- Email: [email protected]
tretinoin hydrogel with each agent alone and vehicle for the treatment of acne vulgaris
Two randomized, double-blind, controlled trials of 2219 subjects to compare the combination clindamycin/tretinoin hydrogel with each agent alone and vehicle for the treatment of acne vulgaris James J. Leyden, MD,a Lincoln Krochmal, MD,b and Alex Yaroshinsky, PhDb Philadelphia, Pennsylvania, and Palo Alto, California Background: The development of a hydrogel to stabilize and solubilize clindamycin and tretinoin provides a single, once-daily treatment for acne vulgaris. Objective: Our aim was to compare the efficacy and safety of the combination of clindamycin (1%) and tretinoin (0.025%) with each agent alone and vehicle. Methods: Two randomized, double-blind, active druge and vehicle-controlled 12-week studies evaluated inflammatory and noninflammatory lesion counts and the Investigator’s Static Global Assessment in 2219 subjects with acne vulgaris. Results: The combination demonstrated superior efficacy to clindamycin, tretinoin, and vehicle. Combination hydrogel was significantly more effective in reducing inflammatory (P \.005), noninflammatory (P # .0004), and total (P \ .0001) lesion counts than the other treatments and vehicle. The proportion of subjects with clear or almost clear skin on the Investigator’s Static Global Assessment was greater with the combination (P \.0001). Limitations: A majority of subjects (82.6%) had grade 2-3 acne vulgaris at baseline; therefore these overall results may not be representative of the response in the subjects (17.4%) with grade 4-5 acne. Conclusion: The combination clindamycin/tretinoin hydrogel was well tolerated and significantly more effective than clindamycin, tretinoin, or vehicle for the treatment of acne vulgaris. ( J Am Acad Dermatol 2006;54:73-81.)
A
cne is a multifactorial disease involving pilosebaceous follicles. Excess sebum production and abnormal desquamation of follicular ep-
From the Department of Dermatology, University of Pennsylvania Hospital, Philadelphiaa; and Connetics Corporation, Palo Alto.b Supported by Connetics Corporation. Disclosure: Dr Leyden is a consultant and/or member of an advisory board or speaker’s bureau for Allergan, Medicis, Galderma, Dermik, Connetics, CollaGenex, Stiefel, Ortho, and Fujisawa. Drs Yaroshinsky and Krochmal are employees of Connetics Corporation, and each holds stock in Connetics. Accepted for publication April 13, 2005. Reprint requests: James J. Leyden, MD, KGL Skin Study Center, 505 Parkway, Broomall, PA 19008. E-mail: [email protected]. Published online November 25, 2005. 0190-9622/$32.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.04.046
ithelium provide an environment (microcomedo) in which Propionibacterium acnes proliferation occurs with noninflammatory comedones and inflammatory papules, pustules, and nodules as the clinical expression of these areas of pathophysiology. In a recent consensus conference, the combination of a topical retinoid and an antibiotic were recommended for the treatment of acne in a majority of patients.1,2 Until now these two classes of drugs had to be used separately because they were not readily formulated in one compound. The inconvenience of such a treatment regimen may reduce the chance for an optimal response because of poor compliance,3-6 particularly in the teenaged population. Recent advances in delivery vehicles now permit the combination of topical tretinoin and clindamycin in one formulation. We describe herein the results from two 12-week randomized, active 73
74 Leyden, Krochmal, and Yaroshinsky
J AM ACAD DERMATOL JANUARY 2006
Table I. Investigator’s Static Global Assessment Scale Grade 0 Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Normal, clear skin with no evidence of acne vulgaris Skin almost clear: rare noninflammatory lesions present, with rare noninflamed papules (papules must be resolving and may be hyperpigmented, though not pink-red) requiring no further treatment in the investigator’s opinion Some noninflammatory lesions are present, with few inflammatory lesions (papules/ pustules only, no nodulocystic lesions) Noninflammatory lesions predominate, with multiple inflammatory lesions evident: several to many comedones and papules/pustules, and there may or may not be one small nodulocystic lesion Inflammatory lesions are more apparent: many comedones and papules/pustules, there may or may not be a few nodulocystic lesions Highly inflammatory lesions predominate: variable number of comedones, many papules/pustules and nodulocystic lesions
druge and vehicle-controlled clinical trials in which the combination of clindamycin (1%) and tretinoin (0.025%) in the hydrogel (Velac, Connetics Corporation, Palo Alto, Calif) was compared with tretinoin, clindamycin, and the vehicle in 2219 subjects.
