Clobetasol

Abstract

Psoriasis is a chronic, papulosquamous condition that affects up to 2% of the U.S. population. Approximately 50% of patients with psoriasis have involvement of the scalp.

This was a multicentre, randomized, vehicle-controlled, double-masked and parallel-group study. The aim was to evaluate the efficacy and safety of clobetasol propionate shampoo, 0.05% versus its corresponding vehicle in subjects aged 12 years and older with moderate to severe scalp psoriasis over a treatment period of 4 weeks. Recurrence of scalp psoriasis was assessed during a two week follow-up period.

A total of 142 subjects were treated. Results after 4 weeks demonstrated that clobetasol propionate shampoo, 0.05% was with a similar safety profile significantly more effective than its vehicle. The novel short contact shampoo formulation of clobetasol propionate is convenient and efficacious and minimizes systemic exposure while being efficient, safe and well-tolerated in the treatment of moderate to severe scalp psoriasis.

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Introduction

Psoriasis is a chronic, papulosquamous condition that affects up to 2% of the U.S. population. Elbows, knees, umbilicus, and gluteal cleft are commonly affected and approximately 50% of patients with psoriasis have involvement of the scalp (1-4). Scalp lesions frequently extend a few centimeters beyond the hairline, but usually do not occur on balding patch with lesions often being erythematous and exhibiting tiny punctuate bleeding spots when overlying scale is removed. Initially they may be more erythematous than scaly and are frequently easier to identify by palpation than by visual inspection (5). Another frequently reported symptom is pruritus, which may be very severe. Alopecia considered by the authors as the most distressing aspects of scalp psoriasis was also described as a potential symptom by Osment et al. and Matsunaga et al (6,7).

Although treatment of scalp psoriasis is similar to that of other areas of the body with and coal tar or topical corticosteroid preparations and other agents such as anthralin or calcipotriol scalp solution, shampoos seem from the most recent point of view to be the most convenient way to treat scalp psoriasis (8). However, currently available shampoos, such as coal tar or anthralin shampoos, do not meet patient quality of life ectations, partially due to their unpleasant smell but also to their capacity to stain light-colored hair (7-9). Other shampoos, containing salicylic acid, sulfur or selenium fail to prove their effectiveness when incorporated in a shampoo (10).

Topical corticosteroids, such as clobetasol propionate, are currently used for the treatment of certain hyperproliferative and/or inflammatory dermatoses, including psoriasis and atopic dermatitis. Their safety and efficacy are well defined in the medical literature. Existing in different strengths, corticosteroids are the preferred treatment for psoriasis in the US and Europe with clobetasol propionate being the most commonly used to treat this disorder (11-16). Several formulations such as alcoholic solutions and lotions, creams and ointments of clobetasol propionate have been available for a certain time now; however their formulation is not optimal for the treatment of scalp psoriasis.

Recently a new foam formulation of clobetasol propionate (Olux[R], Connetics Corporation) for the treatment of scalp psoriasis has been made available. However, even if this new formulation bears several advantages compared to treatments used until its marketing this new formulation still has to be applied twice a day, which may affect treatment compliance, contains 60% alcohol which may dry the hair and may lead to stinging of the scalp, and is indicated only for use not longer than 2 weeks (17).

To provide patients suffering from scalp psoriasis with an efficient, well-tolerated and convenient treatment alternative to currently available treatment, clobetasol propionate shampoo, 0.05% was developed by Galderma R & D, Inc. This short contact formulation contains only 10% alcohol, is to be applied once a day and can be used for a period of four weeks. The aim of the present multi-center, randomized, vehicle-controlled, double-blinded, parallel-group comparison was to assess the efficacy and safety of clobetasol propionate shampoo, 0.05% compared to its vehicle over a treatment period of 4 weeks in patients with moderate to severe scalp psoriasis.

Methods

The study was conducted according to the Declaration of Helsinki and to Good Clinical Practice. Independent Review Board approvals for all study sites were obtained and subjects provided, prior to any procedures, written informed consent.

Study design and population

For this multi-center, randomized, vehicle-controlled, double-masked, parallel-group comparison between clobetasol propionate shampoo, 0.05% and its vehicle suitable subjects were required to be at least of 12 years of age and to have moderate to severe scalp psoriasis, defined as a global severity score of at least 3 on a scale from 0 (clear) to 5 points (very severe). Recurrence of scalp psoriasis was assessed during a 2 week follow up period.

