Clobetasol

Abstract

Atopic dermatitis (AD) is a chronic inflammatory and pruritic skin disorder marked by alternating periods of relapse and remission. This multicenter, randomized, active- and vehicle-controlled, investigator-blinded study compared the efficacy and safety of clobetasol propionate lotion to clobetasol propionate cream formulation and lotion vehicle in the treatment of moderate to severe AD. A total of 229 subjects applied treatment twice-daily for 2 weeks. Clobetasol propionate lotion was significantly more effective than its lotion vehicle at 2 weeks and comparable to the cream formulation. Clinical success after a 2-week, treatment-free follow-up period was greater in the clobetasol propionate lotion group than in the cream group. Clobetasol propionate lotion is effective, safe, well tolerated and offers a better remission profile in the treatment of moderate to severe AD as compared to clobetasol propionate emollient cream.

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Introduction

Atopic dermatitis (AD) is a common inflammatory and pruritic skin disorder that often presents in early childhood, may continue into later life, and usually appears in a personal or family history of atopy. (1-4) AD is a chronic disease marked by alternating periods of exacerbations and remissions with up to 20% of school-aged children being affected by AD, potentially profoundly influencing their quality of life. (5,6)

Due to their potency in inflammatory skin disease, topical corticosteroids are the mainstay of treatment for various dermatoses, and are among the most frequently used dermatologicals. (7,8) An increasing number of preparations of topical corticosteroids have been developed in the past few years focusing on the development of more powerful compounds with improved bioavailability and reduced risk of side effects. (8)

Clobetasol propionate, one of these high-potency topical corticosteroid compounds, has anti-inflammatory, antipruritic, vasoconstrictive, and immune-modulating properties. It is currently used in the treatment of a variety of hyperproliferative and/or inflammatory dermatoses, including psoriasis and AD. (10-12)

Recently, a new lotion formulation of clobetasol propionate 0.05% (Clobex[TM] lotion, Galderma Laoratories L.P. Fort Worth, TX) has been launched to provide a greater breadth of treatment options. The objective of this multicenter, randomized, investigator-blinded, active- and vehicle-controlled, parallel comparison was to demonstrate the efficacy and safety profile of the clobetasol propionate lotion formulation relative to the clobetasol propionate emollient cream formulation and the lotion vehicle in the treatment of moderate to severe AD.

Methods

The study was conducted in accordance with the Declaration of Helsinki and its amendments and with the Guidelines for Good Clinical Practices. IRB approvals for all study sites were obtained before the start of the study and subjects provided written informed consent prior to any study related procedures.

Subjects

A total of 224 male and female subjects with stable moderate to severe AD were enrolled in the study. Individuals had to have a total baseline Dermatological Sum Score (DSS, sum of erythema, excoriation, and induration/papulation) of at least 6 in the target area and at least 3 of the following signs and symptoms: pruritus, flexural lichenification, linearity in adults with a variety of skin lesions, chronic or chronically-relapsing dermatitis, or personal or family history of atopy (asthma, allergic rhinitis, AD). Subjects with concomitant medical or dermatologic disorders precluding accurate evaluation of the AD, or using interfering concomitant therapies or with known sensitivities to any ingredients of the study treatments were not allowed to participate. Specific wash-out periods were to be respected for topical and systemic AD treatments. Topical treatments (excluding sunscreen on the face) other than the test material were not permitted.

Test Material

Each investigator enrolled approximately 10 to 20 subjects. Qualified subjects were randomized into consecutive balanced blocks of 7 to receive clobetasol propionate 0.05% lotion (hereafter named lotion), clobetasol propionate emollient 0.05% cream (hereafter named emollient cream or cream), or the lotion vehicle in a ratio of 3:3:1. Subjects received both verbal and written instructions as to the proper dosing and study medication application techniques.

