OBJECTIVES: The goals were to assess the degree of improvement of facial acne after treatment with the 0.04% tretinoin microsphere gel (TMG) among patients 8 to 12 years of age and to assess tolerability and safety.
METHODS: An open-label study was conducted with 40 patients 8 to 12 years of age (mean age: 10.7 years) with mild/moderate acne, defined on the basis of Evaluator's Global Severity Score (EGSS) values between 2 and 3. Patients were treated with the 0.04% TMG for 12 weeks and were evaluated at baseline and weeks 3, 6, and 12. Primary end points were changes in EGSS and Alternative Evaluator's Global Severity Score values; the secondary efficacy end point was the Investigator's Global Evaluation of treatment responses at week 12.
RESULTS: The mean EGSS value decreased significantly from baseline to week 12 (2.6 vs 2.1; P < .001), with 75% of cases being graded as almost clear or mild. The mean Alternative Evaluator's Global Severity Score value decreased from 3.1 to 2.4 during the 12-week period (P < .001). The mean Investigator's Global Evaluation score was 3.39 at week 12, indicating moderate improvement of acne. Treatment-associated adverse events were minimal, with mild skin irritation being most commonly recorded, generally in the first 3 weeks of therapy.
CONCLUSIONS: The 0.04% TMG pump was effective and safe for the treatment of acne vulgaris in this 8- to 12-year-old population, and the treatment was generally well tolerated. Additional studies in this population are recommended, to confirm these results.
WHAT'S KNOWN ON THIS SUBJECT:
Acne vulgaris is not uncommon in the pediatric population, but existing clinical guidelines for the treatment of acne do not address therapy in preadolescent patients. The safety of retinoids for patients <12 years of age has not been established.
WHAT THIS STUDY ADDS:
This study showed that the tretinoin microsphere gel is a safe, effective, useful option for treatment of acne in preadolescent children. There have been no previous studies of topical retinoid treatment in this age group.
Acne vulgaris often is viewed as a disease of teenagers, because of an estimated prevalence of 70% to 87% in that population.1 Although acne is uncommon among children <8 years of age, it is fairly common in preadolescence and early adolescence.2,3 Lucky et al4 found that 78% of a cohort of 365 girls 9 or 10 years of age had acne lesions. Despite this, few studies on acne vulgaris have been conducted in this population.
The incidence of acne has been correlated with pubertal stage more than with age,5 and the first stage of pubertal development precedes the gonadal maturation that is associated with clinically evident puberty.2,6 Adrenarche, maturation of the adrenal gland, typically occurs at 6 to 7 years of age in girls and at 7 to 8 years of age in boys.2,6 Adrenarche is associated with increased production of dehydroepiandrosterone and dehydroepiandrosterone sulfate, both of which stimulate the sebaceous glands.7 Acne generally develops in association with the onset of adrenarche and may be influenced by dehydroepiandrosterone sulfate levels.4,6
Comedonal acne vulgaris is the form most commonly seen in preadolescence, and it often is confined to the midfacial area.4,5,8,–,10 Standard guidelines published by the Global Alliance to Improve Outcomes in Acne Group do not address specifically the preadolescent population in the recent update on the management of acne.11 However, the management guidelines recommend topical retinoid therapy for first-line treatment of acne, except in more-severe cases in which systemic antibiotic therapy may be added to topical treatment.11,12 The addition of a topical antimicrobial agent is recommended for inflammatory acne.
Severe or long-term acne has been associated with the early onset of menarche in girls and higher levels of dehydroepiandrosterone sulfate and testosterone in both boys and girls.2,4,6,–,8 Moreover, studies showed that girls who developed severe acne in adolescence had significantly greater numbers of comedones <3 years before menarche.2,4 Identifying appropriate treatment at an early stage for these preadolescent patients may help to minimize scarring and the impairment in quality of life that patients with acne frequently experience.12
Tretinoin microsphere gel (TMG) (Retin-A Micro [Ortho Dermatologics, Skillman, NJ]) has been shown to be effective in the treatment of both inflammatory and noninflammatory acne lesions. Both 0.04% and 0.1% concentrations demonstrated early onset of action and favorable safety and tolerability profiles.13,–,15 Efficacy also was demonstrated for both doses of TMG administered through a pump delivery system.16 Because topical retinoid treatment is considered appropriate first-line therapy for mild/moderate acne, we investigated the safety and efficacy of treatment with the TMG pump in a preadolescent population.
