Novel tretinoin 0.05% lotion for the once‐daily treatment of moderate‐to‐severe acne vulgaris in a preadolescent population

Abstract Background Acne vulgaris (acne) is a common skin condition in children and adolescents. Efficacy of tretinoin is well documented in studies that included pediatric patients (12‐18 years of age). With acne routinely presenting in younger patients, data are needed in this important group. Lotion formulations are commonly used across dermatology and are well liked by patients. Objective To evaluate the safety and efficacy of a novel once‐daily tretinoin 0.05% lotion in preadolescent subjects (≤ 13 years) with moderate‐to‐severe acne. Methods Post hoc analysis of two multicenter, randomized, double‐blind, vehicle‐controlled phase 3 studies in moderate‐to‐severe acne. Preadolescent subjects (N = 154) randomized (1:1) to receive tretinoin 0.05% lotion or vehicle, once daily for 12 weeks. Efficacy assessments included changes in baseline inflammatory/noninflammatory lesions and treatment success (at least 2‐grade reduction in Evaluator's Global Severity Score [EGSS] and clear/almost clear). Safety, adverse events (AEs), and cutaneous tolerability evaluated throughout. Results At Week 12, mean percent reduction in inflammatory and noninflammatory lesion counts were 49.5% and 44.0% compared with 31.4% and 18.8% with vehicle (both P = 0.001). Treatment success was achieved by 23.7% of subjects by Week 12, compared with 7.2% (P = 0.009). The majority of AEs were mild and transient: most frequently were application site pain (5.6%) and application site dryness (2.8%). Local cutaneous safety and tolerability assessments were generally mild‐to‐moderate and improved by Week 12. Conclusions Tretinoin 0.05% lotion was significantly more effective than vehicle in achieving treatment success and reducing inflammatory and noninflammatory lesions in preadolescent acne. It was well tolerated, with all treatment‐related AEs deemed mild or moderate.

approved cleanser and warm water, rinsing thoroughly and gently patting their face dry. During the study, each subject was permitted to use only approved nonmedicated cleansers, moisturizers, and sunscreens. Lists of approved cleanser and moisturizers were provided. Subjects applied a pea-sized amount of study drug, dotted on six facial areas, and gently rubbed into the skin covering the entire face (excluding mouth, eyes, inside nose, and lips).
Study drug was applied the same time of day, once daily for 12 weeks.

| Efficacy evaluation
Efficacy evaluations comprised inflammatory and noninflammatory lesion counts and an EGSS assessment at screening, baseline, and subsequent study visits (Weeks 4,8,and 12). Efficacy end points included mean percent change from baseline to Week 12 in inflammatory and noninflammatory lesion counts and the proportion of subjects achieving at least a 2-grade reduction from baseline EGSS and "clear" or "almost clear" at that same visit.
Additional assessments included a patient satisfaction score (PSS) and a validated acne-specific quality of life (Acne-QoL) questionnaire (Merck & Co., Inc. Whitehouse, NJ). At baseline, subjects were asked to rate their satisfaction with prior acne therapy with a PSS of 1-10 (where 10 was the most satisfied and a score of 5 or greater was considered as "satisfied"). At Week 12, they were asked to rate their level of satisfaction with study treatment. Subjects assessed facial shine/oiliness at baseline and Week 12 using a 4-point scale, and those recording a score of 1-3 were asked to rate degree of bothersomeness (using a 5-point scale).

| Safety evaluation
Cutaneous safety (erythema and scaling) and tolerability (itching, burning, and stinging) were evaluated on a scale from 0 (none) to 3 (severe). Adverse events (AEs) were evaluated throughout; severity and relationship with study medication were assessed.

| Statistical analysis
The intent-to-treat (ITT) population comprised all subjects randomized and provided with study drug and vehicle. The safety population comprised all randomized subjects who were presumed to have used the study medication or vehicle at least once and who provided at least one postbaseline evaluation. The primary method of handling missing efficacy data in the ITT analysis set was based on estimation using the Markov chain Monte Carlo multiple imputation methods.
No imputations were made for missing safety data.
Treatment comparisons of percent reductions in lesions counts utilized a ranked analysis of covariance with factor of treatment and the respective baseline lesion count as covariate. Significance of EGSS reductions was obtained from logistic regression (using Firth's Penalized Likelihood) with factors of treatment group. There was no imputation of missing data for quality of life analyses. Mean Acne-QoL scores at Week 12 were compared using an analysis of covariance with factors of treatment and the respective baseline lesion count as covariate. Shininess/oiliness and PSS scores were compared between treatment groups using a Wilcoxon Rank Sum test. All statistical analyses were conducted using SAS ® version 9.3 or later. Statistical significance was based on 2-tailed tests of the null hypothesis resulting in P values of 0.05 or less.
All AEs occurring during the studies were recorded and classified on the basis of medical dictionary for drug regulatory activities terminology (MedDRA) for the safety population. Treatment emergent adverse events (TEAEs), defined as any AE with an onset on or after the date of first drug application, were summarized by treatment group and relationship with study drug. Each subject was counted only once within a system organ class or a preferred term using the event with the greatest severity or causality, respectively.

