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Tretinoin gel microspheres 0.04% versus 0.1% in adolescents and adults with mild to moderate acne vulgaris: A 12-week, multicenter, randomized, double-blind, parallel-group, phase IV trial
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Tretinoin Gel Microspheres 0.04% Versus 0.1% in Adolescents and Adults with Mild to Moderate Acne Vulgaris: A 12-Week, Multicenter, Randomized, Double-Blind, Parallel-Group, Phase IV Trial Richard Berger, MD1; Ronald Rizer, PhD2; Alicia Barba, MD3; David Wilson, MD4; Daniel Stewart, DO5; Rachel Grossman, MD6; Marge Nighland, BS6; and Jonathan Weiss, MD7 1Hill
Top Research, Inc., Milltown, New Jersey; 2Stephens and Associates, Colorado Springs, Colorado; 3International Dermatology Research Inc., Miami, Florida; 4Education and Research Foundation, Inc., Lynchburg, Virginia; 5Midwest Cutaneous Research Corp., Clinton Township, Michigan; 6Johnson & Johnson Consumer Products Worldwide, Skillman, New Jersey; and 7Gwinnett Clinical Research Center, Inc., Snellville, Georgia ABSTRACT Background: Topical retinoids are considered firstline therapy in the treatment of acne vulgaris, yet can be associated with cutaneous irritation, including erythema, peeling, dryness, burning, and itching. Tretinoin gel microsphere (TGM) formulations were developed to minimize these effects. A lower-strength TGM formulation may be desirable to further reduce exposure to tretinoin. Objective: This study was conducted to assess the efficacy and safety profile of a lower-dose TGM (0.04%) formulation compared with TGM 0.1% for the treatment of mild to moderate acne vulgaris. Methods: In this multicenter, double-blind, parallelgroup, Phase IV dose-ranging study, patients with facial acne were randomized to apply either TGM 0.04% or TGM 0.1% to the face each night for 12 weeks. Patients must have discontinued systemic retinoid treatment for at least 1 year before the study and were not to have used any topical retinoids, systemic antibiotics, nicotinamide, or systemic steroids for at least 1 month. All other topical medications applied to the face (including corticosteroids, antimicrobials, salicylic acid, and benzoyl peroxide) were to be discontinued at least 2 weeks before the study. End points were the acne lesion count (total, inflammatory, and noninflammatory lesions) and the investigators’ and patients’ assessments of improvement. Adverse events (including severity and relationship to treatment) and signs and symptoms of cutaneous irritation at the treatment site were monitored at each study visit. 1086
Results: One hundred fifty-six patients (78 TGM 0.04%, 78 TGM 0.1%) were randomized and received treatment. Patients ranged in age from 12 to 41 years (mean, 18.4 years) and were predominantly white (n = 89 [57.1%]) and male (n = 80 [51.3%]). Both TGM 0.04% and TGM 0.1% were associated with a reduction from baseline in total, inflammatory, and noninflammatory lesions. The differences between groups in the change in lesion counts from baseline to weeks 2, 4, 8, and 12 were not statistically significant. However, there was a greater reduction in inflammatory lesions at week 2 for TGM 0.1% compared with TGM 0.04% (14.8% vs 6.0%, respectively; P < 0.047). Both treatment groups had similar improvements in the investigators’ global evaluation and the patients’ assessment of the response to treatment. Both TGM 0.04% and TGM 0.1% were well tolerated. The most common adverse events were skin-associated burning sensation (2.6% in the TGM 0.04% group and 7.7% in the TGM 0.1% group) and irritation (6.4% and 3.8%, respectively). In the TGM 0.04% group, significantly fewer patients experienced dryness of the treatment area during the early phase of treatment (P < 0.027). However, for other measures of cutaneous irritation (peeling, burning/stinging, and itching), either there were no statistically significant differences beAccepted for publication April 25, 2007. doi:10.1016/j.clinthera.2007.06.021 0149-2918/$32.00 Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2007 Excerpta Medica, Inc.
Volume 29 Number 6
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R. Berger et al. tween treatment groups or, in the case of erythema, there was a significant difference in favor of TGM 0.1% (P = 0.035). Conclusions: Both TGM 0.04% and TGM 0.1% were associated with reductions in lesion counts in these patients with mild to moderate facial acne. Both concentrations were generally well tolerated. The results suggested an early (week 2) incremental benefit for the use of TGM 0.1% in the treatment of inflammatory lesions. (Clin Ther. 2007;29:1086–1097) Copyright © 2007 Excerpta Medica, Inc. Key words: acne vulgaris, cutaneous irritation, inflammatory lesions, tretinoin gel microspheres.
INTRODUCTION Acne vulgaris is a follicular disorder that begins when the microenvironment of sebaceous follicles undergoes specific changes that result in plugging of the pilosebaceous follicle and development of the microcomedo.1 The microcomedo, in turn, gives rise to acne lesions, including noninflammatory comedones and inflammatory papules, pustules, and nodules.2 While the precise etiology of acne remains unknown, its manifestations are thought to be the product of 4 pathogenic events: increased sebum production, obstruction of the pilosebaceous unit by abnormal keratinization, proliferation of Propionibacterium acnes, and inflammation mediated by both chemotactic factors and various enzymes.2 Inflammatory lesions have been found to contribute to the negative psychosocial consequences associated with acne, including diminished self-esteem and quality of life.3,4 Retinoids, natural or synthetic derivatives of vitamin A, are highly effective in the treatment of acne vulgaris because of their ability to modify abnormal follicular keratinization.5 Tretinoin acts by modulating the proliferation and differentiation of epidermal cells within the stratum corneum and restores normal desquamation of follicular cells, thereby facilitating comedolysis.6 These effects are mediated by tretinoin’s interaction with a family of nuclear retinoic acid receptors. In addition, tretinoin may decrease the inflammatory component of acne through a decrease in the expression of toll-like receptor 2 and cytokine induction by P acnes.7 Adverse effects associated with retinoid use include erythema, dryness, peeling, and burning,8 which may be the result of thinning of the stratum corneum.6 June 2007
Tretinoin gel microsphere (TGM) technology was developed to minimize the cutaneous irritation seen with other topical tretinoin-containing acne products. Microsphere technology is a drug-delivery system designed to entrap the active ingredient and release it onto the skin. Microsphere delivery results in minimal absorption, leading to lower accumulation in the epidermis.9 Furthermore, when exposed to ultraviolet light, TGM is more stable than conventional gel formulations of tretinoin.10,11 TGM 0.1% has been found to be more effective than vehicle in reducing the severity of acne lesions, as measured by a reduction in acne lesion counts.12,13 In two 12-week studies involving 144 and 148 patients,12 inflammatory lesion counts were reduced by a mean of 37% (P = 0.028) and 29% (P = NS), respectively, among patients treated with TGM 0.1%, compared with 18% and 24% among controls who received vehicle. The mean percent reductions in noninflammatory lesion counts were 49% and 32% (both, P < 0.001) among patients receiving TGM therapy and 22% and 3% among those who received vehicle. In a singlecenter, double-blind, half-face study comparing 4 consecutive days of topical application of TGM 0.1% and tretinoin cream 0.025% in 35 patients with acne vulgaris,13 facial shine was significantly reduced 3 or 6 hours after treatment with the TGM formulation compared with tretinoin (P = 0.008 and P < 0.001, respectively). Facial shine, or oiliness, is a condition that often accompanies acne vulgaris and may contribute to its psychosocial consequences for the patient. A single-center, randomized, double-blind, halfface study compared the irritation potential of 14 consecutive days of TGM 0.1% and tretinoin cream 0.1% in 25 white women with sensitive skin.14 Cutaneous irritation at the application site (defined as dryness and erythema) was significantly less severe after treatment with TGM 0.1% compared with tretinoin 0.1% cream (P < 0.001 for both variables). Twenty-three (92%) of 25 patients indicated a preference for the TGM formulation over the tretinoin cream (P < 0.001). Clinical safety studies of TGM 0.1% (the highest strength) have found no phototoxic or photoallergic potential.15 A lower-strength TGM formulation that was both well tolerated and effective might further reduce exposure to tretinoin. The present study was conducted to assess the efficacy and tolerability of a lower-dose TGM (0.04%) formulation compared with TGM 0.1% in the treatment of mild to moderate acne vulgaris. 1087
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PATIENTS AND METHODS Study Design This randomized, double-blind, parallel-group, Phase IV study was conducted at 6 study centers from March 1, 2004, through September 17, 2004, in patients with mild to moderate facial acne vulgaris. The study protocol was approved by an independent review board and conducted in accordance with the Declaration of Helsinki and the good clinical practice guidelines. All patients provided written informed consent before participation; in the case of adolescent patients, both the patient and his or her guardian gave written consent. Patients were randomized to receive TGM 0.04%* or TGM 0.1%* in a 1:1 ratio according to a predetermined, computer-generated randomization schedule provided by the manufacturer. Separate randomization lists were prepared for each study center using a prespecified block size. Each of 5 centers enrolled 24 patients, with 12 in each treatment group. The sixth center enrolled 36 patients, who were equally distributed between treatment groups. Patients were instructed to apply the assigned product to the face each night for 12 consecutive weeks. They were provided with a supplemental skin cleanser (Neutrogena Fresh Foaming Facial Cleanser, Neutrogena, Los Angeles, California) to use before each application of test drug, a moisturizer (Neutrogena Healthy Defense Daily Moisturizer) to be used as needed, and a sunscreen (Neutrogena Oil-free Sunblock SPF 30) to be used during periods of extended UV exposure. Patients were instructed to wash the entire face each night with the supplied skin cleanser, rinse immediately, pat the face dry with a towel, and apply a quantity of the assigned test drug equal to ~1/2 inch (~250 mg) to the entire face. Patients were instructed to leave treated areas undisturbed overnight. The supplied moisturizer was to be applied in the morning as needed, but not on the morning of a scheduled study visit. Other medications were not to be applied to the face during the study, and cosmetic use was to be limited. Patients were instructed to avoid or minimize sun exposure and to avoid sunlamps and tanning salons during the study. The supplied sunscreen or a similar product (SPF ≥30) was to be applied to the face whenever extended sun exposure was anticipated, and wearing protective clothing was advised. *Trademark: Retin-A Micro® microspheres (Johnson & Johnson Consumer Companies, Inc., Skillman, New Jersey).