Since the active products were 2 different formulations, the comparison versus emollient cream was investigator-blinded only. Drugs were dispensed by a third person, independent from the investigator, and subjects were asked not to discuss the external aspects of the study medication with the investigator. Application of test material was made as a thin coating twice-daily for 2 weeks to the designated target lesion, as well as to other affected areas.

Clinical Assessments

Efficacy and safety were assessed at baseline, weeks 1, 2, and 4. The primary efficacy variable was the success rate, which was derived from Global Severity scale dichotomized as "success" or "failure," where success was defined as a Global Severity score of 0, 0.5, or 1 (none to mild) and failure was defined as Global Severity scores of 2, 3, or 4 (moderate to very severe). Secondary efficacy variables for this study were Global Severity (full-scale); DSS, individual disease scores (scale 0 [none] to 4 [severe]) of erythema, excoriation, induration/papulation, lichenification, oozing/crusting, and dryness/scaling; pruritus, global improvement. For variables describing 2 signs or symptoms (ie, induration/papulation), the score that best described the most severe sign or symptom was chosen when the scored signs or symptoms differed. For example, a subject who presented with "mild" induration and "moderate" papulation was scored as moderate induration/papulation. A 2-week follow-up period served to assess the durability of response following treatment discontinuation.

Safety was monitored by assessing telangiectasia and skin atrophy, concomitant therapies and adverse events (AEs). Skin atrophy and telangiectasia were scored on a 0 (none) to 3 (severe) scale at all application sites.

Statistics

To detect with a 90% power a difference of 1 point in mean DSS score, the primary efficacy variable between the 2 active treatments by a 2-sided t-test with [alpha] = 0.05, a sample of 168 evaluable subjects at least (84 per group) was needed.

To compare the lotion with its vehicle, a significant difference was needed for both primary efficacy variables; therefore, a power of 95% was needed for each variable separately to provide a 90% power of finding a significant difference on both. A total enrollment of 224 subjects (approximately 96 per active treatment, 32 for the vehicle) was planned, accounting for the anticipated subject ineligibility (10% to 15%) for efficacy at week 2 and the designed randomization ratio of 3:3:1 for the 2 active treatment groups and the vehicle group, respectively.

Clobetasol propionate lotion was compared to its vehicle to demonstrate superior efficacy. Comparisons between clobetasol propionate lotion and clobetasol propionate emollient cream were conducted to demonstrate non-inferiority.

Results

Subjects

A total of 229 subjects were randomized and treated: 96 received clobetasol propionate lotion, 100 received clobetasol propionate emollient cream and 33 received lotion vehicle. A total of 205 subjects in the ITT population completed 2 weeks of treatment with study medication. One subject treated with clobetasol propionate lotion had the disease condition cleared after 1 week of treatment and, therefore, entered the treatment-free period early.

Twenty-three subjects discontinued from the study: nine (9.4%) subjects receiving clobetasol propionate lotion, 7 (7.0%) subjects receiving clobetasol propionate emollient cream, and 7 (21.2%) subjects receiving lotion vehicle. Subject request and loss to follow-up were the major reasons for discontinuation in each treatment group. In the lotion vehicle group, one subject discontinued due to an adverse event (worsening of AD), and one was discontinued due to protocol deviation for over use of study medication.

Baseline demographics are shown in Table 1. There were no significant differences reported in disease characteristics among the treatment groups (p > .05).

Efficacy

At week 2 end point (LOCF) the proportion of subjects who achieved "success" was significantly higher in the lotion group compared to the vehicle group (72.9% vs. 36.4%; p = .001) there was no difference between the active treatments (72.9% vs. 74.0%) (Figure 1). At all other time points, success rates for the lotion group were statistically significantly higher than for the vehicle group (p < .05), and were non-inferior to the emollient cream group (p > .05). After the 2-week treatment-free period, success rates for both the lotion and cream groups remained significantly higher relative to those observed in the lotion vehicle group, with a success rate decreasing by 14.5% in the clobetasol propionate lotion group as compared to an 18.0% decrease in the cream group.

