Acta Derm Venereol 2016; 96: 792–796 CLINICAL REPORT Anti-pruritic Effect of Sertaconazole 2% Cream in Atopic Dermatitis Subjects: A Prospective, Randomized, Double-blind, Vehicle-controlled, Multi-centre Clinical Trial of Efficacy, Safety and Local Tolerability Sonja STÄNDER1, Martin METZ2, Mac H. RAMOS F.3, Marcus MAURER2, Nicole SCHOEPKE2, Athanasios TSIANAKAS1, Claudia ZEIDLER1 and Thomas A. LUGER1 1Competence Center Chronic Pruritus, Department of Dermatology, University Hospital Münster, Münster, 2Allergie-Centrum-Charité, Department of Dermatology and Allergy, Charité –Universitätsmedizin, Berlin, Germany, and 3Galderma-Spirig, Egerkingen, Switzerland This study was a prospective, parallel-group, randomi- e.g. histamine, nerve growth factor (NGF), substance zed, double-blind, vehicle-controlled, multi-centre clini- P (SP), proteases, and cytokines/chemokines (thymic cal trial to compare the efficacy of topical sertaconazole stromal lymphopoietin (TSLP), interleukin (IL) -2, IL-4, 2% cream with vehicle in reducing chronic pruritus in IL-13, prostaglandin E2 and IL-31) (1, 7-9). In severe subjects with atopic dermatitis, and to assess its safety cases of AD, subjects scratch the involved skin areas until and local tolerability. A total of 70 subjects applied either they bleed (1). This worsens the skin condition, resulting of the 2 treatments twice daily for a period of 4 weeks on in a vicious itch-scratch cycle, which severely affects affected, itchy skin areas. Treatment efficacy was eva- the quality of life of subjects and their families (6). Itch luated primarily considering the item itch intensity on management is, therefore, one of the most important is- a 5-point verbal rating scale. Insomnia, state of atopic sues in the treatment of AD (10). There is no generally dermatitis (Scoring Atopic Dermatitis; SCORAD), qua- established therapy for itch in AD. Hence, atopic pruritus lity of life and therapy benefit were also assessed. No is usually treated with a tailored approach (11), either significant difference between active treatment and ve- with moisturizers or with topical and systemic immu- hicle was found at any of the time-points for any of the nosuppressants (12). Although such therapies generally investigated parameters. Under the experimental condi- have a good safety profile, better itch-specific treatment tions of the study, sertaconazole 2% cream did not exert options are needed. anti-pruritic effects that were better than vehicle in sub- Systemic and/or topical antimycotics of the imidazole jects with atopic dermatitis who had chronic pruritus. type have been reported to be effective in AD (13–15). Trial registration ClinicalTrials.gov #NCT01792713. Key Their fungistatic or fungicidal effects can explain this words: sertaconazole; pruritus; itch; atopic dermatitis. as fungi, such as Malassezia furfur, are involved in AD. However, direct immunomodulatory effects have Accepted Oct 29, 2015; Epub ahead of print Nov 3, 2015 also been reported to be responsible for their efficacy Acta Derm Venereol 2016; 96: 792–796. in AD (15). Sertaconazole nitrate is a well-established, well-tolerated, commercially available (Dermofix®, Sonja Ständer, Center for Chronic Pruritus, Department of Ertaczo™, Ginedermofix®, Monazol, Mykosert® or Dermatology, University Hospital Münster, Von-Esmarch- Zalain®) imidazole antifungal agent, which also exerts Str. 58, DE-48149 Münster, Germany. E-mail: sonja. anti-bacterial action (16). Sertaconazole nitrate has been [email protected] shown to reduce the release of cytokines from activated lymphocytes and to mitigate inflammation in animal Atopic dermatitis (AD), one of the most pruritic skin di- models of irritant contact dermatitis and neurogenic seases (1, 2), is a common disorder affecting 15–30% of inflammation (17). Furthermore, sertaconazole repor- children and 2–10% of adults in industrialized countries tedly inhibits contact hypersensitivity and scratching (3). Pruritus, the unpleasant sensation that leads to a de- responses in a murine model of substance P-induced sire to scratch (4), is the most important clinical symptom pruritus, indicating that topical administration may of AD (5, 6) with a prevalence of up to 100% in this result in an efficacious anti-inflammatory activity in a disease (7). The exact pathophysiology of itch in AD is spectrum of cutaneous inflammation models and itch not yet fully understood (8). Studies have demonstrated (17). Kaur et al. (18) have shown that sertaconazole that mechanisms such as increased density of cutaneous mediates its anti-itch effects by increasing prostaglan- nerve fibres participate in the induction and maintenance din D2 levels in mast cells and macrophages through of this troublesome and disabling symptom, in