SUPPORTED

BY AN EDUCATIONAL GRANT FROM

GALDERMA INTERNATIONAL

Efcacy and tolerability of combined topical treatment of acne vulgaris with adapalene and clindamycin: A multicenter, randomized, investigator-blinded study
John E. Wolf Jr, MD,a David Kaplan, MD,b Stephen J. Kraus, MD,c Keith H. Loven, MD,d Toivo Rist, MD,e Leonard J. Swinyer, MD,f Michael D. Baker, BSc,g Yin S. Liu, PhD,g and Janusz Czernielewski, MDh Houston, Texas; Overland Park, Kansas; Atlanta, Georgia; Goodlettsville and Knoxville, Tennessee; Salt Lake City, Utah; Cranbury, New Jersey; and Sophia Antipolis, France
This multicenter, randomized, investigator-blinded study investigated the efcacy and tolerability of adapalene gel 0.1% plus clindamycin phosphate lotion 1%, compared with clindamycin plus vehicle for the treatment of mild to moderate acne vulgaris. A total of 249 patients applied clindamycin lotion twice daily and adapalene (125 patients) or vehicle gel (124 patients) once daily for 12 weeks. A signicantly greater reduction of total (P .001), inammatory (P .004) and noninammatory lesions (P .001) was seen in the clindamycin plus adapalene group than in the clindamycin plus vehicle group. These signicant treatment effects were observed as early as week 4 for both noninammatory and total lesion counts. Both treatment regimens were well tolerated. Although the worst scores for scaling (P .05), dryness (P .01), and stinging/burning (P .05) were higher in the clindamycin plus adapalene group than in the clindamycin plus vehicle group in patients with moderate or severe irritation; in most cases these symptoms were of mild intensity. (J Am Acad Dermatol 2003;49:S211-7.)

urrent clinical practice for mild to moderate inammatory acne frequently involves the prescription of topical and oral antibiotics, which are sometimes given in combination. These antibiotics, which include different tetracyclines, erythromycin and clindamycin are well established and effective agents.1,2 The primary mechanisms of action of topical antibiotics are the anti-PropionibacFrom the Baylor College of Medicine,a Adult and Pediatric Dermatology,b Georgia Clinical Research,c Rivergate Dermatology,d Dermatology Associates of Knoxville,e Dermatology Research Center,f Galderma R&D Inc,g and Galderma R&D.h This article is part of a supplement supported by an educational grant from Galderma International. Disclosures: John Wolf has served as a consultant and Speaker Bureau member for Galderma. Michael Baker is a former employee and current consultant to Galderma R&D Inc. Two of the authors are employees of Galderma. The other authors have no conict of interest to disclose. Funding source: Galderma International funded the research reported here. Reprint requests: John E. Wolf Jr, MD, Baylor College of Medicine, Dermatology Department, One Baylor Plaza (F840), Houston, TX 77030. E-mail: jwolf@bcm.tmc.edu. Copyright 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 0 doi:10.1067/S0190-9622(03)01152-6

terium acnes effect and inhibition of inammation caused by bacteria,3 but they may also have a limited anticomedogenic effect.4 Topical retinoids also have a dual mechanism of action. They possess a strong anticomedogenic effect and have also been shown to be effective against inammatory acne lesions. For example, treatment with tretinoin or adapalene in 2 multicenter trials reduced the number of comedones and the number of inammatory lesions by about 60%.5,6 However, topical retinoids have not been widely used for inammatory acne because of the focus on their efcacy against noninammatory lesions. The use of some topical retinoids, notably tretinoin, has also been limited by the occurrence of pustular aring and irritation shortly after initiation of therapy.7 The combination of antibiotics with topical retinoids is a rational choice, because of their distinct, complementary, and additive mechanisms of action. Controlled clinical trials with combinations of topical clindamycin and tretinoin8 and topical erythromycin and tretinoin8-11 have shown signicantly greater efcacy for the combinations than when either type of therapy was administered alone. In addition, irritation caused by tretinoin was reduced S211