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Study Population Male and female patients between the ages of 12 and 40 years, in good health, with mild to moderate acne vulgaris were included in this study. Mild to moderate acne vulgaris was defined as 20 to 150 total facial lesions. Of these lesions, 10 to 100 were to be comedones (open and closed), and 10 to 50 were to be inflammatory lesions (papules and pustules). No more than 2 were to be nodules (defined as deep inflammatory lesions of 1 cm or greater). In this study, patients were to have discontinued systemic retinoid treatment for at least 1 year before the study. Additionally, patients were not to have used any topical retinoids, systemic antibiotics, nicotinamide, or systemic steroids for at least 1 month. All other topical medications applied to the face (including corticosteroids, antimicrobials, salicylic acid, and benzoyl peroxide) were to be discontinued at least 2 weeks before study initiation. Patients were instructed not to use cosmetic products on the face that contained retinol, salicylic acid, α-hydroxy acid, or bleaching agents such as hydroquinone during the study period. Female patients were excluded from the study if they were pregnant, were lactating, or had been using systemic birth control for <6 months. Other exclusion criteria included erythema not attributed to the acne lesions, peeling, dryness, burning/stinging, and itching on the face. Other skin conditions (eg, rosacea, atopic dermatitis, seborrheic dermatitis, psoriasis) or disease that would require concurrent therapy or confound the evaluation of the tolerability or efficacy of study drug was also a cause for exclusion. Additional exclusion criteria included excessive facial hair (ie, beard, sideburns, or mustache) that would obstruct evaluation; use of photosensitizing, phototherapy, or selftanning agents; and the presence of skin cancer or actinic keratosis on the face. Use of sunlamps and tanning beds was to be avoided, and excessive unprotected exposure to UV light was to be limited.
Efficacy and Tolerability Assessments Patients were evaluated at baseline and after 2, 4, 8, and 12 weeks of therapy. Acne lesion counts were performed at each visit by a single blinded investigator at each site. The counts included inflammatory lesions (papules and pustules), noninflammatory lesions (open and closed comedones combined), and nodules. At 12 weeks, an investigator’s global evaluation of the Volume 29 Number 6
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Statistical Analysis A sample size of 75 patients per group was chosen to provide 80% power to detect an 18.4% difference in treatment-group means for the change from baseline in total lesion count, assuming a common SD of 40% using a 2-group t test with a 2-sided significance level of 0.05. Baseline homogeneity between treatment groups was analyzed using a 2-way analysis of variance for continuous variables, the Cochran-MantelHaenszel (CMH) general association test for nominal categorical variables, and the CMH row mean score test using modified ridit scores for ordinal categorical variables. All patients with a baseline assessment and at least 1 postbaseline efficacy assessment were included in the efficacy data set. Efficacy was assessed in the intentto-treat population, using last-observation-carriedforward methodology for missing values. The primary efficacy end point was the percent change from baseline in total lesion count at week 12. Statistical methods for the assessment of treatment differences were based on a 2-way analysis of covariance model of the percent change from baseline in the week-12 total lesion count, with response value, treatment, and center representing main effects, and the baseline total lesion count as a covariate.16 All statistical tests were 2-sided and were performed at a significance level of 5%, with the exception of an analysis-of-covariance interaction between treatment and center, which used an June 2007
α level of 10%. The SAS general linear model procedure (SAS Institute Inc., Cary, North Carolina) using type III sums of squares was used to perform comparisons between treatment groups for continuous response variables. No adjustment was made for multiple comparisons, as only 1 primary efficacy end point was specified a priori. All other comparisons involving lesion types, time points, and choice of dependent variable (change from baseline and percent change from baseline) were not adjusted for multiple comparisons. SAS version 8.2 was used for all statistical analyses.
RESULTS Patient Disposition and Baseline Characteristics One hundred fifty-six patients were randomized to receive treatment, 78 in each treatment group (Figure 1). One hundred forty-five (92.9%) patients completed treatment, and 11 (7.1%) patients discontinued before study completion. The treatment groups were well balanced with regard to demographic characteristics and the baseline distribution of individual lesion counts (Table I). Patients ranged in age from 12 to 41 years (mean, 18.4 years) and were predominantly white (89 [57.1%]) and male (80 [51.3%]). There were no statistically significant differences between treatment groups in age, sex, or race. The mean (SD) total acne lesion count was 46.0 (17.5), with a mean number of inflammatory lesions of 17.6 and a mean number of noninflammatory lesions of 28.3. The proportions of patients with 0, 1, and 2 nodules were 84.6%, 14.1%, and 1.3%, respectively. At baseline, most patients in both treatment groups were assessed as having no erythema, peeling, dryness, burning/stinging, or itching (72.6%–98.7% of patients across all 5 variables) (Table I). The most frequently occurring signs or symptoms of cutaneous irritation at baseline in both groups were mild erythema (22.4%) and mild dryness (16.7%). No patients had severe irritation, and a moderate level of irritation was noted only for dryness (3.2%) and itching (0.6%). There were no statistically significant differences between treatment groups for any baseline cutaneous irritation variables.
Dosing The mean (SD) duration of therapy was 80.0 (13.7) days in the TGM 0.04% group and 77.9 (16.4) days in the TGM 0.1% group. The difference between treatment groups was not statistically signifi1089
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Assessed for eligibility (N = 156)
Enrolled and randomized to treatment (n = 156)
TGM 0.04% (n = 78)
Withdrew (n = 5) Lost to follow-up (2) Adverse event (facial dermatitis, 1) Personal reasons (1) Protocol violation (use of additional antiacne medication, 1)
TGM 0.1% (n = 78)
Withdrew (n = 6) Lost to follow-up (3) Adverse event (facial dermatitis, 1) Personal reasons (1) Other (moved before completing study, 1)
Completed study (n = 73)
Completed study (n = 72)
Analyzed (intent-to-treat population) (n = 78)
Analyzed (intent-to-treat population) (n = 78)
Figure 1. Flow of patients through the study. TGM = tretinoin gel microspheres. cant. The mean (SD) amount of study drug used over the course of the study was 46.4 (24) and 47.6 (25.1) g, respectively. Again, there was no significant difference between groups.
Efficacy Lesion Counts Both TGM 0.04% and TGM 0.1% were associated with reductions in the total number of acne lesions, both inflammatory and noninflammatory (Figure 2 and Table II). The treatment groups did not differ significantly in terms of the reduction in the total number of acne lesions at weeks 2, 4, 8, or 12. At week 12, the least squares mean percent reduction in total lesion counts from baseline to week 12 was 39.4% for TGM 0.04% and 34.4% for TGM 0.1% (P = NS). 1090
The absolute change from baseline in the total lesion count (18.1 and 16.4, respectively) was not significantly different between groups. With regard to inflammatory lesions, TGM 0.1% was associated with a greater response at week 2 compared with TGM 0.04% (14.8% vs 6.0%, respectively; P < 0.048). No significant differences in the proportion of inflammatory lesions between treatment groups were noted at any subsequent treatment visits, and there were no significant reductions in the proportion of noninflammatory lesions between TGM 0.04% and TGM 0.1% at weeks 2, 4, 8, or 12.
Investigator’s Global Assessment At week 12, investigators’ responses were lacking for 4 TGM 0.04% and 3 TGM 0.1% patients and Volume 29 Number 6
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Table I. Demographic and baseline clinical characteristics of patients with mild to moderate facial acne vulgaris.
