- Email: [email protected]
Double-blind, vehicle-controlled, multicenter comparison of two 0.025% tretinoin creams in patients with acne vulgaris
SUPPORTED BY AN EDUCATIONAL GRANT FROM PENEDERM INC.
Double-blind, vehicle-controlled, multicenter comparison of two 0.025% tretinoin creams in patients with acne vulgaris Anne W. Lucky, MD,a Stanley I. Cullen, MD,b Toni Funicella, MD,c Michael T. Jarratt, MD,c Terry Jones, MD, PA,d and Max E. Reddick, MDe Cincinnati, Ohio; Gainesville, Florida; and Austin, Bryan, and Houston, Texas Background: Preclinical study and human patch tests indicate polyolprepolymer-2 may reduce cutaneous tretinoin-induced irritation. Objective: This study compared the clinical efficacy and safety of a 0.025% tretinoin cream containing polyolprepolymer-2 and its vehicle to a commercially-available 0.025% tretinoin cream. Methods: In this 12-week multicenter, double-blind, parallel group study in patients with mild to moderate acne, objective lesion counts and the investigators’ global evaluations evaluated efficacy. Subjective evaluations of skin irritation were used to study safety. Results: A total of 271 patients were enrolled. The active treatments demonstrated comparable efficacy that was statistically significantly greater than that of the vehicle. Safety evaluations of cutaneous and noncutaneous adverse events also indicated comparable results of the active treatments. Conclusion: The commercially-available 0.025% tretinoin cream and the 0.025% tretinoin cream containing polyolprepolymer-2 demonstrated comparable efficacy and safety. (J Am Acad Dermatol 1998;38:S24-30.)
Acne affects about 85% of the population aged 12 to 25 years.1 Acne lesions occur in association with abnormal keratinization and high sebum production.2 Clinically, lesions are divided into two main categories: 1) Noninflammatory lesions or open and closed comedones, and 2) inflammatory lesions or papules and pustules. Noninflammatory lesions may evolve into inflammatory lesions with or without subsequent scarring. Acne varies widely in its severity, perhaps as a result of individual sensitivity to the irritant properties of Propionibacterium acnes and its metabolites.3 Topical management is generally preferred to systemic therapy in mild to moderate acne if satisfactory results can be maintained.4 Topical tretinoin demonstrated initial success in the treatFrom Dermatology Research Associates, Cincinnati,a Gainesville,b DermResearch Inc., Austin,c J & S Studies, Bryan,d and Research for Health Inc., Houston.e Reprint requests: Anne W. Lucky, MD, Dermatology Research Associates, 7691 Five Mile Road, Cincinnati, OH 45230. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/0/88702
S24
ment of acne in 19695 and, by 1971, topical tretinoin formulations were introduced in the United States. Tretinoin therapy is now wellknown for both its efficacy in the treatment of acne vulgaris and the irritation that frequently accompanies its use.6,7 Significant erythema, dryness, peeling, scaling, and irritation may necessitate discontinuation of treatment,8 and in patients who continue therapy, irritation may lead to compliance problems.9 Tretinoin-induced irritation is dose- and vehicle-related; irritation ranges from high to low with the solution, gel, and cream formulations, respectively.10 In some cases, patients do not progress to an optimal tretinoin concentration because of tolerance problems9 and, until recently, tretinoin formulations were not specifically designed to lessen irritation. Patients with mild to moderate acne vulgaris were studied with the objective of comparing the clinical efficacy and safety of a 0.025% tretinoin cream containing a new polymer (polyolprepolymer-2) and its vehicle to a commercially-available 0.025% tretinoin cream.
Journal of the American Academy of Dermatology Volume 38, Number 4
MATERIALS AND METHODS
Overall study design This multicenter trial of 0.025% tretinoin creams was designed as a double-blind, parallel group study and included six study sites. The efficacy and safety of a tretinoin cream containing polyolprepolymer-2 (Avita, Penederm Inc., Foster City, CA) was compared with its vehicle and the commercially-available 0.025% tretinoin cream (Retin-A, Ortho Pharmaceutical Corp., Raritan, NJ). Approval of the study protocol and the informed consent form were obtained from an Institutional Review Board before initiation of the study.
Inclusion/exclusion criteria All eligible patients were required to have mild to moderate facial acne designated by the following criteria: at least 30 noninflammatory lesions (open and closed comedones), a minimum of 10 inflammatory lesions (papules and pustules), no more than four nodulocystic lesions, and a total lesion count not surpassing 200. No other cutaneous diseases could be present on the face. Patients were also excluded for a history of sensitivity to any of the study medication ingredients. Patients were not eligible for study participation if they had used the following: 1) topical acne treatments, medicated soaps, or topical steroids during the previous 2 weeks, 2) systemic steroids or antibiotics (excluding penicillins) during the previous 4 weeks, or 3) systemic retinoids during the previous 6 months. Participation in any clinical research study within the previous 6 weeks was also grounds for exclusion, regardless of whether an investigational agent was used. Situations involving concomitant use of any other medications that might interfere with acne treatment or its evaluation were assessed individually by the investigator. Female patients were required to be using an accepted method of contraception and have a negative urine pregnancy test before study entry. Current oral contraceptive users were to have been taking the same prescription for at least 3 months and were not allowed to change their contraceptive regimen during the study. Past users of oral contraceptives must have discontinued their use at least 6 months before study entry. Pregnant or nursing women were excluded.
