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Adapalene Gel, 0.1%, as Maintenance Therapy
for Acne Vulgaris
A Randomized, Controlled, Investigator-Blind Follow-up of a Recent Combination Study
Diane M. Thiboutot, MD; Alan R. Shalita, MD; Paul S. Yamauchi, MD, PhD; Catherine Dawson;Nabil Kerrouche; Ste´phanie Arsonnaud; Sewon Kang, MD Objective: To assess the maintenance effect of ada-
Main Outcome Measures: Efficacy and safety criteria
palene gel, 0.1%, relative to gel vehicle in subjects suc- includedmaintenancerate(subjectsmaintainingatleast50% cessfully treated in a previous 12-week study of adapalene- improvement in lesion counts from previous therapy), le- doxycycline, 100 mg, combination therapy.
sion counts (total, inflammatory, and noninflammatory),global severity assessment, cutaneous tolerability, and ad- Design: Multicenter, investigator-blind, randomized, con-
Results: Adapalene maintenance therapy resulted in sig-
Setting: Thirty-four US centers.
nificantly larger maintenance rates (75% vs 54%; PϽ.001)and significantly lower lesion counts (total [P=.005], in- Subjects: A total of 253 subjects with severe acne vul-
flammatory [P=.01], and noninflammatory [P=.02]) com- garis who showed at least moderate improvement from pared with gel vehicle. Adapalene was safe and well tol- baseline (50% improvement from baseline) when treated with either adapalene plus doxycycline or doxycycline Conclusion: This study demonstrates a clinical benefit
plus gel vehicle in a previous 12-week study.
of continued treatment with adapalene gel, 0.1%, as amaintenance therapy for acne.
Interventions: Subjects were randomized to receive ada-
palene gel, 0.1%, or gel vehicle once daily for 16 weeks.
ACNEVULGARISISANEXCEP- geniceffects.Topicalantiacnemedications,
such as retinoids, could be associated with elevated skin irritation. Therefore, careful consideration must be given to the toler- ability of a potential maintenance therapy because cutaneous adverse effects may de- tion, Propionibacterium acnes proliferation, andinflammation.1-3Themanagementofacnecan be complex, often requiring aggressive See also pages
combination therapy and a long-term thera- 605 and 638
peutic strategy.4,5Maintenancetherapyisnec-essary for many patients with acne because Author Affiliations: The
acne lesions have been shown to return af- mend topical retinoids with or without ben- ter discontinuing a successful treatment regi- men.5,6 Despite the variety of medications initial combination treatment with an an- available for the treatment of acute acne, to timicrobial agent.5 The present well-con- our knowledge, there are no published well- trolled study intended to mirror this prac- controlled studies providing evidence for tice recommendation: in an initial study, Brooklyn, NY (Dr Shalita);University of California, Los early stages of comedogenesis and the pre- noid properties,10-12 was evaluated when used cursor of mature acne lesions, the micro- concomitantly with oral doxycycline by sub- comedo.5,7 At present, the most effective jects with severe acne for 12 weeks.13 Eli- comedolytic agents are oral isotretinoin and gible subjects were randomized to receive topical retinoids.8 Oral isotretinoin is an im- doxycycline, 100 mg once daily, in the morn- (Mr Kerrouche); and Universityof Michigan, Ann Arbor practical choice for long-term therapy ow- ing and either adapalene gel, 0.1%, or gel ing to the potential for toxic and terato- vehicle once daily in the evening. At week (REPRINTED) ARCH DERMATOL/ VOL 142, MAY 2006 2006 American Medical Association. All rights reserved.