METHODS Study population A total of 2219 male and female subjects at 37 US sites were enrolled in these two studies. To be included in the studies, subjects had to be 12 years or older with an Investigator’s Static Global Assessment (ISGA) score of 2 or higher, 17 to 40 facial inflammatory lesions (papules plus pustules) including nasal lesions, and 20 to 150 facial noninflammatory lesions (open and closed comedones), excluding nasal lesions (Table I). Informed consent documents were signed. Subjects were excluded if they (1) had any nodulocystic lesions at baseline; (2) had a history or presence of regional enteritis or inflammatory bowel disease and/or similar symptoms, known hypersensitivity or previous allergic reaction to any of the active components of the study medication, and/or current drug or alcohol abuse; (3) had a facial procedure (eg, chemical or laser peel, microdermabrasion) 2 weeks before or during the study, used any
investigational therapy, topical antiacne medications and/or systemic corticosteroids 4 weeks before study start and/or systemic retinoids 12 weeks before study start; (4) were pregnant, nursing, and/or using oral contraceptives with a specific antiandrogenic action or any oral contraceptive treatment initiated within 12 weeks before or during the study; and (5) concurrently or concomitantly used photosensitizers, neuromuscular blocking agents, medications reported to exacerbate acne, certain types of facial products, and/or tanning booths or sunbathing. Subjects were excluded for any other condition that in the judgment of the investigator would put the subject at unacceptable risk for participation in the study. Study design These two studies were randomized, doubleblind, active druge and vehicle-controlled, multicenter clinical studies of the combination of clindamycin (1%) and tretinoin (0.025%) solubilized in an alcoholfree hydrogel compared with clindamycin (1%) hydrogel, tretinoin (0.025%) hydrogel, and hydrogel alone (vehicle). Subjects were randomized to one of four parallel treatment groups in a 2:2:2:1 ratio (combination:clindamycin:tretinoin:vehicle) following a randomization list generated before enrollment. Each subject was assigned a subject number at enrollment, which defined the study drug assignment. Hydrogel treatments were packaged in blinded containers showing the subject number. The investigator, nurse/coordinator, patient, and Connetics personnel were all blinded as to subject treatment assignments. All treatments were administered once daily in the evening from baseline through week 12. Subjects were evaluated at baseline (week 0/day 1), week 2, week 4, week 8, and week 12. These two studies were powered on the basis of results of 6 European efficacy and safety studies comparing combination hydrogel to that of clindamycin and tretinoin.7-10 Allowing for a 20% rate of attrition, it was estimated that 847 subjects (242 in each active group and 121 in the vehicle group) would be required to establish superiority of the combination hydrogel to clindamycin hydrogel, tretinoin hydrogel, and the vehicle at the .05 significance level, with at least 80% power to detect a 10% difference in the reduction of total lesions. For the ISGA comparison, this sample size was calculated to be sufficient to establish superiority of the combination to the comparators at the .05 significance level with 80% power. The power of the pooled analysis including 2219 subjects was in excess of 90%. An institutional review board at each site approved the protocol used at that site.
Leyden, Krochmal, and Yaroshinsky 75
J AM ACAD DERMATOL VOLUME 54, NUMBER 1
Table II. Baseline demographics of the intent-to-treat population (N = 2219) No. of subjects Age Mean (range) #16 y [16 y Sex Male Female Race Asian Caucasian African American Hispanic Other Lesion counts, mean (SD) Total Inflammatory Noninflammatory ISGA 2 3 4 5
Combination hydrogel
Clindamycin hydrogel
Tretinoin hydrogel
Vehicle hydrogel
634
635
635
315
19.3 (12-49) 328 (52%) 306 (48%)
19.6 (11-54) 301 (47%) 334 (53%)
20.2 (11-81) 284 (45%) 351 (55%)
19.0 (12-56) 169 (54%) 146 (46%)
296 (47%) 338 (53%)
297 (47%) 338 (53%)
266 (42%) 369 (58%)
164 (52%) 151 (48%)
11 425 118 65 15
18 406 123 64 24
15 409 131 58 22
9 202 65 31 8
(2%) (67%) (19%) (10%) (2%)
(3%) (64%) (19%) (10%) (4%)
(2%) (64%) (21%) (9%) (3%)
(3%) (64%) (21%) (10%) (3%)
78.3 (32.2) 26.3 (7.4) 52.0 (28.8)
76.4 (30.5) 26.2 (7.5) 50.2 (28.2)
76.7 (30.5) 26.0 (7.2) 50.7 (27.7)
78.1 (31.2) 26.4 (7.0) 51.7 (29.3)
145 388 99 2
132 382 112 9
134 395 100 6
62 194 56 3
(23%) (61%) (16%) (0%)
(21%) (60%) (18%) (1%)
(21%) (62%) (16%) (1%)
(20%) (61%) (18%) (1%)
SD, Standard deviation.