The primary objectives of this study were to assess the degree of improvement of facial acne vulgaris after treatment with 0.04% TMG in a pump dispenser among patients 8 to 12 years of age and to assess the tolerability and safety of the treatment in this population. This investigator-initiated study was designed as an exploratory, open-label, 12-week trial of the 0.04% TMG pump with ∼40 patients. Study participants included boys and nonpregnant, nonlactating girls, 8 to 12 years of age, with mild/moderate acne vulgaris, who were otherwise healthy. Mild/moderate acne was defined on the basis of Evaluator's Global Severity Score (EGSS) values between 2 and 3 on a scale of 0 to 5, with 0 being clear and 5 being very severe (Table 1). Patients also needed to have 5 to 100 noninflammatory acne lesions and 0 to 40 inflammatory lesions to be included in the study. The study was approved by the University of California, San Diego, Human Research Protection Program, and patients and their legally acceptable representatives signed appropriate informed consent and assent forms.
Patients with >2 nodules or cysts were excluded from the study, as were patients with any other skin condition that would require concurrent treatment or would interfere with evaluation, any history of skin cancer or facial actinic keratosis, or known contraindications or hypersensitivity to the study medication or ancillary products provided for the trial. Patients were excluded if they had used any topical retinoid product in the 4 weeks before the start of the trial, any other topical facial treatments in the 2 months before the study, or systemic retinoid therapy in the 6 months before the study. Use of systemic corticosteroid therapy, acne devices or treatments (eg, light therapy or aminolevulinic acid), systemically administered medications that might confound the study results, or experimental drugs or devices in the 2 months before the study was not allowed. Other exclusions included the use of photosensitizing agents and excessive facial hair.
Subjects were not allowed to use any other acne treatments during the study. Study medication was provided by the investigator, along with sunscreen, facial cleanser, and facial moisturizer to be used for the duration of the trial. Patients were evaluated for efficacy and safety at baseline and at weeks 3, 6, and 12 (with all clinical evaluations to be conducted within 7 days of the target date). Patients were photographed, by using standardized photographic methods, at all observation points.
All subjects were instructed to apply 2 full pumpfuls of the 0.04% TMG to the affected facial areas once daily at night or as directed by the investigator. Patients also were instructed to use the provided gentle facial cleanser twice daily and moisturizer every morning as needed.
The primary efficacy end points were improvements in EGSS and Alternative Evaluator's Global Severity Score (AEGSS) values from baseline through week 12. Both of these tools are grading scales for visual evaluation of acne severity. The EGSS uses a 6-point scale ranging from 0 (clear) to 5 (very severe). The AEGSS uses a similarly designed, 7-point scale ranging from 0 (clear) to 6 (severe) and was used in this study as a supplemental assessment tool. The additional grade in the latter scale clarifies the distinction between mild, mild/moderate, and moderate; this is intended to differentiate between few and several inflammatory lesions and between mild and moderate erythema. Evaluations with both scales were conducted at each study visit; the EGSS was considered the primary scoring tool.
The secondary efficacy end point was the week 12 Investigator's Global Evaluation (IGE) findings scored on a 7-point scale, with 0 being cleared and 6 being worsening (Table 1). Safety evaluations were made at all observation points, along with assessment of compliance with the study protocol. A 1-sample t test was used for statistical analysis of lesion count changes in the intent-to-treat (ITT) population, which consisted of all patients who completed enrollment screening and baseline evaluation. For the primary end point, missing data were replaced with the last observation carried forward. For patients without a recorded baseline value, no change was recorded at all subsequent time points. Patients who did not undergo assessment at week 12 were considered as having no change for this statistical analysis.
