SUPPORTED BY AN EDUCATIONAL GRANT FROM WESTWOOD-SQUIBB PHARMACEUTICALS, A BRISTOL-MYERS SQUIBB COMPANY
A double-blind, vehicle-controlled paired comparison of halobetasol propionate cream on patients with plaque psoriasis H. Irving Katz, MD,a Earl Gross, MD,b Melodie Buxman, MD, Steven E. Prawer, MD,a Edmund H. Schwartzel, PhD,c and John R. Gibson, MB, ChB, FRCpc Minneapolis, Minnesota, Newington, Connecticut, Lake Oswego, Oregon, and Buffalo, New York The efficacy and safety of halobetasol propionate 0.05% cream, an ultra high-potency corticosteroid preparation, was evaluated in a double-blind, vehicle-controIled, paired comparison study. Patients' psoriatic lesions were evaluated before treatment and after 1and 2weeks of twice-daily treatment with halobetasol propionate and vehicle. Response measures (plaque elevation, erythema, scaling, and pruritus) were evaluated with a 4-point severity scale whereby the sum provided a total score. Patient self-assessment measures were obtained at the 2-week visit by categorizing his or her global responses to queries about each treatment's "effectiveness" and "overaIl rating." AIl efficacy parameters, as judged by the physician, showed statisticaIly significant (p :::: 0.0000 treatment differences favoring halobetasol propionate at both week 1 and week 2 evaluations. Patient global responses for "effectiveness" and "overaIl rating" favored halobetasol propionate 0.05% cream over vehicle after 2weeks of use. No systemic adverse drug effects were reported during the study. No patient was discontinued from the study because of an adverse event, and there was no evidence of skin atrophy after 2 weeks of treatment with either agent. Patient reports of "stings" or "burns" were equally distributed between the active and vehicle treatment groups. This trial demonstrates that halobetasol propionate 0.05% cream is clinically beneficial and without evidence of significant risk in the treatment of plaque psoriasis. (J AM ACAD DERMATOL 1991;25:1175-8.) Psoriasis is a chronic inflammatory skin disease of complex origin that affects two to three million people in the United States and approximately 1%ofthe world's population, 1 Plaque psoriasis, the most common presentation ofthe disease, is frequently chronic with periodic episodes of exacerbation and remission. The use of topical corticosteroids in the treatment of psoriasis is well established. 2 Halobetasol propionate (Ultravate)* is a new synthetic corticosteroid that has shown potential as a topical treatment for steroid-responsive dermatoses. Formulations of
From the Minneapolis Clinical Study Center," the Department of Dermato!ogy,b Newington Veterans Administration Medical Center, and the Pharmaceutical Research Institute," Bristol-Myers Squibb Company. Reprint requests: John R. Gibson, MD, Bristol-Myers Squibb Pharmaceutical Research Institute, 100 Forest Avenue, Buffalo, NY 14213-1091.
16/0/32806 *The international nonproprietary name is ulobetasol.
halobetasol propionate can be classified in the super high-potency category.3 This report describes a U.S. multicenter clinical trial designed to evaluate th~ efficacy and safety of halobetasol propionate 0.05% cream and its vehicle in the treatment of plaque psoriasis. SUBJECTS AND METHODS
Patients 18 years of age or older and of either sex, with at least two discrete, comparable, bilateral lesions of moderate or greater severity, were eligible for study participation. Moderately severelesions were defined as those demonstrating at least two features of psoriasis (erythema, scaling, plaque elevation, or pruritus), each ofat least moderate severity (grade 2) on the 4-point rating scale. Lesions to be evaluated had a minimum surface area of at least 10 cm2 each. Patients who were suffering from pustular or erythodermic psoriasis, who had used active topical medication (such as tars or corticosteroids) within I week or had used systemic medications (such as corticosteroids, PUVA, methotrexate, or retinoids) within the past 6 months were not eligible for study participation. Women who participated in the study were postmeno-
1175
1176
Journal of the American Academy of Dermatology
Katz et al.
