method. The unit of analysis was ng/mL, with an analysis sensitivity lower limit of quantitation (LLOQ) of 2.5 ng/mL of cantharidin in plasma.
Assessments
The primary objective was to assess the systemic absorption of cantharidin via plasma testing over a 24-hour exposure period after a single topical application of VP-102 to subjects with at least 21 MC lesions as outlined above. The secondary objectives included safety of VP-102, as well as measures of efficacy, and QoL prior to and throughout treatment. Efficacy was assessed by the proportion of VP-102-treated subjects achieving complete clearance of all treatable MC lesions (baseline and new) on EOS/Day 84. Additional efficacy endpoints included the proportion of subjects achieving total clearance at days 21, 42, and 63, and percent reduction of MC lesions from baseline to each time point. Lesion counts were performed by a study investigator prior to each treatment application and at EOS.
The impact of VP-102 treatment on QoL was evaluated using the CDLQI completed by the subject, parent, or caregiver at baseline, and on visit days 21, 42, 63, and the EOS visit (day 84).
Safety and tolerability were assessed by determination of adverse events (AEs) and through parent/guardian reporting on the appearance of the skin, the presence of erythema, and/ or blistering within 24 hours after each drug application via the Patient Evaluation of Response to Investigational Treatment (PERIT) form. Local skin reactions (LSRs) were only reported as AEs if they were outside of the expected response to treatment with cantharidin in the opinion of the investigator. Treatmentemergent AEs (TEAEs) were defined as AEs that occurred at or after the first treatment application.
Investigational Agent
This study introduced the first clinical use of VP-102; a drugdevice combination with a topical solution packaged in a single-use applicator. The active pharmaceutical ingredient of VP-102 is a controlled, highly pure, standardized, viscous topical solution containing 0.7% (w/v) cantharidin manufactured under Good Manufacturing Practices. The film-forming solution also contains gentian violet (a surgical dye to facilitate physician recognition of treated vs untreated lesions) and denatonium benzoate (a bittering agent included to deter potential oral ingestion of the drug). Upon applying the solution via the applicator, the solution dries leaving a thin film that is then washed off up to 24 hours later.
Statistical Methods
Subject disposition, baseline characteristics, MC medical history, and study drug exposure are summarized using descriptive statistics for continuous variables and frequencies and percentages of discrete variables. Adverse event data for the safety population are listed individually and the incidence of AEs is summarized using frequency counts. Analyses included all subjects that entered the study (intent to treat, or ITT group).
Assessments
The primary objective was to assess the systemic absorption of cantharidin via plasma testing over a 24-hour exposure period after a single topical application of VP-102 to subjects with at least 21 MC lesions as outlined above. The secondary objectives included safety of VP-102, as well as measures of efficacy, and QoL prior to and throughout treatment. Efficacy was assessed by the proportion of VP-102-treated subjects achieving complete clearance of all treatable MC lesions (baseline and new) on EOS/Day 84. Additional efficacy endpoints included the proportion of subjects achieving total clearance at days 21, 42, and 63, and percent reduction of MC lesions from baseline to each time point. Lesion counts were performed by a study investigator prior to each treatment application and at EOS.
The impact of VP-102 treatment on QoL was evaluated using the CDLQI completed by the subject, parent, or caregiver at baseline, and on visit days 21, 42, 63, and the EOS visit (day 84).
Safety and tolerability were assessed by determination of adverse events (AEs) and through parent/guardian reporting on the appearance of the skin, the presence of erythema, and/ or blistering within 24 hours after each drug application via the Patient Evaluation of Response to Investigational Treatment (PERIT) form. Local skin reactions (LSRs) were only reported as AEs if they were outside of the expected response to treatment with cantharidin in the opinion of the investigator. Treatmentemergent AEs (TEAEs) were defined as AEs that occurred at or after the first treatment application.
Investigational Agent
This study introduced the first clinical use of VP-102; a drugdevice combination with a topical solution packaged in a single-use applicator. The active pharmaceutical ingredient of VP-102 is a controlled, highly pure, standardized, viscous topical solution containing 0.7% (w/v) cantharidin manufactured under Good Manufacturing Practices. The film-forming solution also contains gentian violet (a surgical dye to facilitate physician recognition of treated vs untreated lesions) and denatonium benzoate (a bittering agent included to deter potential oral ingestion of the drug). Upon applying the solution via the applicator, the solution dries leaving a thin film that is then washed off up to 24 hours later.