Safety and tolerability evaluations were conducted at all study visits and included assessments of cutaneous irritation (erythema, dryness, peeling, burning/stinging, and itching). Subjects were instructed to contact the investigator if they experienced any problems between study visits. The Wilcoxon signed rank test was used to evaluate changes in safety end points.
A total of 40 patients were enrolled in the study and received treatment with the 0.04% TMG; 36 patients completed the study through week 12. Baseline demographic characteristics are detailed in Table 2. The mean age of the patient population was 10.7 years; 33 patients (82.5%) were female and 7 (17.5%) were male. Fourteen subjects (35%) were white, 14 (35%) were Hispanic, 2 (5%) were black, and 10 (25%) were in other categories. Of the 33 female patients, 15 (45.5%) had reached menarche, with the mean age of menarche being 10.6 years. The mean age at the onset of acne was 9.1 years. The location of acne was most commonly on the forehead (36.8%) or nose (28.9%). The mean EGSS value at baseline was 2.6; 19 patients (47.5%) were considered to have mild acne, 20 (50.0%) moderate acne, and 1 (2.5%) severe acne. The mean AEGSS value at baseline was 3.1; 14 patients (35.0%) were considered to have mild acne, 13 (32.5%) mild/moderate acne, 8 (20.0%) moderate acne, and 5 (12.5%) moderately severe acne. The mean number of noninflammatory lesions was 50.2, and the mean number of inflammatory lesions was 9.2.
In the ITT population, the mean EGSS and AEGSS values both improved significantly from baseline to week 12, the mean EGSS from 2.6 to 2.1 and the mean AEGSS from 3.1 to 2.4 (P < .001 for both) (Fig 1). Table 3 provides the EGSS and AEGSS observations at all time points. In the EGSS assessment of the 36 patients who completed the study, 18 patients (50%) demonstrated improvement of 1 grade, 18 (50%) demonstrated no change, and none demonstrated worsening. In the AEGSS assessment, 5 patients (13.9%) demonstrated improvement of 2 grades, 15 (41.7%) demonstrated improvement of 1 grade, 16 (44.4%) demonstrated no change, and none demonstrated worsening. The mean IGE score for the 36 patients evaluated at week 12 was 3.39, which indicated moderate improvement of acne from baseline (Table 4). Overall, 32 patients (88.8%) experienced improvement.
Reductions in the numbers of acne lesions in the ITT population were statistically significant at week 12, compared with baseline (Fig 2). The mean noninflammatory lesion count was reduced by 36.9% at week 12 (P < .001), the mean inflammatory lesion count was reduced by 39.1% (P=.020), and the total lesion count was reduced by 37.3% (P < .001).
Figure 3 features photographs of 2 patients taken at baseline and at week 12. The first patient, who had moderate acne at baseline, demonstrated improvement of 1 EGSS grade at week 12, maintained his baseline AEGSS value of 3, and demonstrated moderate improvement in the IGE. The second patient had mild acne at baseline and maintained her EGSS value at week 12; her AEGSS value improved from 3 to 2, and she demonstrated mild improvement in the IGE.
A total of 27 patients (67.5%) experienced an adverse event; events not involving cutaneous tissue (eg, nasopharyngitis, cough, and gastrointestinal disorders) were determined to be unrelated to treatment. Table 5 details the treatment-related adverse events, which were experienced by 15 patients (37.5%) in the ITT population. These events, which generally lasted <1 week and were more significant during the first 3 weeks of treatment, included skin irritation, postinflammatory pigmentation changes, and grade 1 sunburn. Skin irritation was the most-common, treatment-related event, occurring in 12 patients (30%), but was scored as mild at the end of the study (mean erythema score: 0.9; mean peeling score: 0.4; mean burn/stinging score: 0.1; mean itching score: 0.1; mean dryness score: 1.3 [with 1 indicating normal skin]) (Table 1). There were no discontinuations related to adverse events. One patient discontinued treatment because of worsening of acne.