| Baseline characteristics
One hundred fifty-four subjects were included in the post hoc analysis. Of those, 139 (90.3%) completed the studies, including 64 preadolescent subjects (86.5%) on tretinoin 0.05% lotion and 75 (93.8%) on vehicle ( Figure 1). The most common reasons for study discontinuation were "lost to follow-up" or "subject request." Demographic data (Table 1) were similar across the treatment groups. Mean age (standard deviation [SD]) was 12.4 (0.94) years.
There were no noticeable differences between treatment groups with regard to lesion counts or EGSS. At baseline, the mean number

| Treatment success
By Week 12, 23.7% of subjects were treatment successes (at least a 2-grade improvement in global severity by EGSS and "clear" or "almost clear") following treatment with tretinoin 0.05% lotion compared to only 7.2% on vehicle (P = 0.009); see Figure 4.

| Patient satisfaction and quality of life
Subject satisfaction with treatment was significantly greater with tretinoin 0.05% lotion than vehicle by Week 12 (P = 0.008). Although there were no statistically significant differences in the improvement

| Safety
A similar number of subjects in each treatment group (22 and 18, tretinoin 0.05% lotion and vehicle, respectively) reported treatment emergent (TE) AEs. All TEAEs experienced in the tretinoin 0.05% lotion group were mild or moderate events ( Table 2).

| Cutaneous safety and tolerability
Erythema and scaling were recorded by the investigator. Overall mild-to-moderate erythema was noted in 43% of subjects at baseline, with 12% reporting mild-to-moderate scaling. Mean scores for both erythema and scaling increased at Week 4 (to 0.6 and 0.5, respectively, where 0 = mild) following treatment with tretinoin 0.05% lotion, returning to baseline levels by the end of the study  significant decrease in EGSS from baseline to Week 12 (from 2.6 to 2.1, P < 0.0001). Eight patients (22.2%) were "clear" or "almost clear." Skin irritation occurred in 35% of patients, being generally mild and transient. 8 In a subsequent double-blind study with tretinoin microsphere 0.04% gel in 110 children (9-11 years) with moderate acne, there was a significantly greater improvement in noninflammatory lesions (44.0% reduction) compared to vehicle (30.8%, P = 0.04) at Week 12. 9 In a post hoc analysis of two studies comparing tretinoin microsphere 0.1% gel and tretinoin 0.05% gel in young adolescents (10-14 years) with mild-to-moderate acne, comparable lesion reduction and treatment success were noted. Tretinoin 0.05% gel demonstrated better cutaneous tolerability. 10 Fourteen percent of participants reported dry skin, 8% skin burning sensation, 5% erythema, and 5% dermatitis exfoliative compared with 32%, 11%, 23%, and 23%, respectively, with tretinoin gel microsphere 0.1% (all P < 0.001, except skin burning sensation).
Tretinoin 0.05% lotion is a novel topical treatment for moderateto-severe acne leveraging polymerized emulsion technology. The development rationale was to provide a tretinoin formulation with improved efficacy and tolerability that could be especially suited to a preadolescent population. The polymerized emulsion provides a mesh (a polymeric network) which helps structure the emulsion providing uniform distribution of active and hydrating ingredients at the surface of the skin, reducing the presence of concentrated drug in specific areas (hot spots). It also forms a barrier which helps keep the skin hydrated by reducing epidermal water loss and increasing skin water content.
Tretinoin 0.05% lotion was shown to provide significantly greater efficacy than vehicle in two pivotal phase 3 studies. 11 Data reported herein were consistent with these overall findings. Tretinoin 0.05% lotion offered significantly more efficacy than vehicle in inflammatory and noninflammatory lesion reduction and treatment success, with greater patient satisfaction (compared with vehicle) and preference (compared with previous acne therapy). Efficacy in comedonal acne (44% mean reduction) was similar to that reported previously with tretinoin microsphere 0.04% gel, 9 although our analysis included preadolescent subjects with severe disease. To our knowledge, we are the first to report efficacy in inflammatory lesions (50% mean reduction).
Results in this pediatric population were similar to those seen in the overall study populations. The only difference of note is that the vehicle tended to be less effective in the pediatric population.
In the overall study populations, tretinoin 0.05% lotion showed significantly greater QoL benefits relative to vehicle. Although there were numerical differences in our post hoc analysis, they were not significant and may reflect the appropriateness of some of the individual questions to a preadolescent acne population, given the relatively low mean scores are baseline compared with the overall study populations.
Tretinoin 0.05% lotion was generally safe and very well tolerated. 11 The most commonly reported treatment-related AEs included application site reactions and skin-related events attributed to the known properties of tretinoin. There were slightly more treatmentrelated AEs when compared to the overall study populations.
Most noteworthy was the extremely low irritation potential of this novel tretinoin formulation. The level of irritation seen with tretinoin 0.05% lotion in our study appears lower than that reported in clinical studies with tretinoin microsphere gel (0.04% or 0.1% concentrations) or tretinoin gel 0.05% in preadolescent acne; 8-10 however, direct comparisons are difficult to make in the absence of head-to-head trials.

| CONCLUSION
A novel tretinoin 0.05% lotion formulation was an effective and well-tolerated topical treatment for moderate-to-severe comedonal and inflammatory preadolescent acne.

ACKNOWLEDG MENTS
The authors acknowledge Brian Bulley, MSc, of Konic Limited for medical writing support. Ortho Dermatologics funded Konic's activities pertaining to this manuscript.

LFE and JLS were study investigators and are advisors for Ortho
Dermatologics. EG, SH, and VB are employees of Bausch Health.