Efficacy evaluation Efficacy data were collected at each visit. The efficacy analysis was conducted on the intent-to-treat population, which included all subjects who were randomized and given study medication. The primary efficacy end points were the percent reduction from baseline to week 12 (end of treatment) in lesion counts (total, inflammatory, and noninflammatory) and the proportion of subjects who had an ISGA score of 0 (clear) or 1 (almost clear) at week 12 (end of treatment). For subjects who discontinued treatment before week 12, the last observation was carried forward for all efficacy end points. The secondary end point was the time to 50% reduction in total lesion counts. The analysis plan was finalized before study completion and before study results were unblinded. The analysis plan specified analysis of each individual study as well as a pooled analysis of the two trials. Pooled analysis of the data was deemed appropriate because of the following similarities between the two trials: (1) subject populations, (2) study design, (3) study procedures and event schedules, (4) primary and secondary end points, (5) studies conducted in parallel and in similar geographic regions/climates, (6) identical investigators’ training materials, and (7) a single investigators’ meeting for both studies.
Statistical analyses A Cochran-Mantel-Haenszel test stratified by site was used to compare success rates (proportion of subjects with a score of 0 or 1 on the ISGA) across treatment groups. A parametric analysis of variance model was used to compare the percent reduction in lesion counts between the combination and clindamycin, combination and tretinoin, and combination and vehicle. A log-rank test was used to compare the time to 50% reduction in total lesion counts with each treatment. Values for P less than .05 were considered statistically significant. Safety evaluation Safety data were collected at each office visit. All enrolled subjects were included in the safety analysis.
RESULTS Baseline characteristics A total of 2219 subjects were enrolled at 37 investigative sites and randomly assigned to one of four study drug treatments: combination (n = 634), clindamycin (n = 635), tretinoin (n = 635), and vehicle (n = 315). All treatments were applied once daily in the evening. Baseline demographic data of enrolled subjects are summarized in Table II. Baseline characteristics across the 4 treatment groups
76 Leyden, Krochmal, and Yaroshinsky
J AM ACAD DERMATOL JANUARY 2006
Fig 1. Schematic profile of randomized controlled study.
Fig 2. Mean percent reduction (SE) in inflammatory lesion counts from baseline to week 12 (end of treatment; intentto-treat population). Asterisk, P # .0043 versus combination gel (parametric analysis of variance model with last observation carried forward).
Fig 3. Mean percent reduction (SE) in noninflammatory lesion counts from baseline to week 12 (end of treatment; intent-to-treat population). Asterisk, P # .0004 versus combination gel (parametric analysis of variance model with last observation carried forward).
were not statistically different. Approximately half the subjects were 16 years of age or younger. At baseline, the mean number of total lesions (inflammatory and noninflammatory) was 77.3 per subject. The 12-week treatment period was completed by 1902 subjects (85.7%). Reasons for discontinuation included subject request, adverse experiences, noncompliance, and disease progression (Fig 1).
(Table II). From baseline to week 12 (end of treatment), the percentage reduction in the combination group was significantly higher than in each of the other 3 treatment groups (P \.005; Fig 2). Noninflammatory lesion counts. At baseline, the mean number of noninflammatory lesions was 51.1 (Table II). From baseline to week 12 (end of treatment), the percentage reduction in the combination group was significantly higher than in each of the other 3 treatment groups (P # .0004; Fig 3). Total lesion counts. At baseline, the mean number of total (inflammatory and noninflamma-
Efficacy Inflammatory lesion counts. At baseline, the mean number of inflammatory lesions was 26.2
J AM ACAD DERMATOL
Leyden, Krochmal, and Yaroshinsky 77
VOLUME 54, NUMBER 1
Fig 4. Mean percent reduction (SE) in total lesion counts from baseline to week 12 (end of treatment; intent-to-treat population). Asterisk, P # .0001 versus combination gel (parametric analysis of variance model with last observation carried forward).