Test materials Three topical preparations were compared in this study as follows: 1) a 0.025% tretinoin cream formulation containing polyolprepolymer-2 (Avita, Penederm Inc., Foster City, CA) 2) the cream vehicle of this product, with tretinoin replaced by FD&C Yellow #5, and 3) a commercially-available 0.025% tretinoin cream (Retin-A, Ortho Pharmaceutical Corp., Raritan, NJ). To
Lucky et al. S25 maintain a blinded environment, all study preparations were supplied in identical tubes. Each tube was labeled with the appropriate patient number, study number, and sponsor information.
Experimental procedures Patients were randomized to receive one of the three treatments. After randomization, each patient received one 45-gm tube of the assigned study medication. The first dose (day 0) was applied by the patient under medical supervision in the clinic. Subsequent applications were to be made unsupervised on the evenings of days 1 to 83 (total of 12 weeks). Before drug application at bedtime, patients were instructed to wash their faces with Purpose soap (Johnson & Johnson, Skillman, NJ) dry the skin gently, and wait 20 to 30 minutes. No other cleansers, moisturizers, aftershave lotions, or other facial products were allowed. Approximately one-half inch of medication was to be squeezed onto a fingertip and spread gently over the entire face. Study medication was not to be applied to any part of the body other than the face. The patient was allowed to use other topical medications to treat nonfacial acne lesions, as long as application did not extend above the jaw line. Noncomedogenic facial makeup was allowable, if approved by the investigator. Treated areas were to be protected from the sun as much as possible, by the use of protective clothing and hats when outdoors. The use of a provided sunscreen (DuraScreen, Penederm Inc.) was recommended when sun exposure could not be avoided.
Evaluations Patients were evaluated at baseline and at study days 14, 28, 56, and 84. Efficacy assessments included objective lesion counts and the investigators’ global evaluations of improvement. The investigators’ global evaluations judged overall improvement compared with baseline, a general clinical assessment, and reduction in lesions. The overall global evaluation was summarized as excellent, good, fair, no change, or worse. Skin irritation and potential adverse events were evaluated by both patient and investigator. The investigator graded the degree of erythema, peeling, and dryness as 0 = none, 1 = mild, 2 = moderate, and 3 = severe. The patient was asked to rank the degree of burning, itching, and tightness on a similar scale. All adverse events experienced during the trial were recorded. Patients experiencing significant adverse events were withdrawn from the study at the discretion of the investigator. If severe irritation occurred, the dosing frequency of study medication could be reduced to every other night. If irritation was not alleviated by reduced dosing frequency, a facial moisturizer chosen by the investigator could be used.
S26 Lucky et al.
Journal of the American Academy of Dermatology April 1998
Table I. Patient demographics Commerciallyavailable tretinoin
Males 45 (45%) Females 54 (55%) Mean age (yr) 19.7 ± 5.6
Fig. 1. Mean percent decrease in total lesion count.
Statistical analysis For all statistical analyses, p values < 0.05 were considered to be significant. Mean lesion counts were tested for significant treatment, investigator, and treatment-by-investigator interaction effects by means of an ANOVA model (SAS PROC GLM). Mean absolute change and mean percent change in counts were also analyzed with the same model that included baseline lesion counts as a covariate. For an added measure of efficacy, the categorized values of percent improvement and global evaluations were analyzed by means of a categorical means score model (SAS PROC CATMOD). Therapeutic equivalency was evaluated by examining analysis results patterns for total lesion counts and by testing for equivalency of mean absolute and mean percent changes in total lesion counts at day 84. Six skin safety variables (erythema, peeling, dryness, burning, itching, and tightness) were tested for significant treatment, investigator, and treatment-byinvestigator effects by means of the categorical means score model described above. RESULTS
Study population A total of 271 patients were entered into this study after providing written informed consent. Patients were randomized to receive the commercially-available tretinoin cream (n = 99), the tretinoin cream containing polyolprepolymer-2 (n = 99), or its vehicle (n = 73). The treatment groups were statistically equivalent with regard to age and sex. The demographic characteristics of the study population are detailed in Table I. Patient exclusions and dropouts Of the original 271 patients, 232 were acceptable for efficacy analysis. Thirty-nine patients
Tretinoin with polyolprepolymer-2
Vehicle
49 (49%) 50 (51%) 20.2 ± 5.5
42 (58%) 31 (42%) 20.1 ± 6.2
were excluded because of the following: lost to follow-up (n = 16), noncompliant (n = 12), personal reasons (n = 5), lack of efficacy (n = 2), concurrent illness (n = 1), protocol violation (n = 1), and other (n = 2). Four patients violated protocol entrance criteria because of a delayed initial pregnancy test, but were allowed to continue in the study after a negative test. The protocol allowed the use of facial moisturizers to treat excessive dryness, peeling, or tightness not alleviated by reduced dosing frequency of study medication. Three patients (one receiving vehicle, two receiving commercially-available tretinoin) used facial moisturizers in a manner not in accordance with protocol guidelines (dosing frequency not reduced before moisturizer use, or dosing frequency reduced simultaneously with moisturizer use). These patients were considered evaluable and are included in the efficacy analysis. Twelve patients received concomitant medications during the study that could have potentially influenced the treatment of acne. In each situation, the investigator’s assessment determined that the medication would not have affected the patient’s acne under study conditions. Lesion counts Acne lesion counts (total, noninflammatory, inflammatory) were performed at baseline and at days 14, 28, 56, and 84. Total lesion counts. There were no statistically significant differences in the total acne lesion count between the three groups until days 56 and 84, when total lesion counts in patients receiving either active treatment were statistically significantly lower than those of patients in the vehicle group. The mean percent decrease in total lesion count was significantly higher for patients receiving either tretinoin preparation as opposed to vehicle at days 28, 56, and 84 (Fig. 1). The two active
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Lucky et al. S27
Fig. 2. Mean percent decrease in noninflammatory lesion count.