Characteristic
TGM 0.04% (n = 78)
TGM 0.1% (n = 78)
P
Age, mean (SD), y
18.2 (6.3)
18.7 (6.5)
0.636
Sex, no. (%) Male Female
43 (55.1) 35 (44.9)
37 (47.4) 41 (52.6)
Race, no. (%)* White Black Asian Hispanic Native American Other
44 (56.4) 12 (15.4) 2 (2.6) 17 (21.8) 2 (2.6) 1 (1.3)
45 (57.7) 18 (23.1) 1 (1.3) 12 (15.4) 1 (1.3) 1 (1.3)
46.6 (17.8) 17.3 (6.2) 29.1 (16.3)
45.5 (17.2) 17.9 (6.8) 27.4 (17.0)
66 (84.6) 11 (14.1) 1 (1.3)
66 (84.6) 11 (14.1) 1 (1.3)
18 (23.1) 2 (2.6)
17 (21.8) 2 (2.6)
13 (16.7) 2 (2.6) 1 (1.3)
13 (16.7) 3 (3.8) 1 (1.3)
2 (2.6) 1 (1.3)
3 (3.8) 0
Lesion counts, mean (SD) Total Inflammatory Noninflammatory Nodules 0 1 2 Cutaneous irritation, no. (%) Erythema, mild Peeling, mild Dryness Mild Moderate Burning/stinging, mild Itching Mild Moderate
0.330
0.316
0.645 0.577 0.464 1.000
0.834 1.000 0.759
1.000 0.942
TGM = tretinoin gel microspheres. *Percentages may not total 100 due to rounding.
were thus coded as “no change” for analytic purposes. A response of excellent, good, or fair was recorded for 79.5% (62/78) of patients treated with TGM 0.04% and 73.1% (57/78) of patients treated with TGM 0.1% (Figure 3). In the TGM 0.04% group, the proportions of patients recorded as having responses of excellent, good, and fair were 23.1% (18/78), 30.8% (24/78), and 25.6% (20/78), respectively; the corresponding proportions of the TGM 0.1% group were 28.2% (22/78), 26.9% (21/78), and 19.2% (15/78). There were no significant differences between treatJune 2007
ment groups in the investigator’s global evaluation of treatment response.
Patient’s Self-Assessment At week 12, a self-assessment was lacking for 3 (3.8%) patients in the TGM 0.04% group and 3 (3.8%) patients in the TGM 0.1% group; thus, a response of “not improved” was used for analytic purposes. In each treatment group, 85.9% (67/78) of patients reported that their acne was either “much improved” or “somewhat improved” (Figure 4). The pro1091
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TGM 0.04% TGM 0.1%
45 40
% Reduction
35 30 25 20 15 10 *
5 0 0
2
4
6
8
10
12
Week Figure 2. Percent reduction in mean (SEM) inflammatory lesion counts. TGM = tretinoin gel microspheres. *P = 0.047.
Table II. Percent reduction in mean (SD) acne lesion counts in study patients. Variable
TGM 0.04%
TGM 0.1%
P
% Reduction in total lesion count Week 2 Week 4 Week 8 Week 12
10.5 (22.1) 22.2 (30.0) 31.6 (27.4) 39.4 (36.2)
12.8 (22.1) 17.2 (30.0) 30.1 (27.4) 34.4 (36.2)
0.513 0.294 0.743 0.383
% Reduction in inflammatory lesion count Week 2 Week 4 Week 8 Week 12
6.0 (27.4) 21.0 (36.5) 31.3 (37.4) 34.7 (41.0)
14.8 (27.5) 21.6 (36.6) 31.9 (37.4) 37.9 (41.0)
0.047 0.921 0.929 0.623
% Reduction in noninflammatory lesion count Week 2 Week 4 Week 8 Week 12
13.0 (28.3) 22.1 (38.9) 29.7 (37.1) 40.0 (50.3)
11.8 (28.3) 14.1 (38.9) 25.3 (37.1) 30.0 (50.3)
0.780 0.201 0.463 0.214
TGM = tretinoin gel microspheres.
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Tolerability Twenty-nine (37.2%) patients receiving TGM 0.04% and 32 (41.0%) receiving TGM 0.1% reported at least 1 adverse event. The most commonly reported adverse events are summarized in Table III. The most frequently occurring skin and subcutaneous tissue adverse event in patients receiving TGM 0.04% was general facial skin irritation (6.4%). In patients receiving TGM 0.1%, the most frequently occurring skin and subcutaneous tissue adverse events were a sensation of facial skin burning (7.7%) and erythema (5.1%). The incidence of all other facial skin and subcutaneous tissue adverse events in either treatment group was <4% and included such events as sunburn and exfoliative dermatitis. In both treatment groups, the majority (20/23 [87.0%]) of facial skin and subcutaneous tissue adverse events were considered related to treatment. All adverse events were of mild to mod-
erate intensity, with the exception of 1 incident each of mononucleosis (TGM 0.04%) and nephrolithiasis (TGM 0.1%). Both events were considered unrelated to study medication, and both patients recovered. There were no serious adverse events. Two patients, 1 receiving TGM 0.04% and 1 receiving TGM 0.1%, withdrew from the study due to facial dermatitis after 3 and 5 days of treatment, respectively.
Cutaneous Irritation Overall, 41 (52.6%) of 78 patients in the TGM 0.04% group and 41 (52.6%) of 78 patients in the TGM 0.1% group experienced at least 1 cutaneous treatment effect (erythema, peeling, dryness, burning/ stinging, or itching), as rated by a physician (Table IV). Changes in erythema were not significantly different between groups at weeks 2, 4, or 8. Increases in erythema were fairly consistent at weeks 2, 4, 8, and 12 in the 2 treatment groups. At week 12, the proportion of patients with worsening erythema was 25.6% (n = 20) for TGM 0.04% and 12.9% (n = 10) for TGM 0.1% (P = 0.035). Changes in dryness were significant between treatment groups at week 2 (P < 0.027) and week 4 (P < 0.030), indicating an increase in dryness in patients
TGM 0.04% TGM 0.1%
100 90 80
% of Patients
70 60 50 40 30 20 10 0
Fair/Better
No Change/Worse
Figure 3. Investigator’s global evaluation of the treatment response (improvement in facial acne, rated on a 5-point scale) at week 12. No statistically significant difference was observed between the 2 tretinoin gel microsphere (TGM) formulations.
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TGM 0.04% TGM 0.1%
100 90 80
% of Patients
70 60 50 40 30 20 10 0
Much/Somewhat Improved
Not Improved/Worse
Figure 4. Patients’ self-assessment of the treatment response (improvement in facial acne, rated on a 5-point scale) at week 12. No statistically significant difference was observed between the 2 tretinoin gel microsphere (TGM) formulations.
Table III. Most commonly reported (occurring in ≥2% of patients) adverse events in patients with facial acne vulgaris (no. [%]). Adverse Event Skin burning sensation Skin irritation Erythema Exfoliative dermatitis Sunburn Sinusitis Dermatitis Dry skin Nasopharyngitis
TGM 0.04% TGM 0.1% (n = 78) (n = 78) 2 (2.6) 5 (6.4) 1 (1.3) 1 (1.3) 3 (3.8) 1 (1.3) 2 (2.6) 2 (2.6) 2 (2.6)
6 (7.7) 3 (3.8) 4 (5.1) 3 (3.8) 1 (1.3) 3 (3.8) 2 (2.6) 2 (2.6) 2 (2.6)
TGM = tretinoin gel microspheres.
receiving TGM 0.1% compared with TGM 0.04%. The increase in dryness occurred most commonly at week 2, with worsening observed in 23.1% (n = 18) of patients in the TGM 0.04% group and 42.3% (n = 33) of patients in the TGM 0.1% group. 1094
Changes in peeling, burning/stinging, and itching did not differ significantly between groups at any study week.
