Metronidazole gel (0.75%) in Japanese patients with rosacea: A randomized, vehicle-controlled, phase 3 study

Abstract

Topical metronidazole is not currently approved in Japan as a treatment for the indication of rosacea, although 0.75% metronidazole gel was authorized in 2014 for the management of cancerous skin ulcers. We conducted a randomized, double-blind, vehicle-controlled study to evaluate the efficacy and safety of 0.75% metronidazole gel in Japanese patients with inflammatory lesions (papules/pustules) and erythema associated with moderate to severe rosacea. Overall, 130 patients were randomly assigned to receive 0.75% metronidazole gel (n = 65) or vehicle (n = 65), and 120 patients completed 12 weeks of treatment. The primary efficacy outcome was the proportion of patients who achieved both of the following at week 12: an improvement of >50% in the number of inflammatory lesions (papules/pustules) and a positive change of at least one degree in erythema severity. This composite outcome was achieved by 72.3% of metronidazole-treated patients versus 36.9% of vehicle-treated patients, with the between-group difference demonstrating significant improvement with 0.75% metronidazole gel (p < 0.0001). All secondary efficacy endpoints (patients achieving a score of ≥3 for percent change in the number of inflammatory lesions at week 12; patients achieving a score of ≥3 for change in erythema severity at week 12; patients achieving an Investigator's Global Assessment score of 0 or 1 at week 12; percent change over time in the number of inflammatory lesions; change over time in erythema severity) also showed improvement in the 0.75% metronidazole gel group. The incidence of adverse events was higher with metronidazole (40.0%) than with vehicle (29.2%). Of these, treatment-related, treatment-emergent adverse events occurred in 9.2% and 6.2% in the metronidazole and the vehicle group, respectively, but there were no new safety concerns. Overall, the results of this study have confirmed the efficacy and safety of 0.75% metronidazole gel in Japanese patients with rosacea.

Keywords: Japanese; clinical trial, phase III; metronidazole; rosacea.

FIGURE 1

Patient disposition (Consolidated Standards of Reporting Trials). AE, adverse event; mITT, modified intention‐to‐treat

FIGURE 2

Time course of efficacy outcome measures. (a) Change over time in the proportion of patients who achieved score 3 or better for both percent change in the number of inflammatory lesions and change in erythema severity (primary outcome)^†; (b) change over time in percent change in the number of inflammatory lesions^‡; (c) change over time in erythema severity^§ (modified intention‐to‐treat group). Missing data were imputed as non‐responders for (a), and were not imputed for (b) and (c). Data were not adjusted for multiplicity of secondary endpoints or assessment time points. *p < 0.05 vs vehicle; **p < 0.01 vs vehicle. ^†Data are shown as % (exact 95% confidence intervals). ^‡Data are shown as least squares mean (95% confidence intervals). Mixed model for repeated measures, with visit, treatment, and the interaction between visit and treatment as explanatory variables; unstructured correlation structured between visits were assumed. ^§Data are shown as least squares mean (95% confidence intervals). Conditional longitudinal data analysis, which assumed that the mean and standard deviation for the erythema severity score at baseline were the same for both treatment groups

FIGURE 3

Example of response to treatment. (a) Patient #1 at baseline; (b) patient #1 at week 12; (c) patient #2 at baseline; (d) patient #2 at week 12