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when it was coadministered with clindamycin.8 Similar efcacy results were reported when oral antibiotics (doxycycline and tetracycline) were coadministered with topical tretinoin.12,13 Until recently, tretinoin was the only topical retinoid available, but synthetic polyaromatic third-generation retinoids such as adapalene and tazarotene are now widely prescribed for acne vulgaris.1 Adapalene is a naphthoic acid derivative with retinoidlike activity and a more selective receptor binding prole than tretinoin, acting on keratinocyte differentiation, proliferation and inammatory processes associated with acne.14 Adapalene has greater chemical stability and antiinammatory effect,14 lower skin irritation potential and signicantly better tolerability than tretinoin, although demonstrating equal efcacy.15-18 This has been demonstrated in recent clinical studies and a metaanalysis of 900 patients from 5 randomized trials.18-20 This study investigated whether the combination of clindamycin topical lotion 1% and adapalene gel 0.1% had signicantly greater and faster effects than clindamycin 1% plus vehicle as initial therapy for mild to moderate acne vulgaris. A second aim of the study was to determine whether the combination of adapalene plus an antibiotic had an additive effect on reducing the number of inammatory acne lesions. The safety and tolerability of the combination therapy was also investigated.

Table I. Summary of patient disposition

Number of patients (%) Clindamycin Clindamycin plus adapalene plus vehicle Total

ITT population PP population Patients completing study Patients discontinuing study Adverse event Patients request Protocol violation Lost to follow-up Pregnancy

125 109 (87.2) 107 (85.6) 18 (14.4) 1 (0.8) 6 (4.8) 1 (0.8) 9 (7.2) 1 (0.8)

124 249 107 (86.3) 216 (86.7) 110 (88.7) 217 (87.1) 14 (11.3) 1 (0.8) 5 (4.0) 0 (0.0) 7 (5.6) 1 (0.8) 32 (12.9) 2 (0.8) 11 (4.4) 1 (0.4) 16 (6.4) 2 (0.8)

istered topically, once daily in the evening for a 12-week period. All patients also received clindamycin phosphate topical lotion 1% twice daily in the morning and evening. The study was conducted in accordance with ethical principles originating from the Declaration of Helsinki and Good Clinical Practices, and in compliance with US regulatory requirements. The study protocol was reviewed and approved by an Institutional Review Board at each center. All patients provided their written informed consent before entering the study. Study procedures Patients attended the clinic for screening, including demographics, medical history and entry criteria, and baseline assessments. A pregnancy test was conducted in women of childbearing potential. Baseline efcacy and safety assessments were recorded for eligible patients, and study medication was dispensed. Patients treated their facial areas twice daily for 12 weeks. In the morning, they applied clindamycin topical lotion 1% after washing. In the evening they applied clindamycin topical lotion 1% after washing, followed 2 minutes later with randomized study medication (adapalene gel 0.1% or adapalene gel vehicle). In an attempt to standardize washing procedures, Cetaphil Gentle Cleanser was provided to all patients. Patients attended the clinic at weeks 2, 4, 8, and 12 after the start of treatment for monitoring and efcacy and safety evaluations. Patients could withdraw from the study at any time. Where possible, patients who did not complete the study attended the clinic for a nal evaluation. Efcacy and safety assessments At each visit, the investigator counted the number of inammatory (papules and pustules; nodules/ cysts were noted but not included) and noninam-

PATIENTS AND METHODS

Patients Male and female patients with mild to moderate acne vulgaris were enrolled at 7 study centers. Patients were at least 12 years of age and had a global severity grade ranging from 2 to 8, according to the Leeds Revised Acne Grading System.21 They had 10 to 50 inammatory facial lesions (no more than 3 nodules or cysts) and 20 to 150 noninammatory facial lesions. Patients taking certain topical and systemic treatments were required to undergo specied washout periods before they could enter the study. Patients were excluded from the study if they had acne conglobata, acne fulminans, secondary acne, severe acne, or other dermatologic conditions requiring systemic treatment. Women were excluded if they were pregnant, planning a pregnancy or nursing. Men with beards were excluded if these were likely to cause interference with study assessments. Methods This was a multicenter, randomized, investigatorblinded, vehicle-controlled, parallel group study. Patients were randomized in a 1:1 ratio to receive adapalene 0.1% gel or adapalene gel vehicle, admin-

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Table II. Patient demography and baseline characteristics of the ITT population
Number of patients (%) Clindamycin plus adapalene (n 125) Clindamycin plus vehicle (n 124) Total (n 249)