100% 80%
92%
84%
60% 38%
40%
27%
20% 0%
...>o-~_ _
Plaque Elevation
Erythema
o
Pruritus
Scaling
Vehicle
Halobetasol
• ... of patient. achieving a cUnically significant reduction whose baaeline pruritus acoru ~re greater than arc Fig. 1. Percentage of patients achieving a clinically significant reduction in primary response measures at week 2. pausal, surgically sterile, or using oral contraceptives and had a negative pregnancy test. All of the subjects signed a written informed consent. The study was approved by the investigators' respective institutional review boards. On enrollment, each patient was assigned one tube of halobetasol propionate cream and one tube of matching vehicle; halobetasol propionate or vehicle was assigned to a given patient's right or left side by means of a computer-generated randomization schedule. Patients made the initial application of each formulation under the investigator's supervision. They were instructed to apply each medication to the appropriate lesion twice daily with 8 to 12 hours between applications. Evaluations were conducted at enrollment (before treatment) and after 1 and 2 weeks of treatment. Investigator's evaluation consisted of direct examination of target lesions for erythema, scaling, and plaque elevation; pruritus evaluation was based on the investigator's questioning of the patient. For evaluating the four parameters, 4-point (0 to 3) ordinal scales were used. An additional response measure, termed total SCOre, was obtained by totaling the individual scores for the four parameters outlined. These response measures and the use of a 4-point scale are frequently used in the efficacy evaluation of psoriasis treatmen t. 4-6 In addition to the aforementioned, the patient's self-assessment of response to each treatment was obtained at week 2. Patients
were asked to evaluate the treatments for "effectiveness" and "overall rating" by indicating "excellent," "very good," "good," "acceptable," or "poor." An evaluation was also made for the report of "stings" or "burns" for each treatment. Safety was assessed on the basis of reports of adverse experiences, whether volunteered by the patient, elicited by the investigator, or both. A clinically significant difference between treatments or change from baseline over time in the primary response measures (plaque elevation, erythema, scaling, and pruritus) was demonstrated if there was a statistically significant difference or change of at least I unit on the 4-point evaluation scale. The statistical evaluation used the Pratt-Wilcoxon signed-rank test, which compares each prin1ary response measure between treatments at study weeks 0, I, and 2. There was no preset criterion for clinical effectiveness for either total score or for patient selfassessments.
RESULTS One hundred eight patients (87 men and 21 women) of a total of 110 enrolled subjects were considered evaluable. Their ages ranged from 19 to 84 years (mean, 51.7 years). Patients had psoriasis from less than 1 year to 57 years, with a mean of 21 years; the length of the current episode ranged from
Volume 25 Number 6, Part 2 December 1991
Halobetasol cream in psoriasis 1177
100'l>
_
__
__ __ _ _ 79.6%
804 68.9% 60%
.
IlatiD.
o
.
B~lIeDt
IIIJI] Very Good 40%
20~
0%
.
IrrrTTTTTTi
31.1~
........
.
Halobetasol
IIIIIIiID
Good
_
Acceptdle
_
Poor
r---
Vehicle
Fig. 2. Relative frequency of effectiveness ratings by patients.
less than 1 year to 57 years, with a mean of 15.4 years. There were no significant differences in the severity rating for plaque elevation, scaling, erythema, and pruritus between the two treatment groups at entry to the study. The population sample for this study was typical for psoriatics as a group for the characteristics of disease severity, area of involvement and age, race, and sex distributions as reported in the 1979 Health, Education and Welfare report of the Health and Nutrition Examination Survey of 1971 to 1974. 7 Treatment differences, all statistically significant at the p = 0.0001 level, were observed between halobetasol propionate 0.05% cream and its vehicle at both weeks 1 and 2 for all primary response measures. Pruritus, which yielded a statistically significant improvement for the active compound compared with the vehicle after I and 2 weeks of treatment, was not judged to be clinically significant on the basis of the requirement that the median difference on the 0 to 3 scale did not meet the I-unit criterion for clinical significance. However, this is tempered by the fact that nearly one quarter of the patients entered the trial with severity scores of zero for pruritus and thus could not show improvement. When
patients who entered with zero scores for pruritus were excluded from this analysis, 91 % of the re· maining patients showed a clinically significant benefit against pruritus for halobetasol propionate cream, whereas 67% benefited from its vehicle (Fig. 1). The effectiveness of halobetasol propionate 0.05% cream in the treatment of the primary signs and symptoms of psoriasis is also reflected in the reduction ofthe median total score. The median total score for all patients at enrollment was 8; after 2 weeks of treatmen~,the halobetasol propionate-treated group had a median total score of 3, whereas the vehicletreated group had a median total score of 6. The patients' self-assessment of effectiveness showed that 69% of patients rated halobetasol propionate 0.05% cream as either excellent, very good, or good compared with only 20% who gave these ratings to the vehicle (Fig. 2). A total of 18 adverse clinical events occurred in 14 patients; four reactions of a minor nature in four patients were considered possibly or probably related to halobetasol propionate treatment. No patient was discontinued from the study because of an adverse reaction, and no evidence of skin atrophy or systemic adverse effects was reported by the investigators. Reports of "stings" or "burns" were equally divided
