE 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 no- dular prurigo. However, the results showed no significant difference between aprepitant and placebo. Therefore, there is high level of need for new treatment options that target the biological mechanisms of CP. Substance P (SP), which binds to neurokinin receptor 1 (NKR1), is a major mediator of pruritus (8, 9). NKR1 is expressed both in the central nervous system and in the skin (10). Animal models have demonstrated an anti-pruritic effect by SP inhibition at the NKR1 (11, 12). In an NC/Nga mouse model, oral treatment with the NKR1-antagonist aprepitant, reduced the level of serum immunoglobulin E (IgE), tissue SP levels, and cutaneous infiltration of regulatory T cells (13). The clinical relevance of NKR1-antagonism in humans has been shown in several case series of acute and CP of various origin, using the inhibitor aprepitant (14–21). In an open-label, not placebo-controlled proof-of-concept study, 20 patients with therapy-refractory CP of various origins experienced significant (p < 0.001) antipruritic effect within one week of monotherapy with aprepitant 80 mg once daily (22). This also included patients with chronic nodular prurigo (CNPG), who showed good responses (22). However, there is a lack of evidence regarding the antipruritic effect of aprepitant from con- trolled studies. The aim of this study was to close this gap, and to compare the effect of aprepitant with placebo, not only regarding symptom relief, but also considering pruriginous lesions, quality of life and patient benefits, as recommended by the International Forum for the Study of Itch (IFSI) (23). This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica. doi: 10.2340/00015555-3120 Acta Derm Venereol 2019; 99: 379–385