Characteristics of the study population.
In total, 417 patients were enrolled in the study. Thirty-seven patients underwent evaluation for determination of the MED but were not subsequently exposed to UVR (mainly due to failed determination of the MED) and thus were not treated with the study medication. A total of 380 patients were exposed to UVR and treated with at least one dose of study medication (safety population) (Table ). A total of 145 (38.2%) of these patients developed a lesion. Twenty-one of the 145 patients (14.5%) developed lesions immediately before the start of administration of the study medication. These lesions were noted but were not monitored. One hundred twenty patients (31.6%) developed delayed classical lesions (intent-to-treat [ITT] population). All data shown are derived from the ITT population. Evaluation of the per-protocol population revealed similar results.
Patient disposition and type of developed lesion
Overall, 80% of the patients were females. The average age was 39 years (age range, 18 to 76 years), and the mean number of herpes labialis episodes per year prior to the study was 5.3. The average duration of UVR exposure was 13 min (range, 4 to 24 min) in the two treatment groups. There were no notable differences between the two treatment groups.
Development and evaluation of lesions.
Only 50 of 190 patients (26%) developed delayed classical lesions (lesions that developed between 46 h and 7 days following UVR exposure) during treatment with ME-609, whereas 70 of 190 patients (37%) treated with placebo cream developed delayed classical lesions, a reduction of 29% (P = 0.022). In addition, three patients in the ME-609 group and one patient in the placebo group experienced delayed lesions that did not progress beyond the papule stage (delayed aborted lesion). As shown in Fig. , 101 of the 120 patients in the study (84%) with delayed classical lesions exhibited lesions that appeared on the first or second day after the initiation of therapy (2 to 3 days after UVR exposure). Only 17 patients treated with ME-609 reported the occurrence of a delayed classical lesion during the first day of treatment, whereas 40 patients treated with placebo reported the occurrence of a delayed classical lesion during the first day of treatment, a reduction of 58%. The reduction in the incidence of a delayed classical lesion during the first day of treatment with ME-609 thus explains the overall reduction of incidence in the entire study.
FIG. 1. Start of lesions shown as time from UVR exposure in patients developing classical lesions, per treatment group. Day zero includes the first 24 h following UVR exposure. □, ME-609; , placebo.
The 50 patients in the ME-609 treatment group who developed delayed classical lesions had a median time to healing to normal skin of 9.0 days, whereas the time was 10.1 days (P = 0.037) for the 70 placebo-treated patients who developed delayed classical lesions (Table ). Similarly, the healing time measured as the time to the loss of the hard crust was reduced 19% by ME-609 treatment, from 6.8 to 5.4 days, although this reduction did not reach statistical significance (P = 0.084). The Kaplan-Meier curves of time to normal skin are shown in Fig. .
Treatment effects (ITT population) with respect to development of delayed classical lesions and all lesions
The Kaplan-Meier curve (ITT population) for time to normal skin in patients with delayed classical lesions, per treatment group. Cum. prop., cumulative proportion; thick line, ME-609; thin line, placebo.
ME-609 treatment also reduced the median maximal lesion area of the delayed classical lesions by 28% (P = 0.072). The mean durations of the lesion stages in patients with delayed classical lesions are shown in Fig. . The major effect of ME-609 treatment was on the vesicle and crusting stage, whose durations were reduced by a total of 1.6 days (25%) compared with the durations in patients who received the placebo treatment.
FIG. 3. Median durations of lesion stages in patients (ITT population) with delayed classical lesions. The papule stage () is the time from the start of a lesion (papule) to the time of observation of the first vesicle. The vesicle stage () is the time (more ...)
The present study is the first study of herpes labialis to divide unpleasant sensations into pain, which was an overall measure of unprovoked soreness, and tenderness, which described unpleasantness upon touch of the region of a lesion. Pain was evaluated as the proportion of patients who developed classical delayed lesions and who reported pain. In addition, the severity of pain and the duration of pain were also studied. No statistically significant treatment effects with respect to pain were observed in the study. Eighty-one percent of placebo recipients and 76% of those receiving ME-609 developed pain. Moderate pain developed in 26 and 36% of the placebo and the ME-609 groups, respectively, and severe pain developed in 11 and 4% of the placebo and the ME-609 groups, respectively.
Forty-two of the patients who were treated with ME-609 and who developed delayed classical lesions experienced tenderness, whereas 65 patients who were in the control group and who developed delayed classical lesions experienced tenderness (odds ratio, 2.94; P = 0.11) (Table ). In addition, only 18 of the ME-609-treated patients experienced tenderness of moderate or severe intensity, whereas 38 patients in the placebo group experienced tenderness of moderate or severe intensity. The overall severity of tenderness was reduced by an odds ratio of 2.33 (P = 0.018). In addition, there was a trend toward a reduction in the median duration of tenderness in the ME-609-treated patients from 5.0 to 4.0 days (P = 0.078). Only 8 of the ME-609-treated patients who developed delayed classical lesions graded their current episode as “worse than their usual recurrences,” whereas 24 patients in the placebo group gave their lesions such a grade. The overall patient opinion of the current episode was more favorable for the patients treated with ME-609 than for those treated with placebo, with an odds ratio of 2.78 (P = 0.006) (Table ).
Treatment effects (ITT population) of secondary parameters with respect to delayed classical lesions
Viral swabs from 34 of 49 (69%) ME-609-treated patients with delayed classical lesions and 54 of 70 (77%) of the placebo-treated patients with delayed classical lesions were positive for virus isolation at least once (P was not significant). The times to cessation of viral shedding were similar for both groups (data not shown).
The incidence and nature of adverse events were similar for both treatment groups. The treatment was well tolerated, and there were no serious adverse events.