Cumulative Irritation Comparison of Adapalene Gel and Solution with 2 Tazarotene Gels and 3 Tretinoin Formulations

THERAPEUTICS FOR THE CLINICIAN

Cumulative Irritation Comparison of Adapalene Gel and Solution With 2 Tazarotene Gels and 3 Tretinoin Formulations

Alan Greenspan, MD; Christian Loesche, MD; Nancy Vendetti; Kathleen Georgeian; Richard Gilbert, PhD; Michel Poncet, PhD; Michael D. Baker, BS; Pascale Soto, RPh

Forty-two subjects with normal skin were enrolled gel 0.025%, and 1 discontinued adapalene in a single-center study to assess the cumula- gel 0.1%. None of the subjects discontinued use tive irritancy potential of adapalene (Differin® of the white petrolatum or the adapalene solu- gel 0.1% and Differin solution 0.1%) compared tion 0.1%. Adapalene gel and solution 0.1% with tazarotene (Tazorac® gels 0.05% and 0.1%), were statistically (P.01) less irritating than tretinoin (Retin-A Micro® gel 0.1%, Avita® cream both tazarotene gels 0.1% and 0.05%, tretinoin 0.025%, and Avita gel 0.025%), and white petro- microsphere gel 0.1%, and tretinoin gel 0.025%, latum (negative control). All test materials were and they were not statistically different from applied randomly, under occlusion, to sites tretinoin gel 0.025%. located on either side of the midline— the mid Cutis. 2003;72:76-81. thoracic area of the subjects’ backs. All patches were applied daily, Monday through Friday, to dapalene (Differin®) is a naphthoic-acid the same sites, unless the degree of reaction to derivative with retinoid activity that is a test product or adhesive necessitated removal A effective in the treatment of mild to moder- (grade 3). ate acne vulgaris.1-4 Adapalene, in both gel and Thirty-eight of the 42 subjects (90.5%) com- cream formulations, at the marketed and approved pleted the study. Thirty-four of those 38 subjects concentration of 0.1%, is better tolerated than (89.5%) had to discontinue using both tazar- most tretinoin formulations, including tretinoin otene concentrations due to intolerance. Patch microsphere gel 0.1% (Retin-A Micro®) and discontinuations for the remaining test materials tretinoin cream 0.025% (Avita®).5-10 The cumula- were as follows: 7 subjects discontinued use of tive irritancy assay (patch test) is designed to assess tretinoin microsphere gel 0.1%, 3 discontinued the irritation potential of topically applied materi- tretinoin cream 0.025%, 1 discontinued tretinoin als. Irritation results obtained from this type of assay are due to direct damage to the epidermal cells, and no immunologic (allergic) mechanism is Accepted for publication March 19, 2003. involved. Results of this standard assay are widely Drs. Greenspan and Gilbert and Mss. Vendetti and Georgeian accepted to be indicators of irritation. This study are with TKL Research, Inc, Paramus, New Jersey. Drs. Loesche and Poncet and Mr. Soto are with Galderma Research & compared the irritation potential of adapalene gel Development, Sophia Antipolis, France. Mr. Baker is with and solution with several retinoid and retinoidlike Galderma Research & Development, Princeton, New Jersey. products containing either tazarotene or tretinoin. Dr. Greenspan is on the speakers bureau and is a paid consultant for Galderma Laboratories, LP. Mss. Vendetti and Georgeian and Methods Dr. Gilbert report no conflict of interest. This study was supported by Galderma Laboratories, LP. This cumulative irritancy study was conducted as a Reprints: Stephanie Arsonnaud, Galderma Research & single-center, randomized, controlled, investigator/ Development, 5 Cedar Brook Dr, Suite 1, Cranbury, NJ 08512. evaluator, double-blind, intraindividual compari-

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Table 1. Table 2. Erythema Grading Scale Irritation Classification*