Variable

Sex Male Female Age (years) Mean SD Range Race White Black Asian Hispanic Other Skin phototype I II III IV V VI Mean lesion counts (SD) Total counts Inammatory counts Noninammatory counts Global acne grade Grade 2 Grade 3 Grade 4 Grade 5 Grade 6 Grade 7 Grade 8

55 (44.0) 70 (56.0) 19.0 7.84 12-53 103 (82.4) 13 (10.4) 1 (0.8) 7 (5.6) 1 (0.8) 2 (1.6) 35 (28.0) 51 (40.8) 19 (15.2) 12 (9.6) 6 (4.8) 70.2 34.21 20.8 10.43 49.3 29.09 33 (26.4) 35 (28.0) 26 (20.8) 10 (8.0) 12 (9.6) 5 (4.0) 4 (3.2)

59 (47.6) 65 (52.4) 17.6 6.13 12-42 108 (87.1) 9 (7.3) 1 (0.8) 5 (4.0) 1 (0.8) 1 (0.8) 41 (33.1) 48 (38.7) 21 (16.9) 7 (5.6) 6 (4.8) 69.0 32.81 20.6 9.25 48.2 27.74 35 (28.2) 25 (20.2) 23 (18.5) 16 (12.9) 15 (12.1) 7 (5.6) 3 (2.4)

114 (45.8) 135 (54.2) 18.3 7.06 12-53 211 (84.7) 22 (8.8) 2 (0.8) 12 (4.8) 2 (0.8) 3 (1.2) 76 (30.5) 99 (39.8) 40 (16.1) 19 (7.6) 12 (4.8)

matory (open and closed comedones) acne lesions on the face. The numbers of open comedones, closed comedones, papules, and pustules were all counted separately. The investigators also assessed the global grade of acne severity with the Leeds Revised Acne Grading System.21 The investigator assessed local facial tolerability at each visit by rating erythema, scaling, dryness and stinging/burning on separate categoric scales as none (0), mild (1), moderate, (2) or severe (3). They also questioned the patients to elicit adverse events. Efcacy evaluation The primary efcacy end point was the comparison of the counts of total, inammatory, and noninammatory lesions at baseline and week 12 last observation carried forward (LOCF) end points. Secondary end points included a comparison of the global severity grade at all time points and the lesion counts at weeks 2, 4 and 8 with respect to baseline.

Safety evaluation The primary safety end point was the comparison of erythema, scaling, dryness, and stinging/burning at baseline and at each follow-up visit. Adverse events (dermatologic and nondermatologic) were also recorded. Statistical analyses Two study populations were analyzed. The intent-to-treat (ITT) population included all patients enrolled and randomized. The per-protocol (PP) population excluded patients who were considered unevaluable because of protocol violations. Between treatment group comparisons for demographic data were performed with the Cochran Mantel Haenszel (CMH) statistics stratied by center for the categorical variables, and the analysis of variance model with treatment and center as main factors, for the continuous variables. Efcacy analyses were conducted for both the ITT and PP popula-

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the primary efcacy variables of total, inammatory and noninammatory lesion counts, descriptive statistics (means and standard deviations) were calculated for each treatment group at each post-baseline time point. After transformation to square roots, these primary variable changes in lesion counts were analyzed by analysis of covariance with the transformed baseline count as a covariate and treatment and center as main effects in the model. For the global acne severity score, the CMH test with ridit scores, controlling for center, was used to analyze the data. Local safety data were analyzed by visit (including the worst score) using the CMH test stratied by center. Adverse event data were summarized in frequency tables by treatment group, but no statistical analysis was performed. All statistical tests were 2-sided and had the signicance probability level set at .05.