Fig. 3. Mean percent decrease in inflammatory lesion count.
Table II. Percentage of patients with improvement categorized in the investigators’ global assessments as excellent or fair to good Degree of improvement
Excellent Fair to Good
Commerciallyavailable Tretinoin with tretinoin polyolprepolymer-2
25% 60%
29% 52%
Vehicle
14% 41%
treatments were not statistically different from one another at any time for total lesion counts or mean percent decrease in total lesions. Noninflammatory lesion counts. There were no statistically significant differences in noninflammatory lesion counts between the three groups until days 56 and 84, when noninflammatory lesion counts in the active treatment groups were statistically significantly lower than those in the vehicle group. The mean percent decrease in noninflammatory lesions was significantly higher in patients applying the commercially-available tretinoin and tretinoin with polyolprepolymer-2 as compared with vehicle at days 14, 28, 56, and 84 (Fig. 2). The two active treatments were not statistically different from one another at any time for noninflammatory lesion counts or mean percent decrease in total noninflammatory lesions. Inflammatory lesion counts. No statistically significant differences in the inflammatory lesion counts between the three groups were seen at any time during the study. On day 84, a statistically significant reduction in inflammatory lesions was seen in patients applying commercially-available tretinoin as compared with vehicle (Fig. 3).
Fig. 4. Incidence of patients experiencing burning.
Investigators’ global evaluations of efficacy Investigators were asked to provide a global evaluation of patients at each of the study visits. Those in the commercially-available tretinoin group had statistically significantly better global evaluation scores compared with the vehicle at days 56 and 84. In those receiving tretinoin with polyolprepolymer-2, global evaluation scores were statistically significantly better compared with vehicle at all assessments on and after day 14. The active treatment groups were not statistically significantly different from one another at any time. By day 84, the degree of improvement was categorized as “excellent” in 25% of the patients applying commercially-available tretinoin and 29% of patients applying tretinoin with polyolprepolymer-2; 14% of vehicle patients were categorized as “excellent” (Table II). “Fair to good” improvement was noted in 60% of patients receiving commercially-available tretinoin, in 52% of those receiving tretinoin with polyolpre-
S28 Lucky et al.
Fig. 5. Incidence of patients experiencing itching.
Fig. 6. Incidence of patients experiencing tightness.
polymer-2, and in 41% of vehicle patients. Although the degree of improvement for those receiving the active treatments was statistically significantly better than for those receiving vehicle, the two active treatments were not statistically different from one another. Adverse events Cutaneous. The incidence of cutaneous adverse effects generally peaked at day 14 and declined thereafter (Figs. 4 to 9). There were 18 adverse events involving the skin and appendages reported by patients receiving commerciallyavailable tretinoin and 12 events reported by patients receiving tretinoin with polyolprepolymer-2. The most frequent events included an eruption (six with commercially-available tretinoin, three with tretinoin with polyolprepolymer-2, and three with vehicle), dry skin (five each with commercially-available tretinoin and tretinoin with polyolprepolymer-2, and none with vehicle), and
Journal of the American Academy of Dermatology April 1998
Fig. 7. Incidence of patients experiencing erythema.
exfoliation (two with commercially-available tretinoin, one with tretinoin with polyolprepolymer-2, and one with vehicle). Most events were rated as either mild or moderate in severity. The patients’ subjective assessments of burning, itching, and tightness appear in Figs. 4 to 6. These peaked at day 14 in patients receiving active treatment and then gradually cleared over the course of the study. At several evaluation points, the active groups showed statistically significantly higher incidences of these side effects than the vehicle control group. However, there were no statistically significant differences in these side effects between the commercially-available tretinoin and the tretinoin with polyolprepolymer-2 groups at any time. The frequency of erythema, peeling, and dryness as judged by the investigators appears in Figs. 7 to 9. Although both active groups showed statistically significantly higher incidences of these side effects than the vehicle group at almost every evaluation point, the active groups were not statistically significantly different from one another at any time. Noncutaneous. The majority of adverse events were classified under the “body as a whole” category, and included flu-like syndrome, headaches, and pain. In total, adverse events were reported by 42% (42 of 99) of patients applying commercially-available tretinoin, 44% (44 of 99) of patients applying tretinoin with polyolprepolymer-2, and 36% (26 of 73) of vehicle patients. There were no statistically significant differences between groups in the number of patients reporting at least one event. Five cases of pain (three commerciallyavailable tretinoin, one tretinoin with polyolprepolymer-2, and one vehicle patient) were consid-
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Lucky et al. S29
Fig. 8. Incidence of patients experiencing peeling.