Fig 5. Kaplan-Meier curve of the time to 50% reduction in subject’s total lesion counts.
tory) lesions was 77.3 (Table II). From baseline to week 12 (end of treatment), the percentage reduction in the combination group was significantly higher than in each of the other 3 treatment groups (P # .0001; Fig 4). The median time to 50% reduction in total lesion counts was 8 weeks with combination, which was significantly faster than with clindamycin (12 weeks; P \.0001), with tretinoin (12 weeks; P \ .001), and with vehicle (median time not reached; P \ .0001). A Kaplan-Meier analysis of the cumulative percentage of subjects with a 50% reduction in lesion counts at each time point is shown in Fig 5. ISGA scale. At baseline, subjects were required to have an ISGA score of 2 or greater (Table II). Approximately 75% of subjects had a score of 3 or greater. By week 12, the number of subjects who met the criteria for success, grade 0 to grade 1 (Table I), in the combination group was significantly higher than in each of the other 3 treatment groups (P \ .0001; Fig 6). An example of the improvement attained in a typical subject is shown in Fig 7.
Fig 6. Investigator’s Static Global Assessment (ISGA): Percentage of subjects with clear or almost clear skin (success) at week 12 (end of treatment; intent-to-treat population). Asterisk, P # .0001 versus combination gel (Cochran-Mantel-Haenszel test [a = .05] stratified by site with last observation carried forward).
Consistency. When the results reported in the preceding paragraphs as combined data were evaluated as two separate clinical trials, the results were similar across both trials for all primary end points. In each study, 12 comparisons were made between combination treatment and the other 3 treatment groups (clindamycin, tretinoin, and vehicle) with regard to the 4 primary end points (inflammatory, noninflammatory, total lesions, and ISGA score). In one study all 12 comparisons were statistically significant in favor of the combination treatment, and in the other study 11 of 12 were statistically significant in favor of the combination. Table III presents the P values for the primary end points from each individual study. Safety The combination hydrogel was well tolerated, as were the clindamycin hydrogel and tretinoin hydrogel. No adverse experiences were seen in 1943 subjects (87.6%). The most common adverse experiences were at the application site and included dryness, desquamation, burning, erythema, pruritus, sunburn, and irritation. Table IV summarizes the incidences of treatment-related adverse experiences by treatment group. Other application site adverse experiences that occurred in more than one subject included irritation, rash, pigmentation, pain, and swelling. An application site adverse experience was the cause for study withdrawal in 27 subjects (1.2%), including burning in 6 subjects, dryness in 4, rash in 4, and other in 13. Aggravation of depression was the cause for one subject to withdraw. Of those subjects who withdrew because of an adverse experience, 60.7% were in the tretinoin group, and the
78 Leyden, Krochmal, and Yaroshinsky
J AM ACAD DERMATOL JANUARY 2006
Fig 7. Images of typical patient at baseline (A) and after treatment with combination hydrogel at week 12 (B).
Table III. P value of each end point for the two studies individually End point
Study
Combination vs clindamycin
Combination vs tretinoin
Combination vs vehicle
Total lesion counts
One Two One Two One Two One Two
\.0001 .0001 .0503 .0306 \.0001 \.0001 .0002 .0441
\.0001 .0034 \.0001 .0041 .0065 .0121 \.0001 .0108
\.0001 \.0001 \.0001 \.0001 \.0001 \.0001 \.0001 \.0001
Inflammatory lesion counts Noninflammatory lesion counts ISGA
remaining subjects were in the combination group. There were no serious adverse experiences that were related to treatment. Most treatment-related adverse experiences were mild or moderate. Those that were considered severe occurred in the combination and tretinoin treatment groups and included application site burning (2 and 3 subjects, respectively), application site desquamation (3 and 3 subjects, respectively), application site dryness (2 and 1 subjects, respectively), application site erythema (4 and 1 subjects, respectively), application site pruritus (1 and 3 subjects, respectively), application site rash (0 and 1 subjects, respectively), application site swelling (1 and 0 subjects, respectively), and application site vesicles (1 and 0 subjects, respectively).