Excluded from the study were women who were pregnant, nursing or planning a pregnancy, or subjects with a known allergy to one of the components of the test products. Further exclusion criteria included scalp psoriasis that needed systemic treatment or which required the use of other concomitant therapies for psoriasis during the study. Subjects were also to avoid excessive UV exposure and were to respect specified wash-out periods for systemic anti-psoriatic medications.

Treatments

Subjects were assigned following a computer generated randomization list to either clobetasol propionate shampoo, 0.05%, or clobetasol propionate shampoo vehicle in a 2:1 ratio. All individuals were to apply the study drug once a day and to leave it on the dry scalp for 15 minutes before lathering and rinsing. Subjects were asked to use the study drug over a period of 4 weeks and then to avoid during a 2-week follow-up the study medication and all psoriasis treatments previously excluded. The use of topical emollients, coal tars, vitamin D derivatives, tazarotene, or salicylic acid to treat body psoriasis during the course of the study was allowed.

Efficacy and safety assessments

The primary efficacy variable was the success rate after 4 weeks of treatment, defined as the proportion of subjects with a global severity score (GSS) of 0 (clear) or 1 (minimal). Failure was defined as a GSS of 2 (mild), 3 (moderate), 4 (severe), or 5 (very severe). Subjects were required to have moderate to severe scalp psoriasis (defined as a GSS of at least 3 on a scale of 0 to 5 points) at study entry. Secondary efficacy parameters were: GSS; total severity score (TSS; from 0: none to 3: severe), which was the sum of erythema, plaque thickening, and scaling scores; individual disease scores (rated from 0: none to 3: severe) of erythema, plaque thickening, scaling, pruritus, and percentage scalp surface area of involvement; global assessment of improvement by the investigator; and global assessment of improvement by the subject.

Safety was assessed through adverse events (AEs), including local side effects.

Statistical Methods

The sample size of 120 (80 for clobetasol propionate shampoo 0.05%, and 40 for clobetasol propionate shampoo vehicle) was determined to collect sufficient safety data and to detect a significant difference in success rates of 60% vs. 20% with 90% power at the 0.05 significance level for the 2-tailed alternative. Adjusting for a 10% dropout rate, 132 subjects were planned to be enrolled.

The intent-to-treat (ITT) population was primary for the efficacy analysis. This population consisted of all subjects randomized and who had the study drug dispensed. Success rate was analyzed using the Cochran-Mantel-Haenszel (CMH) test, stratified by center. Additional analyses for the success rate at other time points and for the secondary efficacy variables were conducted as supportive. The CMH test stratified by center, using the RIDIT transformation, was used for the global severity score (full scale), plaque elevation, erythema, scaling, pruritus, and global assessments of improvement by the Investigator and by the subject. Both the per protocol (PP) population with observed cases, and the ITT population, with missing data imputed using the last observation carried forward (LOCF) were analyzed for efficacy.

The TSS was defined as the sum of the scores for erythema, scaling, and plaque thickening. If any of these 3 individual variables was missing, TSS was missing. In calculating the Week 4 LOCF Endpoint for TSS, missing values for each of the 3 individual variables were estimated with LOCF at each visit. For the TSS score, the LOCF estimation was applied to the individual disease score before the total.

For the percentage scalp surface area of involvement, an analysis of covariance was used for changes from baseline where baselines scores were included as covariates and center and treatment as factors. Least Square mean changes from baseline in each group were used to assess the treatment effects.

Results

Subjects Studies

A total of 142 subjects was recruited with 95 individuals in the clobetasol propionate shampoo group, and 47 in the clobetasol propionate shampoo vehicle group; in total 141 subjects completed the study. One subject was discontinued from the study after randomization for having applied within the 2-week washout period, a group III potent corticosteroid. This person was excluded from the safety analyses and the safety population because the study medication was not used. Table 1 depicts demographic data. Scores of erythema, scaling, plaque thickening or pruritus between treatment groups did not show any significant difference at baseline.