At week 2 the full-scale GSS for the lotion group was significantly lower than that for the vehicle group (p = .001); there was no difference between the 2 clobetasol propionate formulations. Statistically significant differences at week 1 and week 4/follow-up were observed between the lotion group and its vehicle group (p < .05) for the GSS, whereas it was comparable in both active treatment groups.

[FIGURE 1 OMITTED]

The difference between the lotion group and the vehicle group for the changes from baseline in DSS was statistically significant (LS means = -2.38; 95%); there was no significant difference between the lotion group and the emollient cream group (Figure 2). Similar results were observed in the statistical analyses of the DSS at all other post-baseline time points.

The number of subjects with reduced severity in individual disease scores was significantly higher (p < .05) in the lotion group as compared to the vehicle group; no significant differences were observed between the lotion group and the emollient cream group. Results of the ITT analyses at week 1 and week 4/follow-up were similar to those at week 2 end point. Significantly larger differences were observed for erythema (p = .044) and induration/papulation (p = .038) for the lotion group relative to the emollient cream group at week 1; no significant difference was detected between the lotion group and the vehicle group for oozing/crusting at week 1 and dryness/scaling at week 1 and week 4. A remarkably higher percentage of subjects reported no pruritus at week 2 endpoint in the lotion group as compared to the vehicle group (58.3% vs. 15.2%, P = .001). Pruritus scores in both active groups were comparable. However, after 2 weeks of a treatment-free follow-up period, pruritus scores in the lotion group were significantly lower compared to that in the emollient cream group (p = .014) and vehicle group (p = .002). A greater percentage of subjects remained without pruritus at week 4 in the lotion group as compared to the emollient cream group and the vehicle group (51.1% vs. 35.5% vs. 18.5%, respectively).

[FIGURE 2 OMITTED]

Regarding global improvement at week 2 end point, the lotion group was significantly superior to the vehicle group (p = .001) and was not significantly different from the emollient cream group, (Figure 3). The majority of subjects in both active treatment showed improvement, whereas the majority of subjects in the vehicle group showed no changes. There were 20 (21.5%) subjects in the lotion group and 18 (18.6%) subjects in the emollient cream group who were cleared at week 2 endpoint compared to none in the lotion vehicle group. Clearance continued after 2 weeks of follow-up with the lotion: 23 (26.1%) subjects were still cleared compared to 14 subjects (15.1%) in emollient cream group, suggesting that the lotion had greater durability of response than the emollient cream, although this difference did not reach significance.

Safety

Clobetasol propionate lotion was generally as well tolerated as clobetasol propionate emollient cream. The incidence of adverse events was comparable among the 3 treatment groups. Forty adverse events were reported during the study, 7 of which were considered possibly or probably related to study medication (4 in the lotion group, one in the emollient cream group and 2 in the lotion vehicle group). Most of the adverse events were mild or moderate in severity and resolved with or without concomitant treatment by the end of the study. No case of clinically significant cases of skin atrophy or telangiectasia was observed. The percent severity of telangiectasia and skin atrophy in each treatment group at week 2 and week 4 was not statistically significant between treatment groups.

[FIGURE 3 OMITTED]

Discussion

AD profoundly influences the quality of life of subjects and a rapid onset of activity and an increased durability of response may help to improve this aspect of daily life. (5,6) Clobetasol propionate is the most potent topical corticosteroid currently available and its clinical efficacy has been well established by over 25 years of clinical use in various formulations including creams, ointments, foams and solutions. (10) A new clobetasol propionate lotion was recently launched to provide an alternative formulation for the treatment of corticosteroid-responsive dermatoses, including AD.

This study was designed to evaluate the safety and efficacy of clobetasol propionate lotion compared to that of clobetasol propionate emollient cream in the treatment of moderate to severe AD.