RESULTS
Disposition of patients A total of 249 patients took part in the study, 125 receiving clindamycin plus adapalene and 124 receiving clindamycin plus vehicle (Table I). This formed the ITT population. The PP population comprised 216 patients (86.7%), 33 being excluded due to inclusion violations, interfering medication missed doses, and compliance to the visit schedule. A total of 217 patients (87.1%) completed the study. Reasons for withdrawing from the study included adverse events (2 patients), patients request (11 patients), protocol violation (1 patient), lost to follow-up (16 patients) and pregnancy (2 patients) (Table I). Patient disposition was similar between the treatment groups. Demographic and baseline characteristics There were slightly more females (54.2%) than males (45.8%) in the ITT population (Table II). Most of the population was white (84.7%), with the remainder being mostly black or Hispanic. The average age was 18.3 years, and ranged from 12 to 53 years. The most common skin phototype reported was III, followed in order by II, IV, V, VI and I. The 2 treatment groups were balanced for these demographic and baseline characteristics. Mean total facial lesion count at baseline was about 70. The number of total, inammatory and noninammatory lesions was similar in the 2 treatment groups (P .765,.984, and .724, respectively). At baseline, most patients had a global acne grade of 2, 3, or 4. Again, the overall grade score was similar in the 2 treatment groups (P .333).

Fig 1. Mean percentage reductions in (a) total, (b) inammatory, and (c) noninammatory lesion counts from 0 to 12 weeks (LOCF) after treatment with clindamycin topical lotion 1% plus adapalene gel 0.1% and clindamycin plus gel vehicle: ITT population.

tions. Missing data were inputted for the ITT population analysis through the LOCF method. The primary analyses for efcacy were performed on the week 12 LOCF end point for the ITT population. For

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Fig 2. Effect of clindamycin topical lotion 1% plus adapalene 0.1% gel on facial acne lesions after 12 weeks of treatment.

Efcacy evaluation Mean percentage changes in total, inammatory and noninammatory lesion counts from baseline at weeks 2, 4, 8, and 12 are shown in Fig 1. For the primary end point, there was a signicantly greater reduction of total lesions (P .001), inammatory lesions (P .004) and noninammatory lesions (P .001) in the clindamycin plus adapalene group than in the clindamycin plus vehicle group at week 12. The mean percentage reductions were 46.7% versus 25.5% for total lesions, 55.0% versus 44.2% for inammatory lesions, and 42.5% versus 16.3% for noninammatory lesions. Lesion counts reduced after initiation of therapy for both treatment groups, but these were signicantly greater reductions for the clindamycin plus adapalene group. Statistically signicantly more reductions of lesions were reported for the clindamycin plus adapalene group than for the clindamycin plus vehicle group from weeks 4 to 12 for total lesions, week 12 for inammatory lesions and weeks 4 to 12 for noninammatory lesions. Similar results were reported for the PP population. Fig 2 depicts the effects of 12 weeks treatment with clindamycin plus adapalene on facial acne lesions in 2 selected patients. The global acne grade improved for both treatment groups during the course of the study. For the ITT population, at weeks 8 and 12 after the initiation of treatment, the overall global grade was signicantly reduced in the clindamycin plus adapalene group compared with the clindamycin plus vehicle

group (P .006 and P .001, respectively). Similar results were reported for the PP population. Safety evaluation The analysis of the severity of erythema, scaling, dryness, and stinging/burning is summarized in Fig 3. Results are shown as the worst scores reported after treatment for the safety population and are grouped as patients with no or mild irritation (Fig 3, a) and those with moderate or severe irritation (Fig 3, b). There was no signicant difference in the severity of erythema between the clindamycin plus adapalene group and the clindamycin plus vehicle group. However, reports of scaling (P .05), dryness (P .01) and stinging/burning (P .05) were greater in the clindamycin plus adapalene group in patients with moderate or severe irritation. In most cases these symptoms were mild in intensity. Furthermore, no statistical difference between the 2 groups was observed at week 12 for any of the assessed signs/symptoms, except erythema (P .045, favoring the clindamyin plus adapalene group). Both treatment regimens were well tolerated during the study. More patients reported adverse events in the clindamycin plus adapalene group than in the clindamycin plus vehicle group (30.4% vs 21.8%). However, dermatologic events were reported by similar proportions of patients in both groups (10.4% vs 9.7%, respectively). Most events were mild or moderate in intensity and were assessed as not re-

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Fig 3. Patients experiencing (a) mild or no irritation or (b) moderate or severe irritation. Summary of worst scores for erythema, scaling, dryness and stinging/burning over 0 to 12 weeks after treatment with clindamycin topical lotion 1% plus adapalene gel 0.1% and clindamycin plus gel vehicle: safety population. Clindamycin plus adapalene versus clindamycin plus vehicle: Erythema, not signicant; Scaling, P .05; Dryness, P .01; Stinging/burning, P .05 for patients with moderate or severe irritation only.

lated to study drug administration. Only 2 patients withdrew from the study because of an adverse event. One patient in the clindamycin plus adapalene group withdrew because of mild facial dryness, and 1 patient in the clindamycin plus vehicle group withdrew because of a moderate herpes simplex infection.