Journal of the American Academy of Dermatology
1178 Katz et al.
between halobetasol propionate- and vehicle-treated patients. DISCUSSION
The results of this study demonstrate that halobetasol propionate 0.05% cream is highly effective as a topical treatment for psoriasis. The preparation also demonstrates a favorable safety profile. In addition, both active and vehicle preparations were positively rated by patients for their cosmetic acceptability and ease of use. The cream's cosmetic attributes will help ensure that patients comply with instructions from physicians for application and use. In conclusion, this multicenter clinical trial clearly demonstrates that halobetasol propionate 0.05% cream is an effective, safe, and well-tolerated ultra high-potency corticosteroid preparation for the treatment of moderate to severe plaque psoriasis.
REFERENCES 1. Arndt KA. Psoriasis. In: Manual of dermatological therapeutics. Boston: Little, Brown & Co. 1989:119-27. 2. Cornell RC, Stoughton RB. Correlation ofthevasoconstriction assay and clinical activity in psoriasis. Arch Dermatol 1985;121:63-7. 3. Loder JS, Gibson JR, Yawalkar SJ, White RS. Halobetasol propionate. In: Maibach HI, Surber C, eds. Topical Corticosteroids. Basel: S Karger (in press). 4. Leer Jr JA. Efficacy of a betamethasone dipropionate topical glycol preparation in the management of severe psoriasis. Clin Ther 1980;3:156-67. 5. Olsen EA, Cornell RC. Topical clobetasol-17-propionate: review of its clinical efficacy and safety. J AM ACAD DERMATOL 1986;15:246-55. 6. Jegasothy B, Jacobson C, Levine N, et al. Clobetasol propionate versus fluocinonide creams in psoriasis and eczema. Int J Dermatol1985;24:461-5. 7. Johnson M-LT, Roberts 1. Prevalence, disability, and health care for psoriasis among persons 1-74 years: United States 1971-74. Hyattsville, Maryland: National Centre For Health Statistics, April 3, 1979; DHEW publication (Vital and health statistics; no 47).
A double-blind, vehicle-controlled paired comparison of halobetasol propionate cream on patients with plaque psoriasis H. Irving Katz, MD,a Earl Gross, MD,b Melodie Buxman, MD, Steven E. Prawer, MD,a Edmund H. Schwartzel, PhD,c and John R. Gibson, MB, ChB, FRCpc Minneapolis, Minnesota, Newington, Connecticut, Lake Oswego, Oregon, and Buffalo, New York The efficacy and safety of halobetasol propionate 0.05% cream, an ultra high-potency corticosteroid preparation, was evaluated in a double-blind, vehicle-controIled, paired comparison study. Patients' psoriatic lesions were evaluated before treatment and after 1and 2weeks of twice-daily treatment with halobetasol propionate and vehicle. Response measures (plaque elevation, erythema, scaling, and pruritus) were evaluated with a 4-point severity scale whereby the sum provided a total score. Patient self-assessment measures were obtained at the 2-week visit by categorizing his or her global responses to queries about each treatment's "effectiveness" and "overaIl rating." AIl efficacy parameters, as judged by the physician, showed statisticaIly significant (p :::: 0.0000 treatment differences favoring halobetasol propionate at both week 1 and week 2 evaluations. Patient global responses for "effectiveness" and "overaIl rating" favored halobetasol propionate 0.05% cream over vehicle after 2weeks of use. No systemic adverse drug effects were reported during the study. No patient was discontinued from the study because of an adverse event, and there was no evidence of skin atrophy after 2 weeks of treatment with either agent. Patient reports of "stings" or "burns" were equally distributed between the active and vehicle treatment groups. This trial demonstrates that halobetasol propionate 0.05% cream is clinically beneficial and without evidence of significant risk in the treatment of plaque psoriasis. (J AM ACAD DERMATOL 1991;25:1175-8.) Psoriasis is a chronic inflammatory skin disease of complex origin that affects two to three million people in the United States and approximately 1%ofthe world's population, 1 Plaque psoriasis, the most common presentation ofthe disease, is frequently chronic with periodic episodes of exacerbation and remission. The use of topical corticosteroids in the treatment of psoriasis is well established. 2 Halobetasol propionate (Ultravate)* is a new synthetic corticosteroid that has shown potential as a topical treatment for steroid-responsive dermatoses. Formulations of
From the Minneapolis Clinical Study Center," the Department of Dermato!ogy,b Newington Veterans Administration Medical Center, and the Pharmaceutical Research Institute," Bristol-Myers Squibb Company. Reprint requests: John R. Gibson, MD, Bristol-Myers Squibb Pharmaceutical Research Institute, 100 Forest Avenue, Buffalo, NY 14213-1091.