DISCUSSION The purpose of this double-blind, randomized, multicenter study was to compare the tolerability and efficacy of TGM 0.04% and TGM 0.1% in the treatment of mild to moderate acne vulgaris. These 2 formulations, which have greater stability than other formulations of tretinoin,10,11 were developed to minimize cutaneous irritation while maintaining acceptable efficacy.17 TGM 0.1% was the first such product to receive approval for marketing in the United States. A lower-strength TGM formulation may further reduce exposure to tretinoin and offer another option for the effective treatment of acne with minimal cutaneous irritation. In this study, TGM 0.04% and TGM 0.1% were associated with reductions in numbers of total lesions, inflammatory lesions, and noninflammatory lesions. The differences between groups in the change in lesion counts from baseline to weeks 2, 4, 8, and 12 were not statistically significant, with the exception of the greater reduction in inflammatory lesions at week 2 with Volume 29 Number 6
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Table IV. Proportions of patients with changes from baseline in ratings of cutaneous irritation variables.* Erythema Change in Rating from Baseline
TGM 0.04%
TGM 0.1%
Peeling TGM 0.04%
TGM 0.1%
Dryness TGM 0.04%
TGM 0.1%
Burning/Stinging TGM 0.04%
TGM 0.1%
Itching TGM 0.04%
TGM 0.1%
Week 2 –2 –1 0 +1 +2 +3 P
0 0 3.8 1.3 61.5 61.5 25.6 26.9 6.4 5.1 2.6 5.1 0.407
0 1.3 65.4 30.8 2.6 0
0 0 57.7 34.6 6.4 1.3 0.167
0 1.3 5.1 5.1 71.8 51.3 17.9 30.8 5.1 9.0 0 2.6 0.027
0 0 0 1.3 79.5 73.1 15.4 17.9 5.1 5.1 0 2.6 0.515
0 0 87.2 11.5 1.3 0
0 3.8 79.5 12.8 3.8 0 0.960
Week 4 –2 –1 0 +1 +2 +3 P
0 0 10.3 10.3 66.7 65.4 19.2 12.8 3.8 7.7 0 3.8 0.399
0 0 2.6 0 76.9 70.5 16.7 23.1 3.8 3.8 0 2.6 0.095
0 0 10.3 6.4 71.8 60.3 15.4 26.9 2.6 5.1 0 1.3 0.029
0 0 1.3 1.3 88.5 80.8 7.7 15.4 2.6 2.6 0 0 0.195
1.3 2.6 92.3 3.8 0 0
0 3.8 89.7 3.8 2.6 0 0.445
Week 8 –2 –1 0 +1 +2 +3 P
0 0 9.0 5.1 62.8 73.1 24.4 16.7 3.8 3.8 0 1.3 0.932
0 0 2.6 0 76.9 80.8 19.2 17.9 1.3 0 0 1.3 0.924
0 1.3 7.7 10.3 76.9 66.7 15.4 17.9 0 2.6 0 1.3 0.633
0 0 1.3 1.3 88.5 87.2 9.0 10.3 1.3 1.3 0 0 0.844
1.3 1.3 93.6 3.8 0 0
0 3.8 88.5 6.4 1.3 0 0.586
Week 12 –2 –1 0 +1 +2 +3 P
0 0 6.4 7.7 67.9 79.5 19.2 10.3 6.4 1.3 0 1.3 0.035
0 0 2.6 2.6 88.5 91.0 6.4 3.8 2.6 1.3 0 1.3 0.651
0 3.8 11.5 9.0 74.4 70.5 11.5 15.4 2.6 0 0 1.3 0.932
0 0 1.3 1.3 94.9 92.3 3.8 5.1 0 1.3 0 0 0.480
1.3 1.3 94.9 2.6 0 0
0 2.6 89.7 6.4 1.3 0 0.219
TGM = tretinoin gel microspheres. *A change of –2 represents the greatest improvement from baseline; a change of +3 represents the greatest worsening from baseline. Statistical significance was set at P ≤ 0.05 (Cochran-Mantel-Haenszel row-mean score test statistic with modified ridit scores, stratified by center).
TGM 0.1% compared with TGM 0.04% (14.8% vs 6.0%, respectively; P < 0.048). Furthermore, the investigators’ global evaluations and patients’ selfassessments of the treatment response indicated similar levels of improvement in both treatment groups. The results of these assessments correlated well with June 2007
the extent of change in acne lesion counts. The reductions in numbers of both inflammatory and noninflammatory lesions may be the result of tretinoin’s effects on the microcomedone, which is the precursor to both lesions.6 The benefit of the higher-strength TGM formulation in terms of inflammatory lesions would 1095
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Clinical Therapeutics require a larger study to show significance. An onset of action early in treatment might also be discernible in a larger study. A limitation of this study is that the exclusion criteria limited the ability to extrapolate the results beyond the small, selected population studied. Both strengths of TGM (0.04% and 0.1%) were generally well tolerated. The type and frequency of adverse events were consistent with the established safety profile of TGM in the treatment of acne vulgaris.18 Although tretinoins are known to be irritating, a randomized, split-face study found that TGM 0.1% was associated with significantly less erythema than tretinoin 0.1% cream (P = 0.014).19 In the present study, TGM 0.04% was associated with significantly fewer patients experiencing dryness of the treatment area during the early stages of treatment (week 2, P < 0.027; week 4, P < 0.030). However, there were either no significant differences between treatment groups on other measures of cutaneous irritation (peeling, burning/stinging, and itching) or a significant increase in erythema with TGM 0.1%. These results are consistent with those of a study by Dosik et al20 that compared the irritancy potential of adapalene 0.1% cream and gel with TGM 0.1% and 0.04% in patients with normal skin. They found no significant difference in the mean cumulative irritation index (a measure of erythema plus local skin reactions) between TGM 0.1% and TGM 0.04%.
CONCLUSIONS In this study, TGM 0.04% and 0.1% were associated with reductions in acne lesion counts. Both concentrations were generally well tolerated. The results suggested an early (week 2) incremental benefit for TGM 0.1% in terms of inflammatory lesions.
ACKNOWLEDGMENTS This study was sponsored by Johnson & Johnson, Inc., Skillman, New Jersey, which was responsible for the study design, analysis and interpretation of the data, and the decision to submit the paper for publication. Data collection was the responsibility of independent investigators. The manuscript was prepared with the assistance of Thomson Pharmaceutical Services, Horsham, Pennsylvania.
REFERENCES 1. Pochi PE. The pathogenesis and treatment of acne. Annu Rev Med. 1990;41:187–198.
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2. Quan M, Strick RA. Management of acne vulgaris. Am Fam Physician. 1988;38:207–218. 3. Koo J. The psychosocial impact of acne: Patients’ perceptions. J Am Acad Dermatol. 1995;32:S26–S30. 4. Lasek RJ, Chren MM. Acne vulgaris and the quality of life of adult dermatology patients. Arch Dermatol. 1998;134: 454–458. 5. Leyden JJ. Retinoids and acne. J Am Acad Dermatol. 1988; 19:164–168. 6. Lavker RM, Leyden JJ, Thorne EG. An ultrastructural study of the effects of topical tretinoin on microcomedones. Clin Ther. 1992;14:773–780. 7. Liu PT, Krutzik SR, Kim J, Modlin RL. Cutting edge: Alltrans retinoic acid down-regulates TLR2 expression and function. J Immunol. 2005;174:2467–2470. 8. Guzzo CA, Lazarus GS, Werth VP. Dermatological pharmacology. In: Hardman JG, Limbird LE, Molinoff PB, et al, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996: 1593–1616. 9. Embil K, Nacht S. The Microsponge Delivery System (MDS): A topical delivery system with reduced irritancy incorporating multiple triggering mechanisms for the release of actives. J Microencapsul. 1996;13:575–588. 10. Nyirady J, Lucas C, Yusuf M, et al. The stability of tretinoin in tretinoin gel microsphere 0.1%. Cutis. 2002;70:295–298. 11. Nighland M, Yusuf M, Wisniewski S, et al. The effect of simulated solar UV irradiation on tretinoin in tretinoin gel microsphere 0.1% and tretinoin gel 0.025%. Cutis. 2006; 77:313–316. 12. Webster GF. Topical tretinoin in acne therapy. J Am Acad Dermatol. 1998;39(Suppl):S38–S44. 13. Nyirady J, Nighland M, Payonk G, et al. A comparative evaluation of tretinoin gel microsphere, 0.1%, versus tretinoin cream, 0.025% in reducing facial shine. Cutis. 2000;66:153–156. 14. Grove GL, Zerweck CR, Nacht S, Leyden JJ. The effects of vehicle composition on the subjective and objective irritancy potential of retinoic acid formulations. Poster presented at: 55th Annual Meeting of the American Academy of Dermatology; March 21–26, 1997; San Francisco, Calif. 15. Nyirady J, Nighland M. Comparative studies to evaluate the phototoxic and photoallergic potential of two antiacne products. Cosmet Dermatol. 2001;14:27–30. 16. Dixon WJ, Massey FJ Jr. Introduction to Statistical Analysis. 2nd ed. New York, NY: McGraw-Hill; 1957. 17. Nyirady J, Bennett ML. Advancement of tretinoin through the microsphere technology. Cosmet Dermatol. 2001;14:22– 24. 18. Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04% [package insert]. Skillman, NJ: Ortho Dermatological; 2002.
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R. Berger et al. 19. Leyden J, Grove G, Zerweck C. Facial tolerability of topical retinoid therapy. J Drugs Dermatol. 2004;3:641–651. 20. Dosik JS, Homer K, Arsonnaud S. Cumulative irritation potential of adapalene 0.1% cream and gel compared with tretinoin microsphere 0.04% and 0.1%. Cutis. 2005;75:238– 243.
