Cantharidin and Occlusion in Verruca Epithelium (COVE-1) was an open-label phase 2 clinical study. The study followed Good Clinical Practice and country-specific laws and regulations. Compliance also conformed with US federal regulatory codes, the Nuremberg Code, and the Declaration of Helsinki [23]. The Copernicus Group Independent Review Board approved the protocol and consent form, oversaw trial conduct, and maintained documentation. Written informed consent/assent was obtained from all adult participants and the parents or guardians of participants younger than 18 years as per the local state regulations.

Eligible patients were required to have one to six common warts (excluding genital, palmar/plantar, and subungual warts) measuring ≤ 10 mm in diameter and ≤ 3 mm in height and deemed based upon the clinical judgment of the investigator to be consistent with the inclusion and exclusion criteria of the trial. Pre-study screening for eligibility, provision of informed consent and assent (when applicable), physical exam, and collection of data on demographics, prior and current concomitant medications, and medical history were completed at a baseline visit within 14 days of the first treatment visit. Participants could not have received any type of treatment for common warts within the 14 days prior to the first treatment of the study drug. All participants received topical treatment with approximately 10–20 μL of solution from a VP-102 applicator to all treatable common warts as well as 1–2 mm of surrounding healthy skin, which were then occluded with 3M™ Blenderm™ tape (3M Co., St. Paul, MN, USA). Participants were instructed to slowly remove the tape to prevent unroofing any blister present and wash off VP-102 with soap and water 24 h following treatment. The participant could remove the tape and study drug from an individual common wart without a protocol violation if significant blistering, pain or treatment-emergent adverse events (TEAEs) occurred prior to the 24-h time point. Participants were enrolled into two separate cohorts which varied in treatment schedule and technique. An infographic of the study protocol can be found in Fig. 1. A wart count was taken at each clinic visit and could include common warts present at baseline and any new common warts that appeared during the study and during a follow-up period (if applicable).

Treatment methods for cohorts 1 and 2, including study drug application at study visits and ERT follow-up. Single asterisk indicates that the minimum interval between treatments was 14 days but it could be longer depending on clinical response. Two asterisks indicate that the drug and tape were removed 24 h post-treatment. The dagger symbol indicates that wart paring was performed at any treatment visit when an adherent thick scale was present and the investigator considered it safe to apply. EOS  End of study visit, EOT end of treatment visit, ERT  evaluation of response to treatment, LSR local skin reaction

The study included two cohorts with different application schedules and methods. Cohort 1 included participants aged ≥ 2 years who were treated with VP-102 until all treatable common warts were clear at each treatment visit every 14 days (visit 1/day 1, visit 2/day 14, visit 3/day 28, and visit 4/day 42), or a maximum of four treatments. An extended treatment interval of > 14 days between treatments could be used if a participant experienced persistent local skin reactions (LSRs) at the study visit. Paring of common warts was not utilized in this cohort. Participants in Cohort 1 were assessed for efficacy and safety at day 84, the end-of-study (EOS) visit.

Cohort 2 included participants aged ≥ 12 years who were treated with VP-102 every 21 days (visit 1/day 1, visit 2/day 21, visit 3/day 42, and visit 4/day 63) for up to four treatments. One additional treatment with VP-102 was applied to a treated area after clearance if clearance occurred prior to four treatments. If adherent scale was present, trained practitioners pared common warts prior to the application of VP-102. Participants in Cohort 2 also had an end-of-treatment (EOT) visit at day 84 with follow-up visits at days 105 and 126, and an EOS visit at day 147.

In both cohorts, the primary efficacy endpoint included the proportion of participants with complete clearance of all treatable common warts (baseline and new) at the day 84 EOT/EOS visit. Primary safety outcomes included incidence of adverse events, physician examinations, concomitant medications, and LSRs. An evaluation of response to treatment (ERT) occurred during treatment visits and via the telephone for both cohorts at 24 h and 7 days after treatment was administered. Clinical response to the treatment of warts was evaluated at each scheduled in-person visit until EOS by counting all remaining warts.

For Cohort 1, the secondary endpoints were to evaluate the efficacy of VP-102 by assessing the change from baseline in the number of treatable common warts (baseline and new) at the EOS visit (day 84), to evaluate the efficacy of VP-102 by assessing the change from baseline in the percentage of clearance of treatable common warts (baseline and new) at the EOS visit (day 84), and to evaluate the efficacy of VP-102 by assessing the proportion of participants exhibiting complete clearance of all treatable common warts (baseline and new) at earlier visits (visit 2/day 14, visit 3/day 28, visit 4/day 42). Exploratory endpoints included percentage change in common warts compared to baseline by visit.

For Cohort 2, the secondary endpoints were to evaluate the efficacy of VP-102 by assessing the change from baseline in the number of treatable common warts (baseline and new) at the EOT visit (day 84), to evaluate the efficacy of VP-102 by assessing the change from baseline in the percentage of clearance of treatable common warts (baseline and new) at the EOT visit (day 84), and to evaluate the efficacy of VP-102 by assessing the proportion of participants exhibiting complete clearance of all treatable common warts (baseline and new) at visit 2/day 21, treatment visit 3/day 42, and visit 4/day 63. Select exploratory endpoints were to evaluate the efficacy of VP-102 by assessing the proportion of participants exhibiting complete clearance of all treatable common warts at follow-up visits on day 105, day 126, and the EOS visit (day 147) as well as the percentage change in common warts compared to baseline at each visit.

Although no formal power calculations were performed, it was estimated that a sample size of 20 subjects (Cohort 1) and 35 subjects (Cohort 2) evaluable at the EOS/EOT visit (day 84 for both cohorts) would be informative regarding common wart clearance rates and build a safety profile for VP-102 in common warts. Efficacy outcomes analyses were completed using the intent-to-treat population, which included any participant who was randomized to treatment. Safety and baseline demographic and disease state outcomes were completed using the safety population, which included any participant who received at least one treatment of VP-102. In calculations of complete clearance, participants with missing data on clearance at any time point were considered not completely clear at that visit. Last observation carried forward was used to calculate percentage change of common warts compared to baseline, change from baseline in treatable common warts, and proportion of participants achieving ≥ 50% clearance. Data were summarized using descriptive statistics (sample size, mean, median, standard deviation, minimum, maximum) for continuous variables and frequencies and percentages for discrete variables.