16/0/32806 *The international nonproprietary name is ulobetasol.
halobetasol propionate can be classified in the super high-potency category.3 This report describes a U.S. multicenter clinical trial designed to evaluate th~ efficacy and safety of halobetasol propionate 0.05% cream and its vehicle in the treatment of plaque psoriasis. SUBJECTS AND METHODS
Patients 18 years of age or older and of either sex, with at least two discrete, comparable, bilateral lesions of moderate or greater severity, were eligible for study participation. Moderately severelesions were defined as those demonstrating at least two features of psoriasis (erythema, scaling, plaque elevation, or pruritus), each ofat least moderate severity (grade 2) on the 4-point rating scale. Lesions to be evaluated had a minimum surface area of at least 10 cm2 each. Patients who were suffering from pustular or erythodermic psoriasis, who had used active topical medication (such as tars or corticosteroids) within I week or had used systemic medications (such as corticosteroids, PUVA, methotrexate, or retinoids) within the past 6 months were not eligible for study participation. Women who participated in the study were postmeno-
1175
1176
Journal of the American Academy of Dermatology
Katz et al.
100% 80%
92%
84%
60% 38%
40%
27%
20% 0%
...>o-~_ _
Plaque Elevation
Erythema
o
Pruritus
Scaling
Vehicle
Halobetasol
• ... of patient. achieving a cUnically significant reduction whose baaeline pruritus acoru ~re greater than arc Fig. 1. Percentage of patients achieving a clinically significant reduction in primary response measures at week 2. pausal, surgically sterile, or using oral contraceptives and had a negative pregnancy test. All of the subjects signed a written informed consent. The study was approved by the investigators' respective institutional review boards. On enrollment, each patient was assigned one tube of halobetasol propionate cream and one tube of matching vehicle; halobetasol propionate or vehicle was assigned to a given patient's right or left side by means of a computer-generated randomization schedule. Patients made the initial application of each formulation under the investigator's supervision. They were instructed to apply each medication to the appropriate lesion twice daily with 8 to 12 hours between applications. Evaluations were conducted at enrollment (before treatment) and after 1 and 2 weeks of treatment. Investigator's evaluation consisted of direct examination of target lesions for erythema, scaling, and plaque elevation; pruritus evaluation was based on the investigator's questioning of the patient. For evaluating the four parameters, 4-point (0 to 3) ordinal scales were used. An additional response measure, termed total SCOre, was obtained by totaling the individual scores for the four parameters outlined. These response measures and the use of a 4-point scale are frequently used in the efficacy evaluation of psoriasis treatmen t. 4-6 In addition to the aforementioned, the patient's self-assessment of response to each treatment was obtained at week 2. Patients
were asked to evaluate the treatments for "effectiveness" and "overall rating" by indicating "excellent," "very good," "good," "acceptable," or "poor." An evaluation was also made for the report of "stings" or "burns" for each treatment. Safety was assessed on the basis of reports of adverse experiences, whether volunteered by the patient, elicited by the investigator, or both. A clinically significant difference between treatments or change from baseline over time in the primary response measures (plaque elevation, erythema, scaling, and pruritus) was demonstrated if there was a statistically significant difference or change of at least I unit on the 4-point evaluation scale. The statistical evaluation used the Pratt-Wilcoxon signed-rank test, which compares each prin1ary response measure between treatments at study weeks 0, I, and 2. There was no preset criterion for clinical effectiveness for either total score or for patient selfassessments.
RESULTS One hundred eight patients (87 men and 21 women) of a total of 110 enrolled subjects were considered evaluable. Their ages ranged from 19 to 84 years (mean, 51.7 years). Patients had psoriasis from less than 1 year to 57 years, with a mean of 21 years; the length of the current episode ranged from
Volume 25 Number 6, Part 2 December 1991
Halobetasol cream in psoriasis 1177
100'l>
_
__
__ __ _ _ 79.6%
804 68.9% 60%
.
