SummaryBackgroundTopical ionic contraviral therapy (ICVT) with digoxin and furosemide inhibits the potassium influx on which DNA viruses rely for replication. Therefore, ICVT was hypothesized to be a potential novel treatment for cutaneous warts.ObjectivesTo assess the clinical efficacy, safety and tolerability of ICVT in adults with cutaneous warts. The secondary objective was to gain insight into the underlying working mechanism of ICVT.MethodsTreatment with ICVT was assessed for efficacy, safety and tolerability in a single‐ centre, randomized, double‐blind, placebo‐controlled phase IIA trial. Eighty adult patients with at least two cutaneous warts (plantar or common) were randomized to one of four treatments: digoxin + furosemide (0·125%), digoxin (0·125%), furosemide (0·125%) or placebo. The gel was administered once daily for 42 consecutive days. Predefined statistical analysis was performed with a mixed‐model ancova. The trial was registered at ClinicalTrials.gov with number NCT02333643.ResultsWart size and human papillomavirus (HPV) load reduction was achieved in all active treatment groups. A statistically significant reduction in wart diameter of all treated warts was shown in the digoxin + furosemide treatment group vs. placebo (−3·0 mm, 95% confidence interval −4·9 to −1·1, P = 0·002). There was a statistically significant reduction in the HPV load of all treated warts in the digoxin + furosemide group vs. placebo (−94%, 95% confidence interval −100 to −19, P = 0·03). With wart size reduction, histologically and immunohistochemically defined viral characteristics disappeared from partial and total responding warts.ConclusionsThis study demonstrates the proof of concept for the efficacy of topical ICVT in adults with cutaneous warts.

Background Assessment of treatment effects in clinical trials requires valid information on treatment adherence, adverse events and symptoms. Paper‐based diaries are often inconvenient and have limited reliability, particularly for outpatient trials. Objectives To investigate the utility of an electronic diary (e‐diary) application for patients with skin diseases in outpatient clinical trials. Methods An e‐diary application was developed and technically validated. Treatment adherence was defined as topical administration by the patient, and patient‐reported outcomes, i.e. pain and itch, were evaluated by the e‐diary in six clinical trials on newly tested topical drugs. Additionally, the proportion of patients capturing the applied topical drug by camera and filling in the pain and itch scores was defined as e‐diary adherence, and patients’ perception of usefulness and acceptability of the e‐diary were evaluated. Results Treatment adherence rates of the included 256 patients were high (median 98%, range 97–99%). E‐diary adherence was also high with a median of 93% (range 87–97%) for capturing the applied drug by camera, and 89% (range 87–96%) and 94% (range 87–96%) for entering respectively the itch and pain score. Daily symptom scores provided good insights into the disease burden, and patients rated the e‐diary as good to excellent with respect to user acceptability. Conclusions The results suggest that the e‐diary is an excellent way to ensure proper treatment administration, indicated by both the high user acceptability scores and high treatment adherence. Moreover, the e‐diary may also be valuable for frequent and reliable monitoring of patient‐reported outcomes in daily clinical practice.

Funding information Cutanea Life Sciences Aims: To assess safety and tolerability and explore pharmacodynamics and efficacy of omiganan in external anogenital warts (AGW) and vulvar high-grade squamous intraepithelial lesions (HSIL). Methods: Two randomized controlled trials in patients with external AGW and vulvar HSIL were conducted. Patients received topical omiganan 2.5% or placebo gel once daily for 12 weeks with a follow-up of 12 weeks. Safety and tolerability were monitored and pharmacodynamics and clinical efficacy of omiganan were assessed by analysing lesion count, size and viral load. Self-reported pain, itch and quality of life were assessed by an electronic diary and questionnaire. Results: Twenty-four AGW and 12 vulvar HSIL patients were enrolled. All patients had a high treatment adherence (99%). No serious adverse events occurred and all adverse events (n = 27) were mild, transient and self-limiting. The treatment groups were not different in terms of safety and tolerability, lesion count and size, and patient-reported outcomes pain, itch and quality of life. Human papillomavirus load significantly reduced after 12 weeks of treatment with omiganan compared to placebo (-96.6%; 95% confidence interval-99.9 to-7.4%; P = .045) in AGW patients only. Conclusion: Topical omiganan appears to be safe in patients with AGW and vulvar HSIL and reduced human papillomavirus load after 12 weeks of treatment in AGW patients.