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Efficacy

The proportion of subjects who achieved "success" at Week 4 Endpoint (LOCF) was significantly higher (p < 0.001) in the clobetasol propionate shampoo group (40; 42.1%) compared to that in the clobetasol propionate shampoo vehicle group (1; 2.1%). Additionally, at Week 4 (observed; p < 0.001) and Week 6 (follow-up; p = 0.003), the success rates for clobetasol propionate shampoo were significantly higher than those for the clobetasol propionate shampoo vehicle group. Similar results were observed in the PP analyses for success rates at Week 4 (observed), Week 4 Endpoint, and Week 6 (follow-up), confirming the results based on the ITT population. Furthermore, about 50% of subjects in the clobetasol propionate shampoo, 0.05%. group who achieved success at Week 4 remained a treatment success at the 2-week follow-up. There was no observation of rebound, defined as having achieved success during treatment and then deteriorated to worse than pre-treatment levels.

At Week 4 Endpoint (LOCF), results for GSS of clobetasol propionate shampoo were superior to those of clobetasol propionate shampoo vehicle (p < 0.001). This was also seen observed at other post-baseline (observed data) time points (P [less than or equal to] 0.002). At the end of treatment more clobetasol propionate shampoo subjects had a score of "mild" or better (68; 71.6%) than those treated with clobetasol propionate shampoo vehicle (7; 14.9%). The majority (approximately 85%) of clobetasol propionate shampoo vehicle subjects had "moderate" to "severe" scalp psoriasis at Week 4 Endpoint (LOCF). Ten (10.5%) subjects in the clobetasol propionate shampoo group were "clear" at the Week 4 Endpoint (LOCF) compared with no subjects in the clobetasol propionate shampoo vehicle group (p-values for all scores < 0.001). Results for the TSS at Week 4 Endpoint (LOCF) based on the LS mean difference and associated 95% CIs, showed that clobetasol propionate shampoo (3.3[+ or -]2.22) was significantly superior (p < 0.001) to clobetasol propionate shampoo vehicle (5.5[+ or -]1.9) in reducing TSS. Figure 1 depicts observed data for all time points.

Clobetasol propionate shampoo was significantly superior (p < 0.001) compared to clobetasol propionate shampoo vehicle in the treatment of pruritus, erythema, scaling, and plaque thickening. Figure 2 depicts results for "none" to "mild severity" for these signs and symptoms at Week 4. Outcomes were significantly in favor for clobetasol propionate shampoo after 2 weeks of treatment (all p [less than or equal to] 0.002) and continued to be significant at the end of the treatment-free observation period (all p [less than or equal to] 0.017).

Figure 3 depicts results of the Global Improvement as rated by both the Investigator and the subject. Global Improvement was significantly better with clobetasol propionate shampoo compared to its vehicle (p < 0.001).

At baseline, the mean percent scalp surface area of involvement was similar between both groups with about 40% of the scalp involved. At Week 4. Endpoint as compared to baseline, the percentage scalp surface area of involvement was significantly more reduced for the clobetasol propionate shampoo, 0.05%, subjects compared with the clobetasol propionate shampoo vehicle subjects (-17.1% vs. -1.0%, respectively; p < 0.001).

Safety and Tolerability

The adverse event (AE) rate was similar between the clobetasol propionate shampoo and clobetasol propionate shampoo vehicle groups. The proportion of subjects with drug-related AEs was higher in the clobetasol propionate shampoo vehicle group: 10 (21.3%) clobetasol propionate shampoo vehicle subjects compared to 13 (13.8%) clobetasol propionate shampoo subjects experienced at least one study drug related AE.

The most frequently reported dermatologic AE was skin discomfort, which included stinging and burning (10.6% of clobetasol propionate shampoo subjects versus 17% of clobetasol propionate shampoo vehicle subjects). One subject treated with clobetasol propionate shampoo reported conjunctivitis, resolving in one day, not requiring treatment and not causing the subject to discontinue the study. No case of skin atrophy, telangiectasia, or acne were was reported by any subjects and no deaths or serious adverse events occurred during the study.