12, the combination of adapalene and doxycycline produced EFFICACY AND SAFETY VARIABLES
significantly larger reductions in total (PϽ.001), inflamma- The primary efficacy variable was the failure rate at week 16, tory (P=.02), and noninflammatory lesions (PϽ.001) rela- defined as the percentage of subjects unable to maintain 50% tive to treatment with doxycycline alone, confirming results improvement in the total lesion count from the previous 12- from previous adapalene-antimicrobial combination stud- week combination therapy study (eg, treatment in a subject en- tering the maintenance phase after having lost 40 lesions in the In the present study, the maintenance effect of ada- combination study was considered a failure if the lesion count palene gel, 0.1%, was evaluated relative to its gel vehicle at the end of the maintenance study was increased by more than in those subjects who showed at least moderate improve- 20 lesions). Data from this assessment are presented graphi- ment (50% improvement from baseline) from the pre- cally herein as a maintenance rate, which is simply 100% mi- vious adapalene-doxycycline combination therapy study.
nus the failure rate. Secondary efficacy variables included le-sion counts (total, inflammatory, and noninflammatory), failurerates for inflammatory and noninflammatory lesions, and global severity of the disease. At the last visit, subject satisfaction wasassessed via a 5-question survey.
Safety and tolerability were assessed through evaluations of STUDY DESIGN AND SUBJECTS
local facial tolerability and adverse events. At each visit, the in- The efficacy and safety of adapalene gel, 0.1% (Differin Gel, 0.1%; vestigator rated erythema, scaling, dryness, and stinging and/or Galderma Laboratories, LP, Ft Worth, Tex), as a maintenance burning on a scale ranging from 0 (none) to 3 (severe). Mean therapy were compared with gel vehicle in a randomized, mul- scores at each postbaseline visit and worst score (worst obser- ticenter, vehicle-controlled, investigator-blind, parallel group vation recorded for a subject during the postbaseline period) study conducted at 34 centers in the United States between No- were recorded. Adverse events were also evaluated at each visit.
vember 13, 2003, and May 25, 2004. Male and female subjectswith acne, aged 12 to 30 years, who showed at least moderate STATISTICAL ANALYSES
improvement from baseline (on a 6-point scale ranging from clearto worse) to after treatment with either adapalene plus doxycy- All data analyses were carried out according to a preestab- cline, 100 mg once daily, or doxycycline, 100 mg once daily, plus lished analysis plan unless specifically noted. A sample size of gel vehicle in a previous 12-week study13 were enrolled. In that 113 subjects per group was deemed necessary to detect a sta- study, a total of 467 subjects were randomized to receive doxy- tistically significant difference in failure rate between treat- cycline once daily in the morning and either adapalene or gel ment groups based on the use of a 2-tailed test with ␣=.05 and vehicle once daily in the evening for 12 weeks. Eligible subjects a power of 90%, an assumption of a 15% difference in efficacy completing the combination study were rerandomized consecu- between the 2 treatment groups, and a dropout rate of 10%.
tively in a 1:1 ratio to receive either adapalene gel, 0.1%, or its Three study populations were analyzed. The safety popu- gel vehicle once daily in the evening for an additional 16 weeks lation was defined as all patients randomized and treated at least as part of the present study. Randomization was achieved using once. The intent-to-treat (ITT) population included all ran- a central telephone system to assure that the numbers of sub- domized subjects who were dispensed study medication. The jects who received adapalene in the first part of the study would per-protocol (PP) population included all randomized sub- be evenly distributed between the 2 groups in the maintenance jects without any major protocol deviations.
phase. The randomization schedule remained blinded from those The aim of this study was to show superior efficacy of main- involved in the clinical conduct of the study. The integrity of the tenance therapy with adapalene gel relative to gel vehicle. Analy- blinding was ensured by packaging the topical medication in iden- ses for efficacy were performed on week 16 data for the ITT tical tubes and requiring a third party other than the investiga- population and the PP population. Last observation carried for- ward (LOCF) methodology was used for the ITT population Exclusion criteria prohibited enrollment of subjects with acne analysis (lesion counts) to account for missing data or for data requiring isotretinoin therapy or other dermatologic condi- from patients who withdrew from the study. In addition, treat- tions requiring interfering treatment. Women were excluded ment was considered a failure for the failure rate analysis (worst if they were pregnant, nursing, or planning a pregnancy as were case) in all subjects with missing data at week 16. Age was tested men with facial hair that would interfere with the assess- at baseline with the analysis of variance model with treatment, ments. Subjects were provided with a daily facial moisturizer center, and their interaction as factors. All other variables were with sun protection factor 15 to use as needed for the symp- analyzed by using the Cochran-Mantel-Haenszel test control- tomatic relief of skin dryness or irritation.