Abnormal Redness Product Grade of the Skin (Erythema) MCII Classification 0 No reaction 0.25 Nonirritating

0.5 Barely visible 0.25–1 (noninclusive) Slightly irritating

1 Mild 1–2 (noninclusive) Moderately irritating

2 Moderate 2–3 (noninclusive) Very irritating

3 Severe *MCII indicates mean cumulative irritancy index.

son involving healthy subjects meeting specific at each study visit, week 1 (days 2 through 5, inclu- inclusion-exclusion criteria. The cumulative irri- sively), week 2 (days 8 through 12, inclusively), tancy assay, a 21-day patch test, was designed to week 3 (days 15 through 19, inclusively), and assess the irritation potential of topically applied week 4 (day 22). dermatologic materials under stressful conditions The backs of the subjects were photographed (ie, occlusion).11 before each reading. When an irritation reaction A total of 42 subjects (6 males and 36 females) related to the product was graded 3 for any site, ranging in age from 22.9 to 74.8 years were enrolled product application was discontinued for the and evaluated. All subjects received adapalene gel incriminated sites. When an irritation reaction 0.1%, adapalene solution 0.1%, tazarotene gel 0.1%, related to the adhesive prohibited the wearing of a tazarotene gel 0.05%, tretinoin microsphere gel 0.1%, patch at a particular site, all patch applications tretinoin cream 0.025%, tretinoin gel 0.025%, and were discontinued for the subject. However, the white petrolatum (negative control). subject was not discontinued from treatment unless, Approximately 0.2 g of each of the 7 test prod- in the investigator’s/evaluator’s opinion, there was ucts and negative control was applied to 8 sites on a safety concern. At that time, an adverse event the upper area of the back according to a prede- form would have been completed. fined randomization list. Application was made All subjects were informed in accordance with under occlusive conditions for 24 hours (4 times the International Conference on Harmonization per week) and 72 hours (once weekly) for 3 weeks. guidelines and Good Clinical Practices. A written At each study visit, skin reactions (erythema consent form, approved by the Institutional scoresother local reactions) were assessed by the Review Board, was supplied by the investigator and same trained board-certified physician evaluator was understood and signed by each subject before during the study, 15 to 30 minutes after removal of inclusion in the study. the product, using the grading scale for erythema (Table 1). Statistical Methodology In addition, other concomitant cutaneous reac- Sample Size, Design, and Randomization—A stan- tions (eg, dryness, cracking, peeling) on test sites dard sample size for this type of cumulative irri- were noted, including adhesive reactions. The tancy clinical study is 25 subjects. To account for principal safety criterion was the mean cumulative the multiplicity of comparisons, planned enroll- irritancy index (MCII) assessed by clinical evalua- ment was estimated at 48 subjects. Enrollment was tion of the erythema at each test site. Evaluation of completed at 42 subjects, with the consent of the the test product application sites was conducted by sponsor. On initiation, each of the 8 products was the same investigator/evaluator throughout the applied to one of the zones (Z1–Z8) according to study. The sites were scored at baseline (day 1) and the predefined randomization schedule. This ran-

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domization schedule was generated by the RANUNI routine of SAS using 88 Latin squares. Table 3. Statistically Analyzed Variables—For evaluating the cutaneous tolerance, a cumulative irritancy Demographic Data index (CII) was calculated for each treatment and for each subject, as follows: CIIsum of irritation All Products score/number of readings. The following conven- N42 tions were applied for the CII calculation: baseline (day 1) score was excluded from the calculation. Age, y When the irritation reaction was rated 3 for any site, Mean (range) 47.3 (22.9–74.8) the product application was discontinued for the incriminated sites, and a score of 3 was assigned to Gender, n (%) the remaining readings (last observation carried for- Male 6 (14.3) ward). When a subject missed a scheduled visit, the scores of the sites from the next visit were assigned Female 36 (85.7) to the previously missed visit. Individual CII scores were averaged across sub- Race, n (%) jects to obtain an MCII score for each treatment. White 39 (92.9) MCII scores were submitted to an analysis of vari- ance with effects for subject, zone, and formula- Black 1 (2.4) tion. To adjust for multiple comparisons, MCII Asian 1 (2.4) score was compared, and formulations were classified using the Tukey multiple comparisons test per- Hispanic 1 (2.4) formed at the 1% and 5% significance levels. According to MCII values, each test product could be classified into the irritation classes (Table 2).