Address correspondence to: Jonathan Weiss, MD, Gwinnett Clinical Research Center, Inc., 2383 Pate Street, Snellville, GA 30078. E-mail: [email protected] June 2007
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Tretinoin Gel Microspheres 0.04% Versus 0.1% in Adolescents and Adults with Mild to Moderate Acne Vulgaris: A 12-Week, Multicenter, Randomized, Double-Blind, Parallel-Group, Phase IV Trial Richard Berger, MD1; Ronald Rizer, PhD2; Alicia Barba, MD3; David Wilson, MD4; Daniel Stewart, DO5; Rachel Grossman, MD6; Marge Nighland, BS6; and Jonathan Weiss, MD7 1Hill
Top Research, Inc., Milltown, New Jersey; 2Stephens and Associates, Colorado Springs, Colorado; 3International Dermatology Research Inc., Miami, Florida; 4Education and Research Foundation, Inc., Lynchburg, Virginia; 5Midwest Cutaneous Research Corp., Clinton Township, Michigan; 6Johnson & Johnson Consumer Products Worldwide, Skillman, New Jersey; and 7Gwinnett Clinical Research Center, Inc., Snellville, Georgia ABSTRACT Background: Topical retinoids are considered firstline therapy in the treatment of acne vulgaris, yet can be associated with cutaneous irritation, including erythema, peeling, dryness, burning, and itching. Tretinoin gel microsphere (TGM) formulations were developed to minimize these effects. A lower-strength TGM formulation may be desirable to further reduce exposure to tretinoin. Objective: This study was conducted to assess the efficacy and safety profile of a lower-dose TGM (0.04%) formulation compared with TGM 0.1% for the treatment of mild to moderate acne vulgaris. Methods: In this multicenter, double-blind, parallelgroup, Phase IV dose-ranging study, patients with facial acne were randomized to apply either TGM 0.04% or TGM 0.1% to the face each night for 12 weeks. Patients must have discontinued systemic retinoid treatment for at least 1 year before the study and were not to have used any topical retinoids, systemic antibiotics, nicotinamide, or systemic steroids for at least 1 month. All other topical medications applied to the face (including corticosteroids, antimicrobials, salicylic acid, and benzoyl peroxide) were to be discontinued at least 2 weeks before the study. End points were the acne lesion count (total, inflammatory, and noninflammatory lesions) and the investigators’ and patients’ assessments of improvement. Adverse events (including severity and relationship to treatment) and signs and symptoms of cutaneous irritation at the treatment site were monitored at each study visit. 1086
Results: One hundred fifty-six patients (78 TGM 0.04%, 78 TGM 0.1%) were randomized and received treatment. Patients ranged in age from 12 to 41 years (mean, 18.4 years) and were predominantly white (n = 89 [57.1%]) and male (n = 80 [51.3%]). Both TGM 0.04% and TGM 0.1% were associated with a reduction from baseline in total, inflammatory, and noninflammatory lesions. The differences between groups in the change in lesion counts from baseline to weeks 2, 4, 8, and 12 were not statistically significant. However, there was a greater reduction in inflammatory lesions at week 2 for TGM 0.1% compared with TGM 0.04% (14.8% vs 6.0%, respectively; P < 0.047). Both treatment groups had similar improvements in the investigators’ global evaluation and the patients’ assessment of the response to treatment. Both TGM 0.04% and TGM 0.1% were well tolerated. The most common adverse events were skin-associated burning sensation (2.6% in the TGM 0.04% group and 7.7% in the TGM 0.1% group) and irritation (6.4% and 3.8%, respectively). In the TGM 0.04% group, significantly fewer patients experienced dryness of the treatment area during the early phase of treatment (P < 0.027). However, for other measures of cutaneous irritation (peeling, burning/stinging, and itching), either there were no statistically significant differences beAccepted for publication April 25, 2007. doi:10.1016/j.clinthera.2007.06.021 0149-2918/$32.00 Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2007 Excerpta Medica, Inc.
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R. Berger et al. tween treatment groups or, in the case of erythema, there was a significant difference in favor of TGM 0.1% (P = 0.035). Conclusions: Both TGM 0.04% and TGM 0.1% were associated with reductions in lesion counts in these patients with mild to moderate facial acne. Both concentrations were generally well tolerated. The results suggested an early (week 2) incremental benefit for the use of TGM 0.1% in the treatment of inflammatory lesions. (Clin Ther. 2007;29:1086–1097) Copyright © 2007 Excerpta Medica, Inc. Key words: acne vulgaris, cutaneous irritation, inflammatory lesions, tretinoin gel microspheres.
INTRODUCTION Acne vulgaris is a follicular disorder that begins when the microenvironment of sebaceous follicles undergoes specific changes that result in plugging of the pilosebaceous follicle and development of the microcomedo.1 The microcomedo, in turn, gives rise to acne lesions, including noninflammatory comedones and inflammatory papules, pustules, and nodules.2 While the precise etiology of acne remains unknown, its manifestations are thought to be the product of 4 pathogenic events: increased sebum production, obstruction of the pilosebaceous unit by abnormal keratinization, proliferation of Propionibacterium acnes, and inflammation mediated by both chemotactic factors and various enzymes.2 Inflammatory lesions have been found to contribute to the negative psychosocial consequences associated with acne, including diminished self-esteem and quality of life.3,4 Retinoids, natural or synthetic derivatives of vitamin A, are highly effective in the treatment of acne vulgaris because of their ability to modify abnormal follicular keratinization.5 Tretinoin acts by modulating the proliferation and differentiation of epidermal cells within the stratum corneum and restores normal desquamation of follicular cells, thereby facilitating comedolysis.6 These effects are mediated by tretinoin’s interaction with a family of nuclear retinoic acid receptors. In addition, tretinoin may decrease the inflammatory component of acne through a decrease in the expression of toll-like receptor 2 and cytokine induction by P acnes.7 Adverse effects associated with retinoid use include erythema, dryness, peeling, and burning,8 which may be the result of thinning of the stratum corneum.6 June 2007
Tretinoin gel microsphere (TGM) technology was developed to minimize the cutaneous irritation seen with other topical tretinoin-containing acne products. Microsphere technology is a drug-delivery system designed to entrap the active ingredient and release it onto the skin. Microsphere delivery results in minimal absorption, leading to lower accumulation in the epidermis.9 Furthermore, when exposed to ultraviolet light, TGM is more stable than conventional gel formulations of tretinoin.10,11 TGM 0.1% has been found to be more effective than vehicle in reducing the severity of acne lesions, as measured by a reduction in acne lesion counts.12,13 In two 12-week studies involving 144 and 148 patients,12 inflammatory lesion counts were reduced by a mean of 37% (P = 0.028) and 29% (P = NS), respectively, among patients treated with TGM 0.1%, compared with 18% and 24% among controls who received vehicle. The mean percent reductions in noninflammatory lesion counts were 49% and 32% (both, P < 0.001) among patients receiving TGM therapy and 22% and 3% among those who received vehicle. In a singlecenter, double-blind, half-face study comparing 4 consecutive days of topical application of TGM 0.1% and tretinoin cream 0.025% in 35 patients with acne vulgaris,13 facial shine was significantly reduced 3 or 6 hours after treatment with the TGM formulation compared with tretinoin (P = 0.008 and P < 0.001, respectively). Facial shine, or oiliness, is a condition that often accompanies acne vulgaris and may contribute to its psychosocial consequences for the patient. A single-center, randomized, double-blind, halfface study compared the irritation potential of 14 consecutive days of TGM 0.1% and tretinoin cream 0.1% in 25 white women with sensitive skin.14 Cutaneous irritation at the application site (defined as dryness and erythema) was significantly less severe after treatment with TGM 0.1% compared with tretinoin 0.1% cream (P < 0.001 for both variables). Twenty-three (92%) of 25 patients indicated a preference for the TGM formulation over the tretinoin cream (P < 0.001). Clinical safety studies of TGM 0.1% (the highest strength) have found no phototoxic or photoallergic potential.15 A lower-strength TGM formulation that was both well tolerated and effective might further reduce exposure to tretinoin. The present study was conducted to assess the efficacy and tolerability of a lower-dose TGM (0.04%) formulation compared with TGM 0.1% in the treatment of mild to moderate acne vulgaris. 1087
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PATIENTS AND METHODS Study Design This randomized, double-blind, parallel-group, Phase IV study was conducted at 6 study centers from March 1, 2004, through September 17, 2004, in patients with mild to moderate facial acne vulgaris. The study protocol was approved by an independent review board and conducted in accordance with the Declaration of Helsinki and the good clinical practice guidelines. All patients provided written informed consent before participation; in the case of adolescent patients, both the patient and his or her guardian gave written consent. Patients were randomized to receive TGM 0.04%* or TGM 0.1%* in a 1:1 ratio according to a predetermined, computer-generated randomization schedule provided by the manufacturer. Separate randomization lists were prepared for each study center using a prespecified block size. Each of 5 centers enrolled 24 patients, with 12 in each treatment group. The sixth center enrolled 36 patients, who were equally distributed between treatment groups. Patients were instructed to apply the assigned product to the face each night for 12 consecutive weeks. They were provided with a supplemental skin cleanser (Neutrogena Fresh Foaming Facial Cleanser, Neutrogena, Los Angeles, California) to use before each application of test drug, a moisturizer (Neutrogena Healthy Defense Daily Moisturizer) to be used as needed, and a sunscreen (Neutrogena Oil-free Sunblock SPF 30) to be used during periods of extended UV exposure. Patients were instructed to wash the entire face each night with the supplied skin cleanser, rinse immediately, pat the face dry with a towel, and apply a quantity of the assigned test drug equal to ~1/2 inch (~250 mg) to the entire face. Patients were instructed to leave treated areas undisturbed overnight. The supplied moisturizer was to be applied in the morning as needed, but not on the morning of a scheduled study visit. Other medications were not to be applied to the face during the study, and cosmetic use was to be limited. Patients were instructed to avoid or minimize sun exposure and to avoid sunlamps and tanning salons during the study. The supplied sunscreen or a similar product (SPF ≥30) was to be applied to the face whenever extended sun exposure was anticipated, and wearing protective clothing was advised. *Trademark: Retin-A Micro® microspheres (Johnson & Johnson Consumer Companies, Inc., Skillman, New Jersey).