ling for “analysis center” and previous treatment for both the Evaluations for this study occurred at baseline and at weeks ITT and PP populations. All tests were 2 sided, and PϽ.05 was 4, 8, 12, and 16. The final visit from the previous 12-week com- considered significant. No adjustment for multiplicity was made.
bination study served as the baseline visit for this 16-week main-tenance study. A urine pregnancy test was required at screen- ing and at the final study visit for all female subjects ofchildbearing potential. Subjects were free to withdraw from the SUBJECT DISPOSITION AND BASELINE
study at any time and for any reason. Subjects not completing CHARACTERISTICS
the entire study were to be fully evaluated when possible.
This study was conducted in accordance with the ethical Of the 309 eligible subjects, 253 (82%) were enrolled in principles originating from the Declaration of Helsinki and Good this study. The subjects were rerandomized to receive either Clinical Practices guidelines of the International Conferenceon Harmonisation of Technical Requirements for Registration adapalene gel, 0.1% (126 subjects), or its gel vehicle (127 of Pharmaceuticals for Human Use and in compliance with lo- subjects; Figure 1). Subject disposition was similar be-
cal regulatory requirements. This study was reviewed and ap- tween the 2 treatment groups. The PP population com- proved by institutional review boards. All patients provided their prised 215 subjects (85%). Discontinuation rates were written informed consent prior to entering the study.
higher in the vehicle group (15.8%) relative to the ada- (REPRINTED) ARCH DERMATOL/ VOL 142, MAY 2006 2006 American Medical Association. All rights reserved.
Table. Subject Demographics and Baseline Characteristics
(Intention-to-Treat Population)*
Adapalene Gel,
Demographic
Gel Vehicle
P
Parameter
Figure 1. Flowchart of subject disposition. ITT indicates intent-to-treat;
palene group (11.1%). The most common reason for dis- continuation in both groups was subject request (6.4% and7.9% for the adapalene and vehicle groups, respectively).
*Data are given as mean ± SD value or number (percentage) of subjects A total of 219 subjects (87%) completed the study.
Baseline subject characteristics of the ITT popula- tion are summarized in the Table. Demographic char-
acteristics and baseline dermatological scores were com-
parable between the 2 treatment groups.
EFFICACY EVALUATION
The maintenance rates for total, inflammatory, and non- inflammatory lesion counts at the study end point (week 16, ITT population, worst case) are shown in Figure 2.
These rates reflect the percentage of subjects maintaining at least 50% improvement from the previous combina-tion study; missing data were treated as treatment fail- ures. Continued treatment with adapalene gel, 0.1%, re- sulted in significantly higher maintenance rates in total lesion counts (75% vs 54%; PϽ.001), inflammatory le- sion counts (74% vs 57%; P=.003), and noninflamma- tory lesion counts (71% vs 55%; P=.007) compared withtreatment with vehicle (Figure 2).
To our knowledge, no formal definition of acne main- tenance currently exists, and therefore this was the first studyfor which this definition of maintenance was used (main- Figure 2. Maintenance rates (percentage of subjects maintaining at least
taining at least 50% improvement). To support the valid- 50% improvement in lesion counts; intent-to-treat population, worst case).
ity of this assessment, a post hoc analysis was performedin which maintenance was defined in stricter terms (main- sion counts for the adapalene group remained stable or taining the same number of lesions relative to baseline). A decreased. Statistically significant differences in favor of significant benefit was also observed for adapalene rela- adapalene could be observed at week 16 (Figure 3) for tive to vehicle (46.4% vs 31.8%; P=.03) for this analysis.
total lesions (P=.001) and inflammatory lesion (P=.004) Significantly lower total (P = .005), inflammatory and noninflammatory lesion (P = .009) counts.