Discussion

Clobetasol propionate, a superpotent topical corticosteroid, is effective for the short term relief of inflammatory and pruritic manifestations of moderate to severe corticosteroid-responsive dermatoses. It is currently available in cream, ointment, emollient cream, gel, foam and different solution formulations. Despite its therapeutic advantage none of these currently available formulations really meets all of the following expectations in one formulation: being a convenient and easy to use, efficient and safe formulation (16). Hence it was thought that a short contact shampoo of clobetasol propionate will provide satisfaction, both to the physicians and the patients.

Efficacy results of the present trial confirmed consistently that clobetasol propionate shampoo was significantly more beneficial than clobetasol propionate shampoo vehicle in treating moderate to severe scalp psoriasis when applied once daily for 15 minutes during 4 weeks to the affected areas. Furthermore, the study demonstrated that after 4 weeks of the treatment success was significantly higher with clobetasol propionate shampoo compared with the vehicle. This success rate continued to be superior during treatment free follow up period and this without showing a single case of rebound.

Significantly more subjects showed a milder condition of their psoriasis on the scalp after the treatment with clobetasol propionate shampoo compared with those subjects treated with the vehicle. Ten percent of individuals having received clobetasol propionate shampoo had no scalp psoriasis at all after four weeks of treatment compared with none of the subjects in the clobetasol propionate shampoo vehicle group. Outcome measures of the TSS; severity of signs and symptoms; global improvement; and percentage of the scalp surface area involved supported these results and underlined the superiority of clobetasol propionate shampoo over clobetasol propionate shampoo vehicle. Only a low number of subjects still showed scaling after treatment with the short-contact shampoo of clobetasol propionate. This is a particularly noteworthy result, given the high prevalence of scaling in individuals with scalp psoriasis and the social impact it results in (18,19).

Although the AE rate was similar between the clobetasol propionate shampoo and clobetasol propionate shampoo vehicle groups, the proportion of subjects with drug-related AEs was higher in the clobetasol propionate shampoo vehicle group, underlining the positive safety profile of a short contact therapy with clobetasol propionate. Due to this short contact, which potentially avoids an important penetration of clobetasol propionate into the deep skin layers of the skin, few drug-related AEs occurred and no case of skin atrophy, telangiectasia, or acne were reported which is, with regards to the current treatment modalities, an important aspect in the treatment of scalp psoriaisis (20-22).

Conclusion

The present study demonstrated that clobetasol propionate administered as a shampoo is a convenient and efficacious short contact therapy that minimizes systemic exposure while being efficient, safe and well-tolerated in the treatment of moderate to severe scalp psoriasis.

Acknowledgements

The authors would like to thank David Whiting MD, Dallas TX; Nicholas Lowe MD, Santa Monica CA; Jonathan Weiss MD, Snellville GA; Keith Loven MD, Goodlettsville TN; Richard Langley MD, Halifax CAN; Scott D. Clark MD, Longmont CO; David M. Pariser MD, Norfolk VA; Jeffrey J. Miller MD, Hershey PA and Alfons Krol MD, Edmonton, Alberta Canada for having taken part in this clinical study and gratefully acknowledge the assistance of Patrick Goritz, Galderma R & D in writing this article.

Funding sources

This research was conducted for Galderma R & D. Inc as a part of the development program of clobetasol propionate shampoo.

Conflict of interest statement

The investigating authors received honoraria from Galderma R & D, Inc. for conducting the clinical study. Two of the authors are employees of Galderma R & D Inc. None of the authors has a financial interest in the company.

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MICHAEL JARRATT, MD (1), DEBRA BRENEMAN, MD (2), ALICE B GOTTLIEB, MD (3), YVES POULIN, MD (4), YIN LIU, PHD (5), VALERIE FOLEY, PHARM D (5)

1. DERMRESEARCH, INC. AUSTIN TX, USA

2. UNIVERSITY DERMATOLOGY CONSULTANTS, CINCINNATI, OH, USA

3. UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY, NEW BRUNSWICK, NJ, USA

4. CENTRE DERMATOLOGIQUE DU QUEBEC, SAINT-FOY, QC, CANADA

5. GALDERMA R & D, INC. CRANBURY, NJ, USA

ADDRESS FOR CORRESPONDENCE:

Valerie Foley

Galderma R & D Inc

5 Cedar Brook Drive

Cranbury, NJ 08512

Phone: (609) 860-8224

Fax: (609) 409-7702

E-mail: valerie.foley@galderma.com

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