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Study Population Male and female patients between the ages of 12 and 40 years, in good health, with mild to moderate acne vulgaris were included in this study. Mild to moderate acne vulgaris was defined as 20 to 150 total facial lesions. Of these lesions, 10 to 100 were to be comedones (open and closed), and 10 to 50 were to be inflammatory lesions (papules and pustules). No more than 2 were to be nodules (defined as deep inflammatory lesions of 1 cm or greater). In this study, patients were to have discontinued systemic retinoid treatment for at least 1 year before the study. Additionally, patients were not to have used any topical retinoids, systemic antibiotics, nicotinamide, or systemic steroids for at least 1 month. All other topical medications applied to the face (including corticosteroids, antimicrobials, salicylic acid, and benzoyl peroxide) were to be discontinued at least 2 weeks before study initiation. Patients were instructed not to use cosmetic products on the face that contained retinol, salicylic acid, α-hydroxy acid, or bleaching agents such as hydroquinone during the study period. Female patients were excluded from the study if they were pregnant, were lactating, or had been using systemic birth control for <6 months. Other exclusion criteria included erythema not attributed to the acne lesions, peeling, dryness, burning/stinging, and itching on the face. Other skin conditions (eg, rosacea, atopic dermatitis, seborrheic dermatitis, psoriasis) or disease that would require concurrent therapy or confound the evaluation of the tolerability or efficacy of study drug was also a cause for exclusion. Additional exclusion criteria included excessive facial hair (ie, beard, sideburns, or mustache) that would obstruct evaluation; use of photosensitizing, phototherapy, or selftanning agents; and the presence of skin cancer or actinic keratosis on the face. Use of sunlamps and tanning beds was to be avoided, and excessive unprotected exposure to UV light was to be limited.
Efficacy and Tolerability Assessments Patients were evaluated at baseline and after 2, 4, 8, and 12 weeks of therapy. Acne lesion counts were performed at each visit by a single blinded investigator at each site. The counts included inflammatory lesions (papules and pustules), noninflammatory lesions (open and closed comedones combined), and nodules. At 12 weeks, an investigator’s global evaluation of the Volume 29 Number 6
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R. Berger et al. treatment response relative to baseline (5-point ordinal scale: excellent, good, fair, no change, and worse) and a patient’s self-assessment of the response to treatment since starting the trial (5-point ordinal response to the question “How would you rate your acne improvement since you started the study?”: much improved, somewhat improved, not improved, worse, and much worse) were performed. The tolerability assessment included the incidence and severity of adverse events, and signs and symptoms of cutaneous irritation (erythema, peeling, dryness, burning/stinging, and itching). Adverse events were elicited by querying the patient at each study visit. Assessment of cutaneous irritation included the investigator’s/clinician’s rating of signs (erythema, peeling, and dryness) and the patient’s rating of the symptoms of irritation (burning/stinging and itching). Each of the signs and symptoms was rated on a 4-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe).
Statistical Analysis A sample size of 75 patients per group was chosen to provide 80% power to detect an 18.4% difference in treatment-group means for the change from baseline in total lesion count, assuming a common SD of 40% using a 2-group t test with a 2-sided significance level of 0.05. Baseline homogeneity between treatment groups was analyzed using a 2-way analysis of variance for continuous variables, the Cochran-MantelHaenszel (CMH) general association test for nominal categorical variables, and the CMH row mean score test using modified ridit scores for ordinal categorical variables. All patients with a baseline assessment and at least 1 postbaseline efficacy assessment were included in the efficacy data set. Efficacy was assessed in the intentto-treat population, using last-observation-carriedforward methodology for missing values. The primary efficacy end point was the percent change from baseline in total lesion count at week 12. Statistical methods for the assessment of treatment differences were based on a 2-way analysis of covariance model of the percent change from baseline in the week-12 total lesion count, with response value, treatment, and center representing main effects, and the baseline total lesion count as a covariate.16 All statistical tests were 2-sided and were performed at a significance level of 5%, with the exception of an analysis-of-covariance interaction between treatment and center, which used an June 2007
α level of 10%. The SAS general linear model procedure (SAS Institute Inc., Cary, North Carolina) using type III sums of squares was used to perform comparisons between treatment groups for continuous response variables. No adjustment was made for multiple comparisons, as only 1 primary efficacy end point was specified a priori. All other comparisons involving lesion types, time points, and choice of dependent variable (change from baseline and percent change from baseline) were not adjusted for multiple comparisons. SAS version 8.2 was used for all statistical analyses.
RESULTS Patient Disposition and Baseline Characteristics One hundred fifty-six patients were randomized to receive treatment, 78 in each treatment group (Figure 1). One hundred forty-five (92.9%) patients completed treatment, and 11 (7.1%) patients discontinued before study completion. The treatment groups were well balanced with regard to demographic characteristics and the baseline distribution of individual lesion counts (Table I). Patients ranged in age from 12 to 41 years (mean, 18.4 years) and were predominantly white (89 [57.1%]) and male (80 [51.3%]). There were no statistically significant differences between treatment groups in age, sex, or race. The mean (SD) total acne lesion count was 46.0 (17.5), with a mean number of inflammatory lesions of 17.6 and a mean number of noninflammatory lesions of 28.3. The proportions of patients with 0, 1, and 2 nodules were 84.6%, 14.1%, and 1.3%, respectively. At baseline, most patients in both treatment groups were assessed as having no erythema, peeling, dryness, burning/stinging, or itching (72.6%–98.7% of patients across all 5 variables) (Table I). The most frequently occurring signs or symptoms of cutaneous irritation at baseline in both groups were mild erythema (22.4%) and mild dryness (16.7%). No patients had severe irritation, and a moderate level of irritation was noted only for dryness (3.2%) and itching (0.6%). There were no statistically significant differences between treatment groups for any baseline cutaneous irritation variables.
Dosing The mean (SD) duration of therapy was 80.0 (13.7) days in the TGM 0.04% group and 77.9 (16.4) days in the TGM 0.1% group. The difference between treatment groups was not statistically signifi1089
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Assessed for eligibility (N = 156)
Enrolled and randomized to treatment (n = 156)
TGM 0.04% (n = 78)
Withdrew (n = 5) Lost to follow-up (2) Adverse event (facial dermatitis, 1) Personal reasons (1) Protocol violation (use of additional antiacne medication, 1)
TGM 0.1% (n = 78)
Withdrew (n = 6) Lost to follow-up (3) Adverse event (facial dermatitis, 1) Personal reasons (1) Other (moved before completing study, 1)
Completed study (n = 73)
Completed study (n = 72)
Analyzed (intent-to-treat population) (n = 78)
Analyzed (intent-to-treat population) (n = 78)
Figure 1. Flow of patients through the study. TGM = tretinoin gel microspheres. cant. The mean (SD) amount of study drug used over the course of the study was 46.4 (24) and 47.6 (25.1) g, respectively. Again, there was no significant difference between groups.
Efficacy Lesion Counts Both TGM 0.04% and TGM 0.1% were associated with reductions in the total number of acne lesions, both inflammatory and noninflammatory (Figure 2 and Table II). The treatment groups did not differ significantly in terms of the reduction in the total number of acne lesions at weeks 2, 4, 8, or 12. At week 12, the least squares mean percent reduction in total lesion counts from baseline to week 12 was 39.4% for TGM 0.04% and 34.4% for TGM 0.1% (P = NS). 1090
The absolute change from baseline in the total lesion count (18.1 and 16.4, respectively) was not significantly different between groups. With regard to inflammatory lesions, TGM 0.1% was associated with a greater response at week 2 compared with TGM 0.04% (14.8% vs 6.0%, respectively; P < 0.048). No significant differences in the proportion of inflammatory lesions between treatment groups were noted at any subsequent treatment visits, and there were no significant reductions in the proportion of noninflammatory lesions between TGM 0.04% and TGM 0.1% at weeks 2, 4, 8, or 12.
Investigator’s Global Assessment At week 12, investigators’ responses were lacking for 4 TGM 0.04% and 3 TGM 0.1% patients and Volume 29 Number 6
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Table I. Demographic and baseline clinical characteristics of patients with mild to moderate facial acne vulgaris.