(P = .01), and noninflammatory (P = .02) lesion counts Analyzing the full-scale global severity assessment, a sig- were observed for subjects receiving maintenance therapy nificant difference in the distribution of severity scores fa- with adapalene gel, 0.1%, relative to vehicle at the study voring the adapalene group was observed between the 2 end point (week 16, ITT, LOCF; Figure 3). During the
treatment groups (P=.005), with more subjects “clear” or course of the study, lesion counts for the vehicle group “almost clear” in the adapalene group relative to the ve- gradually increased from baseline values, while the le- hicle group (27% vs 16%). Similar efficacy results were ob- (REPRINTED) ARCH DERMATOL/ VOL 142, MAY 2006 2006 American Medical Association. All rights reserved.
parameters were all less than 1 (mild) as well. Most sub- jects in both groups experienced mild or no irritation.
The number of subjects experiencing adverse events was similarinbothtreatmentgroups,with25%and23%reported for the adapalene and vehicle groups, respectively. During the course of the study, treatment-related adverse events occurred in 3 (2.4%) of adapalene-treated subjects and 1 (0.8%) of vehicle-treated subjects. The most common treatment-related adverse event was pruritus (2 subjects, possibly related). One subject experienced a serious adverse event deemed unrelated to study treatment (suicide attempt by subject with a history of depression). There were no ad- verse events that led to a study discontinuation, and all treatment-related adverse events were mild in severity.
SUBJECT SURVEY
The results from the 5-question survey are illustrated in Figure 6. Most subjects in both treatment groups were
not bothered by adverse effects (90% in both the ada- palene and vehicle groups; P=.94). Significantly more sub- jects in the adapalene group than in the vehicle group were “very satisfied” or “satisfied” with the treatment effective-ness (75% vs 58%; P=.003) and the overall maintenance treatment (76% vs 65%; P=.01). Similarly, when subjects were asked how they regarded the overall treatment scheme beginning with the combination therapy, a significantly larger percentage of subjects receiving adapalene mainte- nance therapy were “very satisfied” or “satisfied” com- pared with subjects receiving vehicle (84% vs 73%; P=.02).
Figure 3. Total (A), inflammatory (B), and noninflammatory (C) lesion
counts (intent-to-treat population).
In light of the chronic nature of acne, maintenance therapyis considered important for suppressing the developmentof subclinical microcomedones and thereby preventing the recurrence of the disease.5,7 At present, to our knowledge,there are no published well-controlled studies evaluatingthe clinical benefits of maintenance therapies available toguide evidence-based decisions for the long-term manage-ment of this disease. In an effort to add to our current un- Figure 4. Effect of 16 weeks of maintenance therapy with adapalene gel, 0.1%,
following 12 weeks of combination therapy with adapalene gel, 0.1%, plus
derstanding of the potential of maintenance therapies, this doxycycline on severe facial acne lesions. Photographs show subject treated 16-week study evaluated adapalene gel, 0.1%, as a main- with doxycycline and adapalene gel, 0.1%, at baseline of the combination study tenance therapy in subjects who showed at least moderate (A); after 12 weeks of combination treatment with adapalene gel, 0.1%, plusdoxycycline (this time point is also the baseline for the maintenance study) (B); improvement in their severe acne in a previous 12-week and following 16 weeks of maintenance treatment with adapalene gel, 0.1% (C).
adapalene-doxycycline combination therapy study.
This is the first rigorously controlled study evaluating a topical retinoid as a maintenance treatment for acne. The tained in the PP population analysis. Figure 4 illustrates
design of this study set a high threshold for achieving suc- the effect of 16 weeks of maintenance therapy with ada- cess by using a parallel control group, LOCF and worst- palene gel, 0.1%, following 12 weeks of combination therapy case statistical methodology, and rerandomizing subjects with adapalene gel, 0.1%, plus doxycycline on severe fa- after the previous 12-week study. No formal definition of acne maintenance exists. Maintaining at least 50% im- SAFETY EVALUATION
provement was considered an acceptable level in this study.