Fig. 9. Incidence of patients experiencing dryness.
ered possibly or probably related to treatment. No patient discontinued the study because of adverse events.
cant reductions in total and noninflammatory lesions in patients receiving active treatments as compared with vehicle, but the active treatments were not statistically different from one another at any time. Treatment with commercially-available tretinoin, tretinoin with polyolprepolymer-2, and vehicle resulted in no statistically significant differences in inflammatory lesion counts at any evaluation point except for day 84, when the mean percent decrease in these lesions in the commercially-available tretinoin group was statistically significantly greater than that in the vehicle group. Although the active treatments demonstrated statistically significant improvements in the investigators’ global evaluations as compared with vehicle, there were no statistically significant differences between the commercially-available tretinoin and tretinoin with polyolprepolymer-2 treatment groups at any time during the study. Safety evaluations included assessment of irritation by the investigator (erythema, peeling, dryness) and patient (burning, itching, tightness). The incidence of cutaneous adverse effects generally peaked at day 14 and declined thereafter. In most instances, treatment with the vehicle resulted in a statistically significantly lower frequency of all cutaneous events throughout study as compared with the active treatments. Although the incidence of all cutaneous events (except tightness) was numerically lower in the tretinoin with polyolprepolymer-2 treatment group at day 14, there were no statistically significant differences in irritation between the active treatment groups at any time. A larger sample size may provide more definitive evidence of potential differences in irritation. The frequency of noncutaneous adverse events
DISCUSSION
Topical tretinoin has proven efficacious in the treatment of acne for nearly 30 years. Its main disadvantage has been cutaneous irritation. The development of new polymers that may have the potential to reduce retinoid irritation, and the incorporation of these polymers into tretinoin formulations, have produced some encouraging initial results. Formulas containing polyolprepolymer-2 were successful in holding tretinoin on and in the upper levels of the skin in preclinical studies in guinea pigs and, theoretically, may slow drug migration into deeper layers of the epidermis, reducing irritation.11 Additional study in male golden Syrian hamsters indicated that the inclusion of polyolprepolymer-2 in a hydroalcoholic tretinoin gel formulation reduced the penetration of tretinoin into the epidermis and dermis and suggested that the formulation allowed selective drug delivery to the pilosebaceous unit.12 In humans, the results of patch test studies revealed that tretinoin gel and cream formulations containing polyolprepolymer-2 caused less peeling than did the commerciallyavailable tretinoin gel and cream formulations.13 Evaluation of lesion counts and mean percent change in lesion counts in this clinical study indicated that commercially-available tretinoin and tretinoin with polyolprepolymer-2 exhibited comparable efficacy and were significantly more effective than the vehicle in the treatment of mild to moderate acne. There were statistically signifi-
S30 Lucky et al. was not statistically significantly different between the two active treatments, and assessment of the safety parameters in this study as a whole indicates the commercially-available tretinoin cream and the tretinoin cream with polyolprepolymer-2 have comparable safety profiles. REFERENCES 1. Shalita AR. Acne vulgaris: pathogenesis and treatment. Cosmet Toiletries 1983;98:57-60. 2. Leyden JJ. Therapy for acne vulgaris. N Engl J Med 1997;336:1156-62. 3. Webster GF. Inflammatory acne. Int J Dermatol 1990;29:313-7. 4. Seaton TL. Acne. In: Young LY, Koda-Kimble MA, editors. Applied therapeutics: the clinical use of drugs, 6th ed. Vancouver (WA): Applied Therapeutics Inc., 1995. p. 37-1–7. 5. Kligman AM, Fulton JE, Plewig G. Topical vitamin A acid in acne vulgaris. Arch Dermatol 1969;99:469-76. 6. Thiboutot DM. An overview of acne and its treatment. Cutis 1996;57(suppl 1):8-12.
Journal of the American Academy of Dermatology April 1998
7. Kligman AM. How to use topical tretinoin in treating acne. Cutis 1995;56:83-4. 8. Schachner L. The treatment of acne: a contemporary review. Pediatr Clin North Am 1983;30:501-10. 9. Strauss JS. Acne and rosacea. In: Orkin M, Maibach HI, Dahl DV, editors. Dermatology. San Mateo (CA): Appleton & Lange; 1991. p. 332-5. 10. Verschoore M, Bouclier M, Czernielewski J, Hensby C. Topical retinoids: their uses in dermatology. Dermatol Ther 1993;11:107-15. 11. Hisoire G, Bucks D. An unexpected finding in percutaneous absorption observed between haired and hairless guinea pig skin. J Pharm Sci 1997;86:398-400. 12. Niemec SM, Wu HL, Jayaraman S, Hisoire G, Bucks D, Ramachandran C, et al. Effect of polyolprepolymer on the disposition of retinoic acid in various strata of hamster ear following topical in vivo application of gel formulations: correlation with disposition in human skin. Drug Delivery 1997;4:33-6. 13. Mills OH, Berger RS. Irritation potential of topical tretinoin formulations as measured by patch testing in human subjects. J Am Acad Dermatol 1998;38:S11-6.
