Adapalene (Differin®) is a naphthoic-acid derivative with retinoid activity that is effective in the treatment of mild to moderate acne vulgaris.1-4 Adapalene, in both gel and cream formulations, at the marketed and approved concentration of 0.1%, is better tolerated than most tretinoin formulations, including tretinoin microsphere gel 0.1% (Retin-A Micro®) and tretinoin cream 0.025% (Avita®).5-10 The cumulative irritancy assay (patch test) is designed to assess the irritation potential of topically applied materials. Irritation results obtained from this type of assay are due to direct damage to the epidermal cells, and no immunologic (allergic) mechanism is involved. Results of this standard assay are widely accepted to be indicators of irritation. This study compared the irritation potential of adapalene gel and solution with several retinoid and retinoidlike products containing either tazarotene or tretinoin.back to top
METHODS This cumulative irritancy study was conducted as a single-center, randomized, controlled, investigator/evaluator, double-blind, intraindividual comparison involving healthy subjects meeting specific inclusion-exclusion criteria. The cumulative irritancy assay, a 21-day patch test, was designed to assess the irritation potential of topically applied dermatologic materials under stressful conditions (ie, occlusion).11 A total of 42 subjects (6 males and 36 females) ranging in age from 22.9 to 74.8 years were enrolled and evaluated. All subjects received adapalene gel 0.1%, adapalene solution 0.1%, tazarotene gel 0.1%, tazarotene gel 0.05%, tretinoin microsphere gel 0.1%, tretinoin cream 0.025%, tretinoin gel 0.025%, and white petrolatum (negative control). Approximately 0.2 g of each of the 7 test products and negative control was applied to 8 sites on the upper area of the back according to a predefined randomization list. Application was made under occlusive conditions for 24 hours (4 times per week) and 72 hours (once weekly) for 3 weeks. At each study visit, skin reactions (erythema scores±other local reactions) were assessed by the same trained board-certified physician evaluator during the study, 15 to 30 minutes after removal of the product, using the grading scale for erythema (Table 1).
| View this table | Table 1. Erythema Grading Scale |
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In addition, other concomitant cutaneous reactions (eg, dryness, cracking, peeling) on test sites were noted, including adhesive reactions. The principal safety criterion was the mean cumulative irritancy index (MCII) assessed by clinical evaluation of the erythema at each test site. Evaluation of the test product application sites was conducted by the same investigator/evaluator throughout the study. The sites were scored at baseline (day 1) and at each study visit, week 1 (days 2 through 5, inclusively), week 2 (days 8 through 12, inclusively), week 3 (days 15 through 19, inclusively), and week 4 (day 22). The backs of the subjects were photographed before each reading. When an irritation reaction related to the product was graded 3 for any site, product application was discontinued for the incriminated sites. When an irritation reaction related to the adhesive prohibited the wearing of a patch at a particular site, all patch applications were discontinued for the subject. However, the subject was not discontinued from treatment unless, in the investigator’s/evaluator’s opinion, there was a safety concern. At that time, an adverse event form would have been completed. All subjects were informed in accordance with the International Conference on Harmonization guidelines and Good Clinical Practices. A written consent form, approved by the Institutional Review Board, was supplied by the investigator and was understood and signed by each subject before inclusion in the study. back to top
Statistical Methodology Sample Size, Design, and Randomization—A standard sample size for this type of cumulative irritancy clinical study is 25 subjects. To account for the multiplicity of comparisons, planned enrollment was estimated at 48 subjects. Enrollment was completed at 42 subjects, with the consent of the sponsor. On initiation, each of the 8 products was applied to one of the zones (Z1–Z8) according to the predefined randomization schedule. This randomization schedule was generated by the RANUNI routine of SAS using 8x8 Latin squares. Statistically Analyzed Variables—For evaluating the cutaneous tolerance, a cumulative irritancy index (CII) was calculated for each treatment and for each subject, as follows: CII=sum of irritation score/number of readings. The following conventions were applied for the CII calculation: baseline (day 1) score was excluded from the calculation. When the irritation reaction was rated 3 for any site, the product application was discontinued for the incriminated sites, and a score of 3 was assigned to the remaining readings (last observation carried forward). When a subject missed a scheduled visit, the scores of the sites from the next visit were assigned to the previously missed visit. Individual CII scores were averaged across subjects to obtain an MCII score for each treatment. MCII scores were submitted to an analysis of variance with effects for subject, zone, and formulation. To adjust for multiple comparisons, MCII score was compared, and formulations were classified using the Tukey multiple comparisons test performed at the 1% and 5% significance levels. According to MCII values, each test product could be classified into the irritation classes (Table 2).