To support the validity of this assessment, a post hoc analy- Severity scores for erythema, scaling, dryness, and sting- sis was performed in which maintenance was defined in ing and/or burning are summarized graphically in stricter terms (maintaining the same number of lesions rela- Figure 5. As expected, local cutaneous tolerability of study
tive to baseline). Results confirmed this statistically sig- treatments was excellent for both groups. Mean tolerabil- nificant benefit with adapalene relative to the vehicle ity scores for erythema, scaling, dryness, and stinging and/or burning were less than 1 (mild) for all study visits. Worst Overall, the results of this study demonstrate clinical ben- scores at any time during the study for these tolerability efit of continued adapalene use as a maintenance therapy (REPRINTED) ARCH DERMATOL/ VOL 142, MAY 2006 2006 American Medical Association. All rights reserved.
Figure 5. Local tolerability. Effects of adapalene gel, 0.1%, vs gel vehicle on mean scores for skin tolerance variables of erythema (A), scaling (B), dryness (C),
and stinging and/or burning (D). Skin tolerability variables were assessed according to the following scoring scale: none = 0, mild = 1, moderate = 2, and severe = 3.
Mean scores at each postbaseline visit and worst score (worst observation recorded for a subject during the postbaseline period) are included in the figure.
Subjects “Much Better” or “A Lot Better Figure 6. Five-question subject survey. A, Adverse effects? B, Treatment effectiveness? C, How do you feel about yourself? D, Overall maintenance treatment?
E, Overall treatment scheme?
for acne and underscore the importance of treatment ad- induce visible inflammatory lesions. This observation may herence for the success of long-term maintenance therapy.
reflect the natural life cycle of a comedone, gradually re- After 16 weeks of treatment, adapalene provided statisti- generating back to visible acne and then to an inflamma- cally significantly superior results relative to gel vehicle for tory lesion over several months in the absence of therapy.
all efficacy assessments including total, inflammatory, and The trend of diverging lesion count differences be- noninflammatory lesion counts as well as the maintenance tween the adapalene and vehicle groups in the present study rate and global severity. A statistically significant difference suggests that a continued benefit may be obtained beyond betweenadapaleneandvehiclewasfirstobservedat4months.
4 months; however, additional studies of longer duration These results confirm those seen in a recent open-label ada- to support these results will be necessary to confirm this palene maintenance study.16 A possible explanation for this observation. In addition, studies comparing the clinical ben- unexpected late increase of acne lesions in the vehicle-treated efit of adapalene as maintenance with that of other reti- subjects may be that 3 months of previous treatment with noids or benzoyl peroxide may also be of interest.
doxycycline administered in all subjects produced a pro- There was a potential risk that randomization of patients longed antiacne effect; therefore, a delay of 3 months from previously treated with the gel vehicle–doxycycline com- baseline was necessary for the disease process to recur and bination to adapalene therapy may have caused local irri- (REPRINTED) ARCH DERMATOL/ VOL 142, MAY 2006 2006 American Medical Association. All rights reserved.
tation, which could influence the investigator to be blinded.
and Steifel and owns stock in Allergan, Medicis, and Johnson However, as expected from previous studies,10,11 adapalene waswelltoleratedfromthebeginning.Only3subjects(2.4%) Funding/Support: This study was funded by Galderma
receiving adapalene experienced treatment-related adverse Research & Development, Princeton, NJ.
events (compared with 1 in the vehicle group) and the mean
Previous Presentation: An abstract of this study was pre-
worst score for each of the local cutaneous tolerability vari- sented at the American Academy of Dermatology Meet- ables was none or mild for most adapalene-treated subjects.
ing; February 18, 2005; New Orleans, La.