IlatiD.
o
.
B~lIeDt
IIIJI] Very Good 40%
20~
0%
.
IrrrTTTTTTi
31.1~
........
.
Halobetasol
IIIIIIiID
Good
_
Acceptdle
_
Poor
r---
Vehicle
Fig. 2. Relative frequency of effectiveness ratings by patients.
less than 1 year to 57 years, with a mean of 15.4 years. There were no significant differences in the severity rating for plaque elevation, scaling, erythema, and pruritus between the two treatment groups at entry to the study. The population sample for this study was typical for psoriatics as a group for the characteristics of disease severity, area of involvement and age, race, and sex distributions as reported in the 1979 Health, Education and Welfare report of the Health and Nutrition Examination Survey of 1971 to 1974. 7 Treatment differences, all statistically significant at the p = 0.0001 level, were observed between halobetasol propionate 0.05% cream and its vehicle at both weeks 1 and 2 for all primary response measures. Pruritus, which yielded a statistically significant improvement for the active compound compared with the vehicle after I and 2 weeks of treatment, was not judged to be clinically significant on the basis of the requirement that the median difference on the 0 to 3 scale did not meet the I-unit criterion for clinical significance. However, this is tempered by the fact that nearly one quarter of the patients entered the trial with severity scores of zero for pruritus and thus could not show improvement. When
patients who entered with zero scores for pruritus were excluded from this analysis, 91 % of the re· maining patients showed a clinically significant benefit against pruritus for halobetasol propionate cream, whereas 67% benefited from its vehicle (Fig. 1). The effectiveness of halobetasol propionate 0.05% cream in the treatment of the primary signs and symptoms of psoriasis is also reflected in the reduction ofthe median total score. The median total score for all patients at enrollment was 8; after 2 weeks of treatmen~,the halobetasol propionate-treated group had a median total score of 3, whereas the vehicletreated group had a median total score of 6. The patients' self-assessment of effectiveness showed that 69% of patients rated halobetasol propionate 0.05% cream as either excellent, very good, or good compared with only 20% who gave these ratings to the vehicle (Fig. 2). A total of 18 adverse clinical events occurred in 14 patients; four reactions of a minor nature in four patients were considered possibly or probably related to halobetasol propionate treatment. No patient was discontinued from the study because of an adverse reaction, and no evidence of skin atrophy or systemic adverse effects was reported by the investigators. Reports of "stings" or "burns" were equally divided
Journal of the American Academy of Dermatology
1178 Katz et al.
between halobetasol propionate- and vehicle-treated patients. DISCUSSION
The results of this study demonstrate that halobetasol propionate 0.05% cream is highly effective as a topical treatment for psoriasis. The preparation also demonstrates a favorable safety profile. In addition, both active and vehicle preparations were positively rated by patients for their cosmetic acceptability and ease of use. The cream's cosmetic attributes will help ensure that patients comply with instructions from physicians for application and use. In conclusion, this multicenter clinical trial clearly demonstrates that halobetasol propionate 0.05% cream is an effective, safe, and well-tolerated ultra high-potency corticosteroid preparation for the treatment of moderate to severe plaque psoriasis.
REFERENCES 1. Arndt KA. Psoriasis. In: Manual of dermatological therapeutics. Boston: Little, Brown & Co. 1989:119-27. 2. Cornell RC, Stoughton RB. Correlation ofthevasoconstriction assay and clinical activity in psoriasis. Arch Dermatol 1985;121:63-7. 3. Loder JS, Gibson JR, Yawalkar SJ, White RS. Halobetasol propionate. In: Maibach HI, Surber C, eds. Topical Corticosteroids. Basel: S Karger (in press). 4. Leer Jr JA. Efficacy of a betamethasone dipropionate topical glycol preparation in the management of severe psoriasis. Clin Ther 1980;3:156-67. 5. Olsen EA, Cornell RC. Topical clobetasol-17-propionate: review of its clinical efficacy and safety. J AM ACAD DERMATOL 1986;15:246-55. 6. Jegasothy B, Jacobson C, Levine N, et al. Clobetasol propionate versus fluocinonide creams in psoriasis and eczema. Int J Dermatol1985;24:461-5. 7. Johnson M-LT, Roberts 1. Prevalence, disability, and health care for psoriasis among persons 1-74 years: United States 1971-74. Hyattsville, Maryland: National Centre For Health Statistics, April 3, 1979; DHEW publication (Vital and health statistics; no 47).