DISCUSSION
This study was designed to investigate whether the combination of clindamycin topical lotion 1% plus adapalene gel 0.1% provides a signicantly greater and faster efcacy than clindamycin for the treatment of mild to moderate acne vulgaris. Results showed that the addition of adapalene gel 0.1% produced a faster and a clinically signicant enhancement of the efcacy of clindamycin topical

lotion 1% therapy for acne vulgaris. There were signicantly greater reductions in total, inammatory, and noninammatory lesions in the adapalene plus clindamycin group than in the clindamycin plus vehicle group. After 12 weeks of treatment, there was an almost 2-fold greater decrease in total lesion counts for the adapalene group than for the vehicle group (46.7% vs 25.5%). The combination of adapalene and clindamycin signicantly reduced the number of both inammatory and noninammatory lesions, with an approximately 25% greater reduction in inammatory lesions (55.0% vs 44.2%) and a 2- to 3-fold greater reduction in noninammatory lesions (42.5% vs 16.3%) than in the vehicle group at week 12. Patients also demonstrated a faster response to the combination therapy, with a statistically signicantly greater improvement in the reduction of total and noninammatory lesions seen as early as week 4. The clindamycin-adapalene combination produced a similar proportional reduction in total lesion counts at week 2 to that produced by clindamycin plus vehicle at week 12 (23.6% vs 25.5%). Statistically signicant improvements with respect to global acne grade reduction were not seen as early as week 4 in patients receiving clindamycin plus adapalene. It is important to note that patients were required to have a greater number of noninammatory lesions (20 to 150) than inammatory lesions (10 to 50), and this may explain why the addition of adapalene to clindamycin was efcacious in this patient population. Whether this treatment regimen extrapolates to other patient groups with mixed forms of acne is yet to be determined. Adapalene in combination therapy with clindamycin was well tolerated. Reports of scaling, dryness, and stinging/burning were greater in patients receiving clindamycin plus adapalene than in those receiving clindamycin plus vehicle, but most were mild in severity. Reports of erythema were similar in the 2 treatment groups, as was the overall incidence, nature, and severity of adverse events. Of clinical relevance, there were no reports of acne aring and very few reports of irritation after the combination therapy. The signicant antiinammatory effect of adapalene14 may contribute to the good tolerability prole reported here. This favorable tolerability prole conrms that adapalene can be used in patients with mild to moderate inammatory acne. The results of this study have implications for the management of acne vulgaris. The signicantly greater and faster effect on acne lesions obtained by adding adapalene to clindamycin indicates that this combination can be used at the onset of therapy to obtain a better clinical response than that obtained by use of the antibiotic alone. As well as the ex-

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pected effect of a retinoid on noninammatory lesions, adapalene has a signicant antiinammatory effect14 that enhances the therapeutic action of clindamycin on inammatory acne lesions. Adapalene and clindamycin have both complementary and discrete mechanisms of action, which lead to an additive clinical effect, not only for reducing comedones but also in reducing inammatory acne lesions. For patients with mild to moderate inammatory and noninammatory acne lesions, consideration should be given to combining adapalene with topical antibiotics for initial therapy in the clinic. The more rapid action of the combination is likely to lead to greater patient compliance. In addition, the enhanced speed and efcacy of the combination may reduce the duration of antibiotic therapy and therefore help to reduce the potential for developing bacterial resistance. In conclusion, the combination regimen of clindamycin topical lotion 1% plus adapalene gel 0.1% was signicantly more effective than clindamycin plus vehicle for the treatment of mild to moderate acne vulgaris in reducing both inammatory and noninammatory lesions. The combination with adapalene resulted in a signicantly greater and faster efcacy response than that of clindamycin plus vehicle, with no signicant tolerability burden.
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