In addition, results from the subject satisfaction ques- Acknowledgment: We thank the following investigators
tionnaire support the physician assessments because sub- for their involvement in data acquisition: Elizabeth Arthur, jects indicated that the adverse effects did not bother them Rochester, NY; Debra Breneman, Cincinnati, Ohio; Su- and overall they had significantly greater satisfaction with zanne Bruce, Houston, Tex; Alicia Bucko, Albuquerque, adapalene maintenance therapy (P = .01).
NM; Valerie Callender, Mitchellville, Md; Jeffrey Carmel, In acne, as with many dermatological diseases, individual Fremont, Calif; James Del Rosso, Las Vegas, Nev; Zoe Di- variations exist in the progression, remission, and responses ana Draelos, Highpoint, NC; Nancy Egan, Rockland, Me; totherapeuticinterventions.Thepresentstudydemonstrates Javier Flores, Miami, Fla; Joseph Fowler, Louisville, Ky; Jon the efficacy of adapalene therapy at maintaining improve- Hanifin, Portland, Ore; Michael Jarratt, Austin, Tex; Se- ment in acne for 16 weeks following treatment with an oral won Kang, Ann Arbor, Mich; Norman Kanof, Port Chester, antibiotic–topical retinoid combination. In many patients, NY; David Kaplan, Overland Park, Kan; Steven Kempers, this improvement may persist. In others, such as a young Fridley, Minn; Bruce Miller, Portland, Ore; Eugene Mon- teenager, a woman with a strong hormonal component to roe, Milwaukee, Wis; Amit Pandya, Dallas, Tex; Marina their acne, or those with a strong personal or family history Peredo, Smithtown, NY; Tooraj J. Raoof, Encino, Calif; of acne, it is reasonable to expect that relapses may occur Phoebe Rich, Portland, Ore; Ronald Savin, New Haven, despite maintenance therapy. Appropriate therapy should Conn; Joel Schlessinger, Omaha, Neb; Alan Shalita, Brook- then be reinitiated to control the acne and prevent scarring.
lyn, NY; Dow B. Stough, Hot Springs, Ark; Leonard Swinyer, The present 16-week and previous 12-week studies provide Salt Lake City, Utah; Diane Thiboutot, Hershey, Pa; Helen data to support regimens, such as those recommended in Mary Torok, Medina, Ohio; James Turner, Memphis, Tenn; the recent acne treatment guidelines,5 wherein oral antibi- David Whiting, Dallas, Tex; Hector Wiltz, Miami, Fla; John otics can be used initially in combination with topical reti- Wolf, Houston, Tex; and Paul Yamauchi, Santa Monica, noids to gain control over the acne, and maintenance with Calif. We also thank David Cox, Galderma Research & De- adapalene can delay the recurrence of acne. This approach velopment, Princeton, NJ, for editorial assistance.
is especially attractive in an environment with rising con-cerns on the part of physicians and patients regarding long- In summary, this study demonstrates the clinical benefit 1. Thiboutot D. Regulation of human sebaceous glands. J Invest Dermatol. 2004; of continued treatment with adapalene gel, 0.1%, as a main- 2. Pawin H, Beylot C, Chivot M, et al. Physiopathology of acne vulgaris: recent data, tenance therapy following therapy with an oral antibiotic.
new understanding of the treatments. Eur J Dermatol. 2004;14:4-12.
3. Leyden JJ. A review of the use of combination therapies for the treatment of acne Accepted for Publication: July 25, 2005.
vulgaris. J Am Acad Dermatol. 2003;49(3) (suppl):S200-S210.
4. Thiboutot D. New treatments and therapeutic strategies for acne. Arch Fam Med.
Correspondence: Diane M. Thiboutot, MD, Depart-
ment of Dermatology, HU14, Milton S. Hershey Medi- 5. Gollnick H, Cunliffe W, Berson D, et al; Global Alliance to Improve Outcomes in Acne. Management of acne. J Am Acad Dermatol. 2003;49(1) (suppl):S1-S37.
cal Center, The Pennsylvania State University, PO Box 6. Thielitz A, Helmdach M, Ropke E-M, Gollnick H. Lipid analysis of follicular casts 850, Hershey, PA 17033-0850 ([email protected]).
from cyanoacrylate strips as a new method for studying therapeutic effects of Author Contributions: Dr Thiboutot had full access to all
antiacne agents. Br J Dermatol. 2001;145:19-27.