Characteristic
TGM 0.04% (n = 78)
TGM 0.1% (n = 78)
P
Age, mean (SD), y
18.2 (6.3)
18.7 (6.5)
0.636
Sex, no. (%) Male Female
43 (55.1) 35 (44.9)
37 (47.4) 41 (52.6)
Race, no. (%)* White Black Asian Hispanic Native American Other
44 (56.4) 12 (15.4) 2 (2.6) 17 (21.8) 2 (2.6) 1 (1.3)
45 (57.7) 18 (23.1) 1 (1.3) 12 (15.4) 1 (1.3) 1 (1.3)
46.6 (17.8) 17.3 (6.2) 29.1 (16.3)
45.5 (17.2) 17.9 (6.8) 27.4 (17.0)
66 (84.6) 11 (14.1) 1 (1.3)
66 (84.6) 11 (14.1) 1 (1.3)
18 (23.1) 2 (2.6)
17 (21.8) 2 (2.6)
13 (16.7) 2 (2.6) 1 (1.3)
13 (16.7) 3 (3.8) 1 (1.3)
2 (2.6) 1 (1.3)
3 (3.8) 0
Lesion counts, mean (SD) Total Inflammatory Noninflammatory Nodules 0 1 2 Cutaneous irritation, no. (%) Erythema, mild Peeling, mild Dryness Mild Moderate Burning/stinging, mild Itching Mild Moderate
0.330
0.316
0.645 0.577 0.464 1.000
0.834 1.000 0.759
1.000 0.942
TGM = tretinoin gel microspheres. *Percentages may not total 100 due to rounding.
were thus coded as “no change” for analytic purposes. A response of excellent, good, or fair was recorded for 79.5% (62/78) of patients treated with TGM 0.04% and 73.1% (57/78) of patients treated with TGM 0.1% (Figure 3). In the TGM 0.04% group, the proportions of patients recorded as having responses of excellent, good, and fair were 23.1% (18/78), 30.8% (24/78), and 25.6% (20/78), respectively; the corresponding proportions of the TGM 0.1% group were 28.2% (22/78), 26.9% (21/78), and 19.2% (15/78). There were no significant differences between treatJune 2007
ment groups in the investigator’s global evaluation of treatment response.
Patient’s Self-Assessment At week 12, a self-assessment was lacking for 3 (3.8%) patients in the TGM 0.04% group and 3 (3.8%) patients in the TGM 0.1% group; thus, a response of “not improved” was used for analytic purposes. In each treatment group, 85.9% (67/78) of patients reported that their acne was either “much improved” or “somewhat improved” (Figure 4). The pro1091
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TGM 0.04% TGM 0.1%
45 40
% Reduction
35 30 25 20 15 10 *
5 0 0
2
4
6
8
10
12
Week Figure 2. Percent reduction in mean (SEM) inflammatory lesion counts. TGM = tretinoin gel microspheres. *P = 0.047.
Table II. Percent reduction in mean (SD) acne lesion counts in study patients. Variable
TGM 0.04%
TGM 0.1%
P
% Reduction in total lesion count Week 2 Week 4 Week 8 Week 12
10.5 (22.1) 22.2 (30.0) 31.6 (27.4) 39.4 (36.2)
12.8 (22.1) 17.2 (30.0) 30.1 (27.4) 34.4 (36.2)
0.513 0.294 0.743 0.383
% Reduction in inflammatory lesion count Week 2 Week 4 Week 8 Week 12
6.0 (27.4) 21.0 (36.5) 31.3 (37.4) 34.7 (41.0)
14.8 (27.5) 21.6 (36.6) 31.9 (37.4) 37.9 (41.0)
0.047 0.921 0.929 0.623
% Reduction in noninflammatory lesion count Week 2 Week 4 Week 8 Week 12
13.0 (28.3) 22.1 (38.9) 29.7 (37.1) 40.0 (50.3)
11.8 (28.3) 14.1 (38.9) 25.3 (37.1) 30.0 (50.3)
0.780 0.201 0.463 0.214
TGM = tretinoin gel microspheres.
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Tolerability Twenty-nine (37.2%) patients receiving TGM 0.04% and 32 (41.0%) receiving TGM 0.1% reported at least 1 adverse event. The most commonly reported adverse events are summarized in Table III. The most frequently occurring skin and subcutaneous tissue adverse event in patients receiving TGM 0.04% was general facial skin irritation (6.4%). In patients receiving TGM 0.1%, the most frequently occurring skin and subcutaneous tissue adverse events were a sensation of facial skin burning (7.7%) and erythema (5.1%). The incidence of all other facial skin and subcutaneous tissue adverse events in either treatment group was <4% and included such events as sunburn and exfoliative dermatitis. In both treatment groups, the majority (20/23 [87.0%]) of facial skin and subcutaneous tissue adverse events were considered related to treatment. All adverse events were of mild to mod-
erate intensity, with the exception of 1 incident each of mononucleosis (TGM 0.04%) and nephrolithiasis (TGM 0.1%). Both events were considered unrelated to study medication, and both patients recovered. There were no serious adverse events. Two patients, 1 receiving TGM 0.04% and 1 receiving TGM 0.1%, withdrew from the study due to facial dermatitis after 3 and 5 days of treatment, respectively.
Cutaneous Irritation Overall, 41 (52.6%) of 78 patients in the TGM 0.04% group and 41 (52.6%) of 78 patients in the TGM 0.1% group experienced at least 1 cutaneous treatment effect (erythema, peeling, dryness, burning/ stinging, or itching), as rated by a physician (Table IV). Changes in erythema were not significantly different between groups at weeks 2, 4, or 8. Increases in erythema were fairly consistent at weeks 2, 4, 8, and 12 in the 2 treatment groups. At week 12, the proportion of patients with worsening erythema was 25.6% (n = 20) for TGM 0.04% and 12.9% (n = 10) for TGM 0.1% (P = 0.035). Changes in dryness were significant between treatment groups at week 2 (P < 0.027) and week 4 (P < 0.030), indicating an increase in dryness in patients
TGM 0.04% TGM 0.1%
100 90 80
% of Patients
70 60 50 40 30 20 10 0
Fair/Better
No Change/Worse
Figure 3. Investigator’s global evaluation of the treatment response (improvement in facial acne, rated on a 5-point scale) at week 12. No statistically significant difference was observed between the 2 tretinoin gel microsphere (TGM) formulations.
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Clinical Therapeutics
TGM 0.04% TGM 0.1%
100 90 80
% of Patients
70 60 50 40 30 20 10 0
Much/Somewhat Improved
Not Improved/Worse
Figure 4. Patients’ self-assessment of the treatment response (improvement in facial acne, rated on a 5-point scale) at week 12. No statistically significant difference was observed between the 2 tretinoin gel microsphere (TGM) formulations.
Table III. Most commonly reported (occurring in ≥2% of patients) adverse events in patients with facial acne vulgaris (no. [%]). Adverse Event Skin burning sensation Skin irritation Erythema Exfoliative dermatitis Sunburn Sinusitis Dermatitis Dry skin Nasopharyngitis
TGM 0.04% TGM 0.1% (n = 78) (n = 78) 2 (2.6) 5 (6.4) 1 (1.3) 1 (1.3) 3 (3.8) 1 (1.3) 2 (2.6) 2 (2.6) 2 (2.6)
6 (7.7) 3 (3.8) 4 (5.1) 3 (3.8) 1 (1.3) 3 (3.8) 2 (2.6) 2 (2.6) 2 (2.6)
TGM = tretinoin gel microspheres.
receiving TGM 0.1% compared with TGM 0.04%. The increase in dryness occurred most commonly at week 2, with worsening observed in 23.1% (n = 18) of patients in the TGM 0.04% group and 42.3% (n = 33) of patients in the TGM 0.1% group. 1094
Changes in peeling, burning/stinging, and itching did not differ significantly between groups at any study week.