Double-blind, vehicle-controlled, multicenter comparison of two 0.025% tretinoin creams in patients with acne vulgaris Anne W. Lucky, MD,a Stanley I. Cullen, MD,b Toni Funicella, MD,c Michael T. Jarratt, MD,c Terry Jones, MD, PA,d and Max E. Reddick, MDe Cincinnati, Ohio; Gainesville, Florida; and Austin, Bryan, and Houston, Texas Background: Preclinical study and human patch tests indicate polyolprepolymer-2 may reduce cutaneous tretinoin-induced irritation. Objective: This study compared the clinical efficacy and safety of a 0.025% tretinoin cream containing polyolprepolymer-2 and its vehicle to a commercially-available 0.025% tretinoin cream. Methods: In this 12-week multicenter, double-blind, parallel group study in patients with mild to moderate acne, objective lesion counts and the investigators’ global evaluations evaluated efficacy. Subjective evaluations of skin irritation were used to study safety. Results: A total of 271 patients were enrolled. The active treatments demonstrated comparable efficacy that was statistically significantly greater than that of the vehicle. Safety evaluations of cutaneous and noncutaneous adverse events also indicated comparable results of the active treatments. Conclusion: The commercially-available 0.025% tretinoin cream and the 0.025% tretinoin cream containing polyolprepolymer-2 demonstrated comparable efficacy and safety. (J Am Acad Dermatol 1998;38:S24-30.)
Acne affects about 85% of the population aged 12 to 25 years.1 Acne lesions occur in association with abnormal keratinization and high sebum production.2 Clinically, lesions are divided into two main categories: 1) Noninflammatory lesions or open and closed comedones, and 2) inflammatory lesions or papules and pustules. Noninflammatory lesions may evolve into inflammatory lesions with or without subsequent scarring. Acne varies widely in its severity, perhaps as a result of individual sensitivity to the irritant properties of Propionibacterium acnes and its metabolites.3 Topical management is generally preferred to systemic therapy in mild to moderate acne if satisfactory results can be maintained.4 Topical tretinoin demonstrated initial success in the treatFrom Dermatology Research Associates, Cincinnati,a Gainesville,b DermResearch Inc., Austin,c J & S Studies, Bryan,d and Research for Health Inc., Houston.e Reprint requests: Anne W. Lucky, MD, Dermatology Research Associates, 7691 Five Mile Road, Cincinnati, OH 45230. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/0/88702
S24
ment of acne in 19695 and, by 1971, topical tretinoin formulations were introduced in the United States. Tretinoin therapy is now wellknown for both its efficacy in the treatment of acne vulgaris and the irritation that frequently accompanies its use.6,7 Significant erythema, dryness, peeling, scaling, and irritation may necessitate discontinuation of treatment,8 and in patients who continue therapy, irritation may lead to compliance problems.9 Tretinoin-induced irritation is dose- and vehicle-related; irritation ranges from high to low with the solution, gel, and cream formulations, respectively.10 In some cases, patients do not progress to an optimal tretinoin concentration because of tolerance problems9 and, until recently, tretinoin formulations were not specifically designed to lessen irritation. Patients with mild to moderate acne vulgaris were studied with the objective of comparing the clinical efficacy and safety of a 0.025% tretinoin cream containing a new polymer (polyolprepolymer-2) and its vehicle to a commercially-available 0.025% tretinoin cream.
Journal of the American Academy of Dermatology Volume 38, Number 4
MATERIALS AND METHODS
Overall study design This multicenter trial of 0.025% tretinoin creams was designed as a double-blind, parallel group study and included six study sites. The efficacy and safety of a tretinoin cream containing polyolprepolymer-2 (Avita, Penederm Inc., Foster City, CA) was compared with its vehicle and the commercially-available 0.025% tretinoin cream (Retin-A, Ortho Pharmaceutical Corp., Raritan, NJ). Approval of the study protocol and the informed consent form were obtained from an Institutional Review Board before initiation of the study.
Inclusion/exclusion criteria All eligible patients were required to have mild to moderate facial acne designated by the following criteria: at least 30 noninflammatory lesions (open and closed comedones), a minimum of 10 inflammatory lesions (papules and pustules), no more than four nodulocystic lesions, and a total lesion count not surpassing 200. No other cutaneous diseases could be present on the face. Patients were also excluded for a history of sensitivity to any of the study medication ingredients. Patients were not eligible for study participation if they had used the following: 1) topical acne treatments, medicated soaps, or topical steroids during the previous 2 weeks, 2) systemic steroids or antibiotics (excluding penicillins) during the previous 4 weeks, or 3) systemic retinoids during the previous 6 months. Participation in any clinical research study within the previous 6 weeks was also grounds for exclusion, regardless of whether an investigational agent was used. Situations involving concomitant use of any other medications that might interfere with acne treatment or its evaluation were assessed individually by the investigator. Female patients were required to be using an accepted method of contraception and have a negative urine pregnancy test before study entry. Current oral contraceptive users were to have been taking the same prescription for at least 3 months and were not allowed to change their contraceptive regimen during the study. Past users of oral contraceptives must have discontinued their use at least 6 months before study entry. Pregnant or nursing women were excluded.