addition induction of the p38 mitogen-activated protein kinase to various receptors (cold receptor TRPA1, histamine 4 pathway. Prostaglandin D2 is known to have anti- receptor, proteinase activated receptor 2/Mas-related G pruritic activity by suppressing histamine release (19). protein receptor) and central and peripheral mediators, Finally, human studies in fungal infections reported Acta Derm Venereol 96 © 2016 The Authors. doi: 10.2340/00015555-2268 Journal Compilation © 2016 Acta Dermato-Venereologica. ISSN 0001-5555 Anti-pruritic potential of sertaconazole in AD: an RCT 793 anti-pruritic effects from antimycotic treatment with Enrollment Assessed for eligibility (n=71) sertaconazole (20–22). Therefore, sertaconazole with Excluded (n=1) its positive safety profile (16) and its anti-inflammatory lNot meeting inclusion criteria (n=1) and anti-pruritic properties could be a possible solution Randomized (n=70) to address pruritus in AD. However, clinical studies evaluating its anti-pruritic action in AD are sparse Allocation and, as yet, there are no published reports of controlled Allocated to active/ITT active (n=32) Allocated to vehicle/ITT active (n=38) studies. Thus, the aim of this study was to close this lReceived allocated intervention (n=32) lReceived allocated intervention (n=38) gap, by comparing the efficacy of topical sertaconazole Follow-up Discontinued intervention (worsening) (n=5) Lost to follow-up (n=2) 2% cream with vehicle in reducing chronic pruritus in Excluded (major protocol deviations (n=3) Discontinued intervention (worsening) (n=4) subjects with AD, as well as to assess its safety and Excluded (major protocol deviations (n=3) local tolerability. Analysis Analysed/PP (n=24) Analysed/PP (n=29) Fig. 1. Progress of all subjects through the trial. PP: per-protocol population. METHODS Study design during the whole study. Adherence to treatment was assessed by collecting and weighing the treatment tubes at each subject visit. This was a prospective, randomized (1:1), double-blind, vehicle-controlled, parallel-group, phase-II clinical trial con- ducted at 2 sites in Germany (Center for Chronic Pruritus, Study outcomes Department of Dermatology, University Hospital Münster; The primary efficacy success was defined as ≥ 2 grades reduc- Allergie-Centrum-Charité, Department of Dermatology and tion in intensity of pruritus between baseline and week 4, as eva- Allergy, Charité –Universitätsmedizin Berlin, Germany). All luated on a 5-point VRS, which was part of the patient’s global subjects gave written informed consent. The ethics commit- assessment (PGA) questionnaire. The subject answered this at tee at the central coordinating centre (Münster) and at the each visit under the supervision of the investigator. Further ef- participating site (Berlin) both approved the trial. The trial is ficacy variables were: intensity of pruritus and insomnia both on registered at the US National Institutes of Health (ClinicalTri- a VAS, state of atopic dermatitis (SCORAD, Eczema Area and als.gov) #NCT01792713 and at the European Union Clinical Severity Index (EASI)) and of quality of life (Dermatological Trial Register. Life Quality Index (DLQI)). The Patients Benefit Index (PBI) questionnaire was used to evaluate the subjects’ appreciation Study population and treatment of the treatment benefits vs. baseline, and featured 27 items. Each of the 27 items had to be answered as not at all, slightly, Over a period of 11 months, 70 randomly (1:1) selected subjects moderately, quite a lot or as very much. Skin barrier function (30 males, 40 females, 18–75 years, mean age 34.1 (± 14.7) (transepidermal water loss (TEWL)), mycological evaluation years) with pruritus (> 6 weeks, visual analogue scale (VAS) of skin surface, adverse events, vital signs and blood laboratory ≥ 7, (VAS 0–10) during the last 2 days before visit 1; verbal parameters were also assessed during the course of the study. rating scale (VRS) ≥ 3) due to AD (Scoring Atopic Dermatitis; All scales used are generally recognized as reliable, accurate SCORAD ≤ 40) were included in the study. Subjects showing and relevant for subjects with atopic dermatitis (6, 23, 24). unstable or uncontrolled significant medical conditions, infec- tions, addiction to alcohol or/and drugs, dermatological abnor- malities, allergy to any of the treatment’s ingredients, participa- Statistical methods tion in another clinical study, pregnancy or lactation or using To achieve a ≥ 2 point decrease in pruritus intensity during treat- therapies up to 2 or 4 weeks before onset of the study, which ment in 60% of the active treated and in 30% of the vehicle-treated could influence its outcome (antihistamines, corticosteroids, subjects, with a statistical power of ≥ 80% and a significance