Background The quantification of human papilloma virus (HPV)‐induced skin lesions is essential for the clinical assessment of the course of disease and the response to treatment. However, clinical assessments that measure dimensions of lesions using a caliper do not provide complete insight into three‐dimensional (3D) lesions, and its inter‐rater variability is often poor. Objective The aim of this study was to validate a stereophotogrammetric 3D camera system for the quantification of HPV‐induced lesions. Methods The camera system was validated for accuracy, precision and interoperator and inter‐rater variability. Subsequently, 3D photographs were quantified and compared to caliper measurements for clinical validation by Bland–Altman modelling, based on data from 80 patients with cutaneous warts (CW), 24 with anogenital warts (AGW) patients and 12 with high‐grade squamous intraepithelial lesions of the vulva (vulvar HSIL) with a total lesion count of 220 CW, 74 AGW and 31 vulvar HSIL. Results Technical validation showed excellent accuracy [coefficients of variation (CV) ≤ 0.68%] and reproducibility (CVs ≤ 2%), a good to excellent agreement between operators (CVs ≤ 8.7%) and a good to excellent agreement between different raters for all three lesion types (ICCs ≥ 0.86). When comparing 3D with caliper measurements, excellent biases were found for diameter of AGW (long diameter 5%), good biases were found for diameter of AGW (short diameter 10%) and height of CW (8%), and acceptable biases were found for the diameter of CW (11%) and vulvar HSIL (short diameter 14%, long diameter 16%). An unfavourable difference between these methods (bias 25%) was found for the assessment of height of AGWs. Conclusion Stereophotogrammetric 3D imaging is an accurate and reliable method for the clinical visualization and quantification of HPV‐induced skin lesions.

Omiganan (OMN; a synthetic cationic peptide) and imiquimod (IMQ; a TLR7 agonist) have synergistic effects on interferon responses in vitro. The objective of this study was to translate this to a human model for proof-of-concept, and to explore the potential of OMN add-on treatment for viral skin diseases. Sixteen healthy volunteers received topical IMQ, OMN, or a combination of both for up to 4 days on tape-stripped skin. Skin inflammation was quantified by laser speckle contrast imaging and 2D photography, and molecular and cellular responses were analyzed in biopsies. IMQ treatment induced an inflammatory response of the skin. Co-treatment with OMN enhanced this inflammatory response to IMQ, with increases in perfusion (+17.1%; 95% confidence interval (CI) 5.6%-30%; P < 0.01) and erythema (+1.5; 95% CI 0.25%-2.83; P = 0.02). Interferon regulatory factor-driven and NFκBdriven responses following TLR7 stimulation were enhanced by OMN (increases in IL-6, IL-10, MXA, and IFNɣ), and more immune cell infiltration was observed (in particular CD4+, CD8+, and CD14+ cells). These findings are in line with the earlier mechanistic in vitro data, and support evaluation of imiquimod/OMN combination therapy in human papillomavirus-induced skin diseases.Cathelicidins are a family of antimicrobial (cationic) peptides that play an important role in the first line immune defense of the skin, related to their broad antimicrobial activity against bacteria, viruses, and fungi. 1 LL-37 is the only human member of the cathelicidin family. 1 Besides its antimicrobial effects, this peptide also has direct immunomodulatory activity. LL-37 affects the response of neutrophils to viruses, and modulates interferon (IFN) responses induced by viral triggers. 2 LL-37 converts self-RNA into a ligand for toll-like receptor (TLR)7 and TLR8 in human dendritic cells, thereby enhancing IFNα production in human skin. 3 Omiganan (OMN) is a synthetic indolicidin (a cathelicidin isolated from bovine neutrophils), currently under development as topical gel for several clinical indications. OMN is known to have activity against a wide variety of microorganisms, such as gram-positive and gramnegative bacteria and fungi. 4,5 Moreover, OMN enhances IFN responses induced by TLR3 (Poly:IC), TLR7 (imiquimod (IMQ)), TLR8 (ssRNA), and TLR9 (CpG) in human immune cells, comparable but not similar to the effects observed for Grievink et al.). These observations support the future application of OMN