Test materials Three topical preparations were compared in this study as follows: 1) a 0.025% tretinoin cream formulation containing polyolprepolymer-2 (Avita, Penederm Inc., Foster City, CA) 2) the cream vehicle of this product, with tretinoin replaced by FD&C Yellow #5, and 3) a commercially-available 0.025% tretinoin cream (Retin-A, Ortho Pharmaceutical Corp., Raritan, NJ). To
Lucky et al. S25 maintain a blinded environment, all study preparations were supplied in identical tubes. Each tube was labeled with the appropriate patient number, study number, and sponsor information.
Experimental procedures Patients were randomized to receive one of the three treatments. After randomization, each patient received one 45-gm tube of the assigned study medication. The first dose (day 0) was applied by the patient under medical supervision in the clinic. Subsequent applications were to be made unsupervised on the evenings of days 1 to 83 (total of 12 weeks). Before drug application at bedtime, patients were instructed to wash their faces with Purpose soap (Johnson & Johnson, Skillman, NJ) dry the skin gently, and wait 20 to 30 minutes. No other cleansers, moisturizers, aftershave lotions, or other facial products were allowed. Approximately one-half inch of medication was to be squeezed onto a fingertip and spread gently over the entire face. Study medication was not to be applied to any part of the body other than the face. The patient was allowed to use other topical medications to treat nonfacial acne lesions, as long as application did not extend above the jaw line. Noncomedogenic facial makeup was allowable, if approved by the investigator. Treated areas were to be protected from the sun as much as possible, by the use of protective clothing and hats when outdoors. The use of a provided sunscreen (DuraScreen, Penederm Inc.) was recommended when sun exposure could not be avoided.
Evaluations Patients were evaluated at baseline and at study days 14, 28, 56, and 84. Efficacy assessments included objective lesion counts and the investigators’ global evaluations of improvement. The investigators’ global evaluations judged overall improvement compared with baseline, a general clinical assessment, and reduction in lesions. The overall global evaluation was summarized as excellent, good, fair, no change, or worse. Skin irritation and potential adverse events were evaluated by both patient and investigator. The investigator graded the degree of erythema, peeling, and dryness as 0 = none, 1 = mild, 2 = moderate, and 3 = severe. The patient was asked to rank the degree of burning, itching, and tightness on a similar scale. All adverse events experienced during the trial were recorded. Patients experiencing significant adverse events were withdrawn from the study at the discretion of the investigator. If severe irritation occurred, the dosing frequency of study medication could be reduced to every other night. If irritation was not alleviated by reduced dosing frequency, a facial moisturizer chosen by the investigator could be used.
S26 Lucky et al.
Journal of the American Academy of Dermatology April 1998
Table I. Patient demographics Commerciallyavailable tretinoin
Males 45 (45%) Females 54 (55%) Mean age (yr) 19.7 ± 5.6
Fig. 1. Mean percent decrease in total lesion count.
Statistical analysis For all statistical analyses, p values < 0.05 were considered to be significant. Mean lesion counts were tested for significant treatment, investigator, and treatment-by-investigator interaction effects by means of an ANOVA model (SAS PROC GLM). Mean absolute change and mean percent change in counts were also analyzed with the same model that included baseline lesion counts as a covariate. For an added measure of efficacy, the categorized values of percent improvement and global evaluations were analyzed by means of a categorical means score model (SAS PROC CATMOD). Therapeutic equivalency was evaluated by examining analysis results patterns for total lesion counts and by testing for equivalency of mean absolute and mean percent changes in total lesion counts at day 84. Six skin safety variables (erythema, peeling, dryness, burning, itching, and tightness) were tested for significant treatment, investigator, and treatment-byinvestigator effects by means of the categorical means score model described above. RESULTS
Study population A total of 271 patients were entered into this study after providing written informed consent. Patients were randomized to receive the commercially-available tretinoin cream (n = 99), the tretinoin cream containing polyolprepolymer-2 (n = 99), or its vehicle (n = 73). The treatment groups were statistically equivalent with regard to age and sex. The demographic characteristics of the study population are detailed in Table I. Patient exclusions and dropouts Of the original 271 patients, 232 were acceptable for efficacy analysis. Thirty-nine patients
Tretinoin with polyolprepolymer-2
Vehicle
49 (49%) 50 (51%) 20.2 ± 5.5
42 (58%) 31 (42%) 20.1 ± 6.2
were excluded because of the following: lost to follow-up (n = 16), noncompliant (n = 12), personal reasons (n = 5), lack of efficacy (n = 2), concurrent illness (n = 1), protocol violation (n = 1), and other (n = 2). Four patients violated protocol entrance criteria because of a delayed initial pregnancy test, but were allowed to continue in the study after a negative test. The protocol allowed the use of facial moisturizers to treat excessive dryness, peeling, or tightness not alleviated by reduced dosing frequency of study medication. Three patients (one receiving vehicle, two receiving commercially-available tretinoin) used facial moisturizers in a manner not in accordance with protocol guidelines (dosing frequency not reduced before moisturizer use, or dosing frequency reduced simultaneously with moisturizer use). These patients were considered evaluable and are included in the efficacy analysis. Twelve patients received concomitant medications during the study that could have potentially influenced the treatment of acne. In each situation, the investigator’s assessment determined that the medication would not have affected the patient’s acne under study conditions. Lesion counts Acne lesion counts (total, noninflammatory, inflammatory) were performed at baseline and at days 14, 28, 56, and 84. Total lesion counts. There were no statistically significant differences in the total acne lesion count between the three groups until days 56 and 84, when total lesion counts in patients receiving either active treatment were statistically significantly lower than those of patients in the vehicle group. The mean percent decrease in total lesion count was significantly higher for patients receiving either tretinoin preparation as opposed to vehicle at days 28, 56, and 84 (Fig. 1). The two active
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Lucky et al. S27
Fig. 2. Mean percent decrease in noninflammatory lesion count.