Statistical Methods
Subject disposition, baseline characteristics, MC medical history, and study drug exposure are summarized using descriptive statistics for continuous variables and frequencies and percentages of discrete variables. Adverse event data for the safety population are listed individually and the incidence of AEs is summarized using frequency counts. Analyses included all subjects that entered the study (intent to treat, or ITT group).
RESULTS
A total of 33 subjects were enrolled at a single site in the US, 16 in the VP-102 standard population group and 17 in the exposure group. Baseline demographics including age (median 5 years; range, 2–15), gender, race distribution, and body mass index were similar in both groups (Table 1). Subjects in the standard group had a median of 13.5 lesions (range, 3–21) and a median duration of 33 days since clinical diagnosis. Participants in the exposure group had a median lesion count of 35 (range, 25–113) and median duration of 61 days since clinical diagnosis. A total of 97% (32/33) of subjects completed the study; one subject in the exposure group was lost to follow-up after the first treatment visit and was replaced. This subject had blood drawn prior to application and at the 2-hour post-application collection.
Systemic Exposure Results
Plasma drug levels of cantharidin were below the LLOQ in 65 of 66 samples at all timepoints in the exposure group. One subject (2-year-old white male, weight 13.4 kg, with 32 treated lesions) had a single cantharidin result above the LLOQ with a reading of 3.4 ng/mL at the 2-hour post-application blood draw. Readings from the 6- and 24-hour samples in this subject were below the LLOQ. The subject did not experience any systemic AEs indicative of cantharidin absorption.
Efficacy
The percentage of subjects with complete clearance for the ITT population (all subjects that started the study) was 9.1% on day 21, 27.3% on day 42, 39.4% on day 63, and 48.5% on day 84/EOS visit (Figure 1). At day 84/EOS, MC lesion counts had decreased by a mean of 90.4% for the ITT population (Figure 2).
Safety Evaluations
No subjects in either group experienced a severe or serious TEAE or exhibited symptoms indicative of cantharidin absorption. There were no discontinuations due to TEAEs (Table 2A). The three most commonly reported AEs for both groups were pain (19 subjects, 57.6%), cough (6 subjects, 18.2%), and headache (5 subjects, 15.2%). Only pain was considered related to treatment. The PERIT indicated that 93.9% (31/33) of subjects experienced blistering after the first treatment (Day 1). AEs at the application site not expected by the investigators were all mild to moderate in severity (Table 2B). No excessive blistering beyond investigator expectation at or beyond the application site was reported.
Quality of Life
For all subjects the composite CDQLI score decreased from 2.58
Systemic Exposure Results
Plasma drug levels of cantharidin were below the LLOQ in 65 of 66 samples at all timepoints in the exposure group. One subject (2-year-old white male, weight 13.4 kg, with 32 treated lesions) had a single cantharidin result above the LLOQ with a reading of 3.4 ng/mL at the 2-hour post-application blood draw. Readings from the 6- and 24-hour samples in this subject were below the LLOQ. The subject did not experience any systemic AEs indicative of cantharidin absorption.
Efficacy
The percentage of subjects with complete clearance for the ITT population (all subjects that started the study) was 9.1% on day 21, 27.3% on day 42, 39.4% on day 63, and 48.5% on day 84/EOS visit (Figure 1). At day 84/EOS, MC lesion counts had decreased by a mean of 90.4% for the ITT population (Figure 2).
Safety Evaluations
No subjects in either group experienced a severe or serious TEAE or exhibited symptoms indicative of cantharidin absorption. There were no discontinuations due to TEAEs (Table 2A). The three most commonly reported AEs for both groups were pain (19 subjects, 57.6%), cough (6 subjects, 18.2%), and headache (5 subjects, 15.2%). Only pain was considered related to treatment. The PERIT indicated that 93.9% (31/33) of subjects experienced blistering after the first treatment (Day 1). AEs at the application site not expected by the investigators were all mild to moderate in severity (Table 2B). No excessive blistering beyond investigator expectation at or beyond the application site was reported.
Quality of Life
For all subjects the composite CDQLI score decreased from 2.58