DISCUSSION The purpose of this double-blind, randomized, multicenter study was to compare the tolerability and efficacy of TGM 0.04% and TGM 0.1% in the treatment of mild to moderate acne vulgaris. These 2 formulations, which have greater stability than other formulations of tretinoin,10,11 were developed to minimize cutaneous irritation while maintaining acceptable efficacy.17 TGM 0.1% was the first such product to receive approval for marketing in the United States. A lower-strength TGM formulation may further reduce exposure to tretinoin and offer another option for the effective treatment of acne with minimal cutaneous irritation. In this study, TGM 0.04% and TGM 0.1% were associated with reductions in numbers of total lesions, inflammatory lesions, and noninflammatory lesions. The differences between groups in the change in lesion counts from baseline to weeks 2, 4, 8, and 12 were not statistically significant, with the exception of the greater reduction in inflammatory lesions at week 2 with Volume 29 Number 6
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Table IV. Proportions of patients with changes from baseline in ratings of cutaneous irritation variables.* Erythema Change in Rating from Baseline
TGM 0.04%
TGM 0.1%
Peeling TGM 0.04%
TGM 0.1%
Dryness TGM 0.04%
TGM 0.1%
Burning/Stinging TGM 0.04%
TGM 0.1%
Itching TGM 0.04%
TGM 0.1%
Week 2 –2 –1 0 +1 +2 +3 P
0 0 3.8 1.3 61.5 61.5 25.6 26.9 6.4 5.1 2.6 5.1 0.407
0 1.3 65.4 30.8 2.6 0
0 0 57.7 34.6 6.4 1.3 0.167
0 1.3 5.1 5.1 71.8 51.3 17.9 30.8 5.1 9.0 0 2.6 0.027
0 0 0 1.3 79.5 73.1 15.4 17.9 5.1 5.1 0 2.6 0.515
0 0 87.2 11.5 1.3 0
0 3.8 79.5 12.8 3.8 0 0.960
Week 4 –2 –1 0 +1 +2 +3 P
0 0 10.3 10.3 66.7 65.4 19.2 12.8 3.8 7.7 0 3.8 0.399
0 0 2.6 0 76.9 70.5 16.7 23.1 3.8 3.8 0 2.6 0.095
0 0 10.3 6.4 71.8 60.3 15.4 26.9 2.6 5.1 0 1.3 0.029
0 0 1.3 1.3 88.5 80.8 7.7 15.4 2.6 2.6 0 0 0.195
1.3 2.6 92.3 3.8 0 0
0 3.8 89.7 3.8 2.6 0 0.445
Week 8 –2 –1 0 +1 +2 +3 P
0 0 9.0 5.1 62.8 73.1 24.4 16.7 3.8 3.8 0 1.3 0.932
0 0 2.6 0 76.9 80.8 19.2 17.9 1.3 0 0 1.3 0.924
0 1.3 7.7 10.3 76.9 66.7 15.4 17.9 0 2.6 0 1.3 0.633
0 0 1.3 1.3 88.5 87.2 9.0 10.3 1.3 1.3 0 0 0.844
1.3 1.3 93.6 3.8 0 0
0 3.8 88.5 6.4 1.3 0 0.586
Week 12 –2 –1 0 +1 +2 +3 P
0 0 6.4 7.7 67.9 79.5 19.2 10.3 6.4 1.3 0 1.3 0.035
0 0 2.6 2.6 88.5 91.0 6.4 3.8 2.6 1.3 0 1.3 0.651
0 3.8 11.5 9.0 74.4 70.5 11.5 15.4 2.6 0 0 1.3 0.932
0 0 1.3 1.3 94.9 92.3 3.8 5.1 0 1.3 0 0 0.480
1.3 1.3 94.9 2.6 0 0
0 2.6 89.7 6.4 1.3 0 0.219
TGM = tretinoin gel microspheres. *A change of –2 represents the greatest improvement from baseline; a change of +3 represents the greatest worsening from baseline. Statistical significance was set at P ≤ 0.05 (Cochran-Mantel-Haenszel row-mean score test statistic with modified ridit scores, stratified by center).
TGM 0.1% compared with TGM 0.04% (14.8% vs 6.0%, respectively; P < 0.048). Furthermore, the investigators’ global evaluations and patients’ selfassessments of the treatment response indicated similar levels of improvement in both treatment groups. The results of these assessments correlated well with June 2007
the extent of change in acne lesion counts. The reductions in numbers of both inflammatory and noninflammatory lesions may be the result of tretinoin’s effects on the microcomedone, which is the precursor to both lesions.6 The benefit of the higher-strength TGM formulation in terms of inflammatory lesions would 1095
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Clinical Therapeutics require a larger study to show significance. An onset of action early in treatment might also be discernible in a larger study. A limitation of this study is that the exclusion criteria limited the ability to extrapolate the results beyond the small, selected population studied. Both strengths of TGM (0.04% and 0.1%) were generally well tolerated. The type and frequency of adverse events were consistent with the established safety profile of TGM in the treatment of acne vulgaris.18 Although tretinoins are known to be irritating, a randomized, split-face study found that TGM 0.1% was associated with significantly less erythema than tretinoin 0.1% cream (P = 0.014).19 In the present study, TGM 0.04% was associated with significantly fewer patients experiencing dryness of the treatment area during the early stages of treatment (week 2, P < 0.027; week 4, P < 0.030). However, there were either no significant differences between treatment groups on other measures of cutaneous irritation (peeling, burning/stinging, and itching) or a significant increase in erythema with TGM 0.1%. These results are consistent with those of a study by Dosik et al20 that compared the irritancy potential of adapalene 0.1% cream and gel with TGM 0.1% and 0.04% in patients with normal skin. They found no significant difference in the mean cumulative irritation index (a measure of erythema plus local skin reactions) between TGM 0.1% and TGM 0.04%.
CONCLUSIONS In this study, TGM 0.04% and 0.1% were associated with reductions in acne lesion counts. Both concentrations were generally well tolerated. The results suggested an early (week 2) incremental benefit for TGM 0.1% in terms of inflammatory lesions.
ACKNOWLEDGMENTS This study was sponsored by Johnson & Johnson, Inc., Skillman, New Jersey, which was responsible for the study design, analysis and interpretation of the data, and the decision to submit the paper for publication. Data collection was the responsibility of independent investigators. The manuscript was prepared with the assistance of Thomson Pharmaceutical Services, Horsham, Pennsylvania.
REFERENCES 1. Pochi PE. The pathogenesis and treatment of acne. Annu Rev Med. 1990;41:187–198.
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2. Quan M, Strick RA. Management of acne vulgaris. Am Fam Physician. 1988;38:207–218. 3. Koo J. The psychosocial impact of acne: Patients’ perceptions. J Am Acad Dermatol. 1995;32:S26–S30. 4. Lasek RJ, Chren MM. Acne vulgaris and the quality of life of adult dermatology patients. Arch Dermatol. 1998;134: 454–458. 5. Leyden JJ. Retinoids and acne. J Am Acad Dermatol. 1988; 19:164–168. 6. Lavker RM, Leyden JJ, Thorne EG. An ultrastructural study of the effects of topical tretinoin on microcomedones. Clin Ther. 1992;14:773–780. 7. Liu PT, Krutzik SR, Kim J, Modlin RL. Cutting edge: Alltrans retinoic acid down-regulates TLR2 expression and function. J Immunol. 2005;174:2467–2470. 8. Guzzo CA, Lazarus GS, Werth VP. Dermatological pharmacology. In: Hardman JG, Limbird LE, Molinoff PB, et al, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996: 1593–1616. 9. Embil K, Nacht S. The Microsponge Delivery System (MDS): A topical delivery system with reduced irritancy incorporating multiple triggering mechanisms for the release of actives. J Microencapsul. 1996;13:575–588. 10. Nyirady J, Lucas C, Yusuf M, et al. The stability of tretinoin in tretinoin gel microsphere 0.1%. Cutis. 2002;70:295–298. 11. Nighland M, Yusuf M, Wisniewski S, et al. The effect of simulated solar UV irradiation on tretinoin in tretinoin gel microsphere 0.1% and tretinoin gel 0.025%. Cutis. 2006; 77:313–316. 12. Webster GF. Topical tretinoin in acne therapy. J Am Acad Dermatol. 1998;39(Suppl):S38–S44. 13. Nyirady J, Nighland M, Payonk G, et al. A comparative evaluation of tretinoin gel microsphere, 0.1%, versus tretinoin cream, 0.025% in reducing facial shine. Cutis. 2000;66:153–156. 14. Grove GL, Zerweck CR, Nacht S, Leyden JJ. The effects of vehicle composition on the subjective and objective irritancy potential of retinoic acid formulations. Poster presented at: 55th Annual Meeting of the American Academy of Dermatology; March 21–26, 1997; San Francisco, Calif. 15. Nyirady J, Nighland M. Comparative studies to evaluate the phototoxic and photoallergic potential of two antiacne products. Cosmet Dermatol. 2001;14:27–30. 16. Dixon WJ, Massey FJ Jr. Introduction to Statistical Analysis. 2nd ed. New York, NY: McGraw-Hill; 1957. 17. Nyirady J, Bennett ML. Advancement of tretinoin through the microsphere technology. Cosmet Dermatol. 2001;14:22– 24. 18. Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04% [package insert]. Skillman, NJ: Ortho Dermatological; 2002.
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R. Berger et al. 19. Leyden J, Grove G, Zerweck C. Facial tolerability of topical retinoid therapy. J Drugs Dermatol. 2004;3:641–651. 20. Dosik JS, Homer K, Arsonnaud S. Cumulative irritation potential of adapalene 0.1% cream and gel compared with tretinoin microsphere 0.04% and 0.1%. Cutis. 2005;75:238– 243.
Address correspondence to: Jonathan Weiss, MD, Gwinnett Clinical Research Center, Inc., 2383 Pate Street, Snellville, GA 30078. E-mail: [email protected] June 2007
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