<p>BACKGROUND Herpes simplex virus infection is common with an estimated global prevalence of over 90%. Of those harbouring the dormant virus, around one third suffer from recurrent episodic reactivation on the vermillion border of the lip, leading to herpes simplex la- bialis (HSL), or a ‘cold sore’. The painful lesions associated with HSL are treated with a range of therapeutic approaches globally, from pharmaceuticals to complementary and alternative medicines (CAM), many of which have a limited or absent evidence base for efficacy and safety. Honey is one such CAM product with growing evidence for efficacy in wound healing, often applied topically for various dermatological ailments and of interest in the management of HSL. Obtaining robust evidence of the efficacy and safety of novel therapies for HSL is a complex and costly undertaking, traditionally requiring large randomised controlled trials (RCT), and as such has been limited to pharmaceutical funded drug development programmes. Given the paucity of high-quality evidence for many CAM therapies there is a clear need for a novel research methodology to overcome the existing barriers and ensure the timely recruitment of participants with an acute episode of HSL and the collection of valid, standardised outcome data at a modest cost. RESEARCH AIMS The primary aim was to investigate the effectiveness, safety and tolerability of a kānuka honey/glycerin cream compared to 5% aciclovir cream in the treatment of HSL. The secondary aim was to establish whether it was feasible to conduct an adequately powered, interventional RCT which includes electronic capture and transmission of data within a New Zealand wide network of community pharmacies, the Pharmacy Research Network (PRN). METHODS A phase III, open label, RCT of adults aged 16 and over presenting to a community pharmacy with an acute episode of HSL was conducted between September 2015 and December 2017. Participants were recruited within 72 hours of the onset of symptoms, and randomly allocated to either the kānuka honey/glycerin formulation or 5% aciclovir cream, to be applied five times daily until skin returned to normal or study day 14, whichever occurred first. All outcome data were collected remotely using a customised digital system. The primary outcome was time taken for skin to return to nor- mal at the site of the HSL lesion, analysed by Kaplan-Meier estimates with 95% Confidence Internal (CI). The PRN was established for the purpose of undertaking this trial. FINDINGS 952 participants with HSL presenting to one of the 76 pharmacies within the PRN were randomised. For the primary outcome variable of time for skin to return to normal, there was no significant difference between kānuka honey/glycerin and 5% aciclovir cream, 9 (95% CI 8 to 9) vs 8 (95% CI 8 to 9) days respectively, Hazard Ratio (HR) (95% CI) 1.06 (0.92 to 1.22) P=0.56. There was no difference between treatments for all secondary outcomes, including healing time to ulceration, healing time from ulceration to resolution, time to resolution of pain, maximal pain, acceptability and adverse events. The PRN was shown to be a robust clinical research infrastructure, able to fully recruit a large-scale randomised trial at fractional cost of traditional models with acceptable recruitment, attrition and deviation rates. CONCLUSION In one of the largest RCTs of a therapy in HSL, there was no evidence of superior effectiveness for either kānuka honey/glycerin or 5% aciclovir cream. This unique, real- world PRN using electronic capture and transmission of data provides a model for future research of CAM in the community setting.</p>
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