After 2 weeks of treatment, a significantly higher success rate was achieved with clobetasol propionate lotion compared to its vehicle; success rates between both active formulations were comparable. Furthermore, clobetasol propionate lotion demonstrated a longer post-treatment response duration relative to clobetasol propionate cream. In light of the well known side effect profile of this corticosteroid, greater duration of response may be considered a beneficial characteristic allowing for increased control of the disease. (12)

Another key observation from the study was that pruritus was significantly less severe after 2 weeks of treatment and 2 weeks of treatment-free follow-up in the clobetasol propionate lotion group than in the clobetasol emollient cream group and the lotion vehicle group. This observation is important since pruritus is a universal finding in AD, often leading to scratching, lichenification, excoriation, and breakdown of the skin barrier, and therefore, has a major impact on the subject's quality of life. (13) The reason for the observed decreases in pruritus severity in the lotion formulation group remains unexplained. Differences may be due either to the greater penetration capacity of clobetasol propionate into the skin layers with the lotion compared to the emollient cream formulation. They may also be attributed to the greater persistence of the clobetasol propionate in the stratum corneum.

Incidence of adverse events was comparable between treatment groups. No active treatment related adverse event led to the withdrawal of a subject and none of the adolescents reported adverse events related to 1 of the study drugs. The severity profile for telangiectasia and skin atrophy in each treatment group at week 2 and week 4 was similar to baseline and only 1 adolescent in the clobetasol propionate emollient cream group reported mild skin atrophy after 2 weeks of treatment. The results indicate that a short-term treatment with clobetasol propionate lotion is unlikely to cause corticosteroid-related side effects such as skin atrophy and telangiectasia as reported by Charman et al. (14)

Conclusion

The present multicenter study clearly demonstrated that in the treatment of moderate to severe atopic dermatitis clobetasol propionate 0.05% lotion showed comparable efficacy results for success rate, global improvement, global severity and individual signs to clobetasol propionate 0.05% emollient cream and that the new lotion formulation demonstrated an enhanced anti-pruritic potential.

Acknowledgements: The authors would like to thank Toni Funicella, MD, Stephen Kraus, MD, Robert Loss, MD, Kenneth B. Gordon, MD, Eduardo Tschen, MD, and Marty E. Sawaya for their participation in this clinical trial and Patrick Goritz, Galderma R & D for his assistance in writing this publication.

Funding Research: This research was conducted for Galderma Medical Affairs, Inc as a part of the development program of clobetasol propionate 0.05% lotion.

Disclosures: The investigating authors received honoraries for participating in this clinical research project. In addition Dr. Fleischer has project funding from Galderma. Two of the authors are employees of Galderma R & D, Inc. The authors have no other conflict of interest to disclose.

References

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11. Coulson I. Topical steroids for skin disease. Dermatol Pract. 1996; March/April:5-9.

12. Leung DYM, Bieber T. Atopic Dermatitis. Lancet. 2003; Jan;361:150-160.

13. Correale C, Walker C, Murphy L, Craig TJ. Atopic dermatitis: a review of diagnosis and treatment. Am Fam Physician. 1999; Sep 15;60(4):1191-1198.

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Debra Breneman MD, (a) Alan B. Fleischer Jr. MD, (b) David Kaplan MD, (c) Mark Lebwohl MD, (d) Bruce Miller MD, (e) David Pariser MD, (f) Toivo Rist MD, (g) L. Swinyer MD, (h) Yin Liu PhD, (i) Valerie Foley PharmDi

a. Dermatology Clinical Research Institute in Cincinnati, OH

b. Department of Dermatology of the Wake Forest University School of Medicine in Winston-Salem, NC

c. Overland Park, KS

d. Mount Sinai Medical Center in New York, NY

e. Oregon Medical Research Center in Portland, OR

f. Eastern Virginia Medical School and Virginia Clinical Research in Norfolk, VA

g. Knoxville, TN h. Salt Lake City, UT i. Galderma R & D, Princeton, NJ

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