7. Wolf JE. Maintenance therapy for acne vulgaris: the fine balance between effi- of the data in the study and takes responsibility for the in- cacy, cutaneous tolerability, and adherence. Skinmed. 2004;3:23-26.
tegrity of the data and the accuracy of the data analysis.
8. Cunliffe WJ, Holland DB, Clark SM, Stables GI. Comedogenesis: some new aetio- logical, clinical and therapeutic strategies. Br J Dermatol. 2000;142:1084-1091.
Study concept and design: Thiboutot, Shalita, Yamauchi, 9. Koo J. How do you foster medication adherence for better acne vulgaris Dawson, Kerrouche, Arsonnaud, and Kang. Acquisition of management? Skinmed. 2003;2:229-233.
data: Thiboutot, Shalita, Yamauchi, and Kang. Analysis and 10. Haider A, Shaw JC. Treatment of acne vulgaris. JAMA. 2004;292:726-735.
11. Waugh J, Noble S, Scott LJ. Adapalene: a review of its use in the treatment of interpretation of data: Thiboutot, Shalita, Yamauchi, Daw- acne vulgaris. Drugs. 2004;64:1465-1478.
son, Kerrouche, Arsonnaud, and Kang. Critical revision of 12. Cunliffe WJ, Poncet M, Loesche C, Verschoore M. A comparison of the efficacy and tolerability of adapalene 0.1% gel versus tretinoin 0.025% gel in patients the manuscript for important intellectual content: Thibou- with acne vulgaris. Br J Dermatol. 1998;139:48-56.
tot, Shalita, Yamauchi, Dawson, Kerrouche, Arsonnaud, 13. Thiboutot DB, Shalita AR, Yamauchi PS, Dawson C, Arsonnaud S, Kang S; Dif- ferin Study Group. Combination therapy with adapalene gel 0.1% and doxycy-cline for severe acne vulgaris. Skinmed. 2005;4:138-146.
Financial Disclosure: At the time this study was conducted,
14. Wolf JE Jr, Kaplan D, Kraus SJ, et al. Efficacy and tolerability of combined topical treat- 3 of the authors were employees of Galderma (Mss Dawson ment of acne vulgaris with adapalene and clindamycin: a multicenter, randomized,investigator-blinded study. J Am Acad Dermatol. 2003;49(3) (suppl):S211-S217.
and Arsonnaud and Mr Kerrouche). Drs Thiboutot, Shalita, 15. Cunliffe WJ, Meynadier J, Alirezai M, et al. Is combined oral and topical therapy and Kang have served as consultants and conducted clini- better than oral therapy alone in patients with moderate to moderately severe cal trials for Galderma Laboratories and Allergan, Inc. Dr acne vulgaris? a comparison of the efficacy and safety of lymecycline plus ada-palene gel 0.1%, versus lymecycline plus gel vehicle. J Am Acad Dermatol. 2003; Yamauchi has conducted clinical trials for Galderma Labo- ratories and Allergan, Inc. Drs Thiboutot and Shalita have 16. Zhang JZ, Li LF, Tu YT, Zheng J. A successful maintenance approach in inflam- served as consultants for Connetics, Inc, and Dermik Labo- matory acne with adapalene gel, 0.1% after an initial treatment in combinationwith clindamycin topical solution,1% or after monotherapy with clindamycin topi- ratories. Dr Shalita has served as a consultant for Medicis cal solution,1%. J Dermatolog Treat. 2004;15:372-378.
(REPRINTED) ARCH DERMATOL/ VOL 142, MAY 2006 2006 American Medical Association. All rights reserved.

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