Despite the generalized recommendation for topical retinoid treatment for all patients with mild/moderate acne vulgaris,11,17 there have been very few studies of acne conducted in the early adolescent and preadolescent populations. The use and safety of TMG among patients <12 years of age has not been established. This investigator-initiated study was designed to assess the efficacy and tolerability of the 0.04% TMG pump for patients 8 to 12 years of age with mild/moderate acne. Our findings were consistent with study results in older populations.13,–,15
The ITT population was predominantly female (33 girls and 7 boys). We observed an age of acne onset of 9.1 years in this population, which is earlier than findings in previous reports of 11 years for girls and 12 years for boys.1 This may be secondary to the age criteria of the study or may reflect a trend in lower pubertal ages in the population, which has been observed in recent years.18 Our study showed that the mean age of acne onset was lower than the mean age of menarche, which demonstrates that acne lesions occur before children reach puberty. This observation supports previous reports that suggested that acne is the first sign of pubertal maturation,4,6 which is consistent with adrenarche rather than menarche.8
Compliance with acne therapy may be difficult, especially in this age group, because younger patients generally are less concerned than their parents about facial lesions.2 Efforts were undertaken to ensure that patients were complying with the treatment protocol. Investigators orally interviewed patients regarding compliance at each study visit, and patients were instructed to bring all containers of the study drug (empty and partially used) with them for examination.
Potential limitations of this study include the small patient population (N=40); additional research regarding acne treatment in this age group is recommended. Because an open-label study is subject to investigator bias, the use of 3 grading scales (EGSS, AEGSS, and IGE) and the tracking of lesion counts were used to minimize bias. No patients in this study achieved total clearance of acne. Although no patients improved >1 EGSS grade, 12 patients received IGE assessments of moderate improvement, 3 marked improvement, and 3 almost clear. The 1 patient whose EGSS was 4 (severe) at baseline did not experience any change with the study drug; however, it should be noted that the recommended treatment for patients with severe acne includes systemic antibiotic therapy.11,12
Fluctuation of responses was observed for some patients during the study. For example, 1 patient's acne was reported as mild at baseline, almost clear at 3 weeks, mild at 6 weeks, and almost clear at 12 weeks. However, the grade at 12 weeks was the end point of interest, and statistical analyses were conducted on the basis of the observations at that final study visit.
Treatment-related skin irritation was reported for 14 patients (35%) in the ITT population, as is common with topical retinoid treatment. The reported skin irritation was mild for most of the patients, occurred during the first 3 weeks of treatment, and improved by the end of the study. We suggest that a slowly escalating regimen be considered for this preteen population, with application every other day to minimize early irritation. No serious treatment-related events were reported, and no patients discontinued treatment because of adverse events. This is consistent with trials in adolescent and adult populations.13,–,15
The 0.04% TMG pump was effective and safe in the treatment of acne vulgaris in this pediatric population, and the treatment was generally well tolerated. The results from this exploratory study indicate that the 0.04% TMG pump may be a very useful therapy for children in this age group. Additional studies in this population are recommended, to validate these findings.
This study was sponsored by Johnson & Johnson Consumer and Personal Products Worldwide (Skillman, NJ).
Ana Beatris Rossi, MD, and Marge Nighland, BS, of Johnson & Johnson Consumer and Personal Products Worldwide contributed to the design and review of the study protocol. We also acknowledge the assistance of Ann L. Davis, MPH, of the Lockwood Group in the preparation of this manuscript and Mark Van Buskirk, MS, in statistical analysis. Their participation was funded by Johnson & Johnson Consumer and Personal Products Worldwide.
- Accepted February 23, 2010.
- Address correspondence to Lawrence F. Eichenfield, MD, Rady Children's Hospital, 8010 Frost St, Suite 602, San Diego, CA 92123. E-mail:
FINANCIAL DISCLOSURE: Dr Eichenfield has served as an investigator and consultant to Johnson & Johnson Consumer and Personal Products Worldwide and has no equity interest in the company. Dr Dill has served as a consultant for OrthoNeutrogena and has no equity interest in the company.
- AEGSS =
- Alternative Evaluator's Global Severity Score •
- EGSS =
- Evaluator's Global Severity Score •
- IGE =
- Investigator's Global Evaluation •
- TMG =
- tretinoin microsphere gel •
- ITT =
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- Copyright © 2010 by the American Academy of Pediatrics