Table 4. Summary of Mean Cumulative Irritancy Index (MCII) Statistical Comparisons

Product MCII (meanSD) Statistical Grouping* Adapalene gel 0.1% 0.060.18 A Adapalene solution 0.1% 0.050.16 A Tazarotene gel 0.05% 1.690.53 D Tazarotene gel 0.1% 1.810.52 E Tretinoin microsphere gel 0.1% 0.630.56 C Tretinoin cream 0.025% 0.480.38 B Tretinoin gel 0.025% 0.180.32 A

White petrolatum 0.020.04 A

*MCIIs with the same letter are not statistically significantly different (P.05) from each other but are different from MCIIs of other letters.

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2 MCII Score 1

0 123456789101112 13 14 15 16 17 18 19 20 21 Day Adapalene Gel 0.1% Tazarotene Gel 0.05% Adapalene Solution 0.1% Tazarotene Gel 0.1% Tretinoin Cream 0.025% Tretinoin Microsphere Gel 0.1% Tretinoin Gel 0.025% White Petrolatum

Figure 1. Mean cumulative irritancy index (MCII) scoring over a 21-day patch test.

Adapalene Solution 0.1% Tretinoin Cream 0.025%

Tazarotene Tretinoin Gel 0.1% Microsphere Gel 0.1%

Tretinoin White Gel 0.025% Petrolatum

Tazarotene Adapalene Gel 0.05% Gel 0.1%

Figure 2. Example of reactions observed during the study.

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35 35 34

No. of Subjects 15

10 7

5 3 11 0 00 Adalapene White Adalapene Tretinoin Tretinoin Tretinoin Tazarotene Tazarotene Solution 0.1% Petrolatum Gel 0.1% Gel 0.025% Cream Microsphere Gel 0.05% Gel 0.1% 0.025% Gel 0.1%

Figure 3. Patches prematurely discontinued.

Results Although tretinoin gel 0.1% MCII was numerically Of the 42 subjects enrolled, 38 subjects (90.5%) superior to both adapalene gel and solution MCIIs, completed the study. Demographic data are pre- no statistically significant difference could be sented in Table 3. Results are summarized in Table 4 depicted between the 3 products. Repeated appli- and Figure 1. Figure 2 shows a clinical photograph cations of adapalene gel or solution resulted in lev- of typical irritation observed during the study. els of irritation that were not significantly different In the study, the reasons for treatment discontin- from the white petrolatum control. uation were not always due to an erythema score of 3 but also because of other clinical aspects of severe intolerance, such as epidermal peeling with subse- REFERENCES quent superficial erosion (without severe erythema). 1. Verschoore M, Langner A, Wolska H, et al. Vehicle con- Figure 3 shows the number of subjects who discon- trolled study of CD 271 lotion in the topical treatment tinued wearing the patches due to an irritation of acne vulgaris. J Invest Dermatol. 1993;100:221A. score of 3. 2. Verschoore M, Langner A, Wolska H, et al. Efficacy and Adapalene gel and solution 0.1% were each sig- safety of CD 271 alcoholic gels in the topical treatment nificantly less irritating during sustained use than of acne vulgaris. Br J Dermatol. 1991;124:368-371. tazarotene gels 0.05% and 0.1%, tretinoin micro- 3. Bernard BA. Adapalene, a new chemical entity with sphere gel 0.1%, and tretinoin cream 0.025%. retinoid activity. Skin Pharmacol. 1993;6(suppl 1):61-69.

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