Fig. 3. Mean percent decrease in inflammatory lesion count.
Table II. Percentage of patients with improvement categorized in the investigators’ global assessments as excellent or fair to good Degree of improvement
Excellent Fair to Good
Commerciallyavailable Tretinoin with tretinoin polyolprepolymer-2
25% 60%
29% 52%
Vehicle
14% 41%
treatments were not statistically different from one another at any time for total lesion counts or mean percent decrease in total lesions. Noninflammatory lesion counts. There were no statistically significant differences in noninflammatory lesion counts between the three groups until days 56 and 84, when noninflammatory lesion counts in the active treatment groups were statistically significantly lower than those in the vehicle group. The mean percent decrease in noninflammatory lesions was significantly higher in patients applying the commercially-available tretinoin and tretinoin with polyolprepolymer-2 as compared with vehicle at days 14, 28, 56, and 84 (Fig. 2). The two active treatments were not statistically different from one another at any time for noninflammatory lesion counts or mean percent decrease in total noninflammatory lesions. Inflammatory lesion counts. No statistically significant differences in the inflammatory lesion counts between the three groups were seen at any time during the study. On day 84, a statistically significant reduction in inflammatory lesions was seen in patients applying commercially-available tretinoin as compared with vehicle (Fig. 3).
Fig. 4. Incidence of patients experiencing burning.
Investigators’ global evaluations of efficacy Investigators were asked to provide a global evaluation of patients at each of the study visits. Those in the commercially-available tretinoin group had statistically significantly better global evaluation scores compared with the vehicle at days 56 and 84. In those receiving tretinoin with polyolprepolymer-2, global evaluation scores were statistically significantly better compared with vehicle at all assessments on and after day 14. The active treatment groups were not statistically significantly different from one another at any time. By day 84, the degree of improvement was categorized as “excellent” in 25% of the patients applying commercially-available tretinoin and 29% of patients applying tretinoin with polyolprepolymer-2; 14% of vehicle patients were categorized as “excellent” (Table II). “Fair to good” improvement was noted in 60% of patients receiving commercially-available tretinoin, in 52% of those receiving tretinoin with polyolpre-
S28 Lucky et al.
Fig. 5. Incidence of patients experiencing itching.
Fig. 6. Incidence of patients experiencing tightness.
polymer-2, and in 41% of vehicle patients. Although the degree of improvement for those receiving the active treatments was statistically significantly better than for those receiving vehicle, the two active treatments were not statistically different from one another. Adverse events Cutaneous. The incidence of cutaneous adverse effects generally peaked at day 14 and declined thereafter (Figs. 4 to 9). There were 18 adverse events involving the skin and appendages reported by patients receiving commerciallyavailable tretinoin and 12 events reported by patients receiving tretinoin with polyolprepolymer-2. The most frequent events included an eruption (six with commercially-available tretinoin, three with tretinoin with polyolprepolymer-2, and three with vehicle), dry skin (five each with commercially-available tretinoin and tretinoin with polyolprepolymer-2, and none with vehicle), and
Journal of the American Academy of Dermatology April 1998
Fig. 7. Incidence of patients experiencing erythema.
exfoliation (two with commercially-available tretinoin, one with tretinoin with polyolprepolymer-2, and one with vehicle). Most events were rated as either mild or moderate in severity. The patients’ subjective assessments of burning, itching, and tightness appear in Figs. 4 to 6. These peaked at day 14 in patients receiving active treatment and then gradually cleared over the course of the study. At several evaluation points, the active groups showed statistically significantly higher incidences of these side effects than the vehicle control group. However, there were no statistically significant differences in these side effects between the commercially-available tretinoin and the tretinoin with polyolprepolymer-2 groups at any time. The frequency of erythema, peeling, and dryness as judged by the investigators appears in Figs. 7 to 9. Although both active groups showed statistically significantly higher incidences of these side effects than the vehicle group at almost every evaluation point, the active groups were not statistically significantly different from one another at any time. Noncutaneous. The majority of adverse events were classified under the “body as a whole” category, and included flu-like syndrome, headaches, and pain. In total, adverse events were reported by 42% (42 of 99) of patients applying commercially-available tretinoin, 44% (44 of 99) of patients applying tretinoin with polyolprepolymer-2, and 36% (26 of 73) of vehicle patients. There were no statistically significant differences between groups in the number of patients reporting at least one event. Five cases of pain (three commerciallyavailable tretinoin, one tretinoin with polyolprepolymer-2, and one vehicle patient) were consid-
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Lucky et al. S29
Fig. 8. Incidence of patients experiencing peeling.
Fig. 9. Incidence of patients experiencing dryness.
ered possibly or probably related to treatment. No patient discontinued the study because of adverse events.
cant reductions in total and noninflammatory lesions in patients receiving active treatments as compared with vehicle, but the active treatments were not statistically different from one another at any time. Treatment with commercially-available tretinoin, tretinoin with polyolprepolymer-2, and vehicle resulted in no statistically significant differences in inflammatory lesion counts at any evaluation point except for day 84, when the mean percent decrease in these lesions in the commercially-available tretinoin group was statistically significantly greater than that in the vehicle group. Although the active treatments demonstrated statistically significant improvements in the investigators’ global evaluations as compared with vehicle, there were no statistically significant differences between the commercially-available tretinoin and tretinoin with polyolprepolymer-2 treatment groups at any time during the study. Safety evaluations included assessment of irritation by the investigator (erythema, peeling, dryness) and patient (burning, itching, tightness). The incidence of cutaneous adverse effects generally peaked at day 14 and declined thereafter. In most instances, treatment with the vehicle resulted in a statistically significantly lower frequency of all cutaneous events throughout study as compared with the active treatments. Although the incidence of all cutaneous events (except tightness) was numerically lower in the tretinoin with polyolprepolymer-2 treatment group at day 14, there were no statistically significant differences in irritation between the active treatment groups at any time. A larger sample size may provide more definitive evidence of potential differences in irritation. The frequency of noncutaneous adverse events
DISCUSSION
Topical tretinoin has proven efficacious in the treatment of acne for nearly 30 years. Its main disadvantage has been cutaneous irritation. The development of new polymers that may have the potential to reduce retinoid irritation, and the incorporation of these polymers into tretinoin formulations, have produced some encouraging initial results. Formulas containing polyolprepolymer-2 were successful in holding tretinoin on and in the upper levels of the skin in preclinical studies in guinea pigs and, theoretically, may slow drug migration into deeper layers of the epidermis, reducing irritation.11 Additional study in male golden Syrian hamsters indicated that the inclusion of polyolprepolymer-2 in a hydroalcoholic tretinoin gel formulation reduced the penetration of tretinoin into the epidermis and dermis and suggested that the formulation allowed selective drug delivery to the pilosebaceous unit.12 In humans, the results of patch test studies revealed that tretinoin gel and cream formulations containing polyolprepolymer-2 caused less peeling than did the commerciallyavailable tretinoin gel and cream formulations.13 Evaluation of lesion counts and mean percent change in lesion counts in this clinical study indicated that commercially-available tretinoin and tretinoin with polyolprepolymer-2 exhibited comparable efficacy and were significantly more effective than the vehicle in the treatment of mild to moderate acne. There were statistically signifi-
S30 Lucky et al. was not statistically significantly different between the two active treatments, and assessment of the safety parameters in this study as a whole indicates the commercially-available tretinoin cream and the tretinoin cream with polyolprepolymer-2 have comparable safety profiles. REFERENCES 1. Shalita AR. Acne vulgaris: pathogenesis and treatment. Cosmet Toiletries 1983;98:57-60. 2. Leyden JJ. Therapy for acne vulgaris. N Engl J Med 1997;336:1156-62. 3. Webster GF. Inflammatory acne. Int J Dermatol 1990;29:313-7. 4. Seaton TL. Acne. In: Young LY, Koda-Kimble MA, editors. Applied therapeutics: the clinical use of drugs, 6th ed. Vancouver (WA): Applied Therapeutics Inc., 1995. p. 37-1–7. 5. Kligman AM, Fulton JE, Plewig G. Topical vitamin A acid in acne vulgaris. Arch Dermatol 1969;99:469-76. 6. Thiboutot DM. An overview of acne and its treatment. Cutis 1996;57(suppl 1):8-12.
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7. Kligman AM. How to use topical tretinoin in treating acne. Cutis 1995;56:83-4. 8. Schachner L. The treatment of acne: a contemporary review. Pediatr Clin North Am 1983;30:501-10. 9. Strauss JS. Acne and rosacea. In: Orkin M, Maibach HI, Dahl DV, editors. Dermatology. San Mateo (CA): Appleton & Lange; 1991. p. 332-5. 10. Verschoore M, Bouclier M, Czernielewski J, Hensby C. Topical retinoids: their uses in dermatology. Dermatol Ther 1993;11:107-15. 11. Hisoire G, Bucks D. An unexpected finding in percutaneous absorption observed between haired and hairless guinea pig skin. J Pharm Sci 1997;86:398-400. 12. Niemec SM, Wu HL, Jayaraman S, Hisoire G, Bucks D, Ramachandran C, et al. Effect of polyolprepolymer on the disposition of retinoic acid in various strata of hamster ear following topical in vivo application of gel formulations: correlation with disposition in human skin. Drug Delivery 1997;4:33-6. 13. Mills OH, Berger RS. Irritation potential of topical tretinoin formulations as measured by patch testing in human subjects. J Am Acad Dermatol 1998;38:S11-6.