DISCUSSION These two randomized, double-blind, active drugand vehicle-controlled, multicenter clinical trials compared a combination of clindamycin and tretinoin with each agent alone and vehicle applied once daily for 12 weeks in subjects with grade 2 to grade 5 acne vulgaris (Table I). At the end of treatment, 37% of subjects treated with the combination had clear or almost clear skin as assessed with the ISGA scale; this compares favorably with 27%, 25%, and 14% of subjects achieving this result on clindamycin, tretinoin, and vehicle, respectively. The combination was effective in treating both inflammatory and noninflammatory lesions. In fact, 12 comparisons were made between the combination treatment group and
Leyden, Krochmal, and Yaroshinsky 79
J AM ACAD DERMATOL VOLUME 54, NUMBER 1
Table IV. Incidence of treatment-related adverse experiences (N = 2219) Combination hydrogel
No. of subjects Subjects with treatment-related adverse experience Subjects who withdrew due to adverse experience Application site dryness Application site desquamation Application site burning Application site erythema Application site pruritus Application site sunburn Application site irritation
Clindamycin hydrogel
Tretinoin hydrogel
Vehicle hydrogel
634 119 (19%)
635 34 (5%)
635 107 (17%)
315 16 (5%)
11 (2%)
0 (0%)
17 (3%)
0 (0%)
48 47 41 33 21 5 3
3 2 5 3 6 3 1
57 51 40 35 24 9 6
(9%) (8%) (6%) (6%) (4%) (1%) (1%)
12 2 3 6 7 5 1
(2%) (\1%) (\1%) (1%) (1%) (1%) (\1%)
(8%) (7%) (6%) (5%) (3%) (1%) (\1%)
(1%) (1%) (2%) (1%) (2%) (1%) (\1%)
Subjects reporting a particular adverse experience more than once are counted only once for that adverse experience. Treatment-related experiences are dened as denitely, probably, or possibly related to the study drug.
the other three treatment groups (clindamycin, tretinoin, vehicle) with regard to the 4 primary end points (inflammatory, noninflammatory, and total lesion counts and ISGA score), and all 12 were statistically significant in favor of the combination. In addition, the response time (time to 50% reduction in total lesion counts) was significantly shorter with the combination (8 weeks) as compared with either agent alone (12 weeks) or vehicle. These results were consistent with those of smaller clinical studies of the combination clindamycin/tretinoin hydrogel conducted in Europe.7-10 The present studies substantially expand our understanding of the combination hydrogel by including comparisons with the active ingredients alone and vehicle and by including a much larger study population. Clindamycin is a commonly prescribed topical antibiotic for the treatment of acne and improves symptoms of acne by reducing levels of P acnes and decreasing inflammation.11,12 Topical tretinoin is a commonly prescribed topical retinoid for the treatment of acne and has been for more than 30 years. Tretinoin normalizes follicular desquamation13,14 and slows the desquamation process.15 The development of a hydrogel to stabilize these two efficacious drugs in one formulation at room temperature made it possible to treat multiple causes of acne vulgaris with one product. This may translate into better therapeutic adherence and better outcomes. As with any combination topical product containing retinoids and antibiotics, the disadvantage is that there is a fixed concentration of the two agents, and the flexibility of multiple concentrations of a retinoid is lost. In addition, the flexibility of removing exposure to the antibiotic is gone. The 3 active treatments evaluated in this study were well tolerated, with 88% of subjects showing no
adverse experiences at all. In those subjects treated with tretinoin, 8% developed dryness, 6% had burning, 5% had erythema, and 3% withdrew. In the clindamycin and vehicle groups, 1% to 2% of subjects developed these signs and there were no withdrawals. In the combination group, 2% withdrew, and the rates of dryness and erythema were similar to those seen with tretinoin. Overall, the incidence of irritation and application site reactions in the combination and tretinoin alone groups over the 12-week treatment period was low. This may be a result of formulating the medications in the alcoholfree hydrogel. Further studies are warranted to explore this observation.
CONCLUSIONS The results of these two randomized, controlled clinical trials demonstrate that the fixed combination of clindamycin and tretinoin was well tolerated and resulted in significantly greater improvements in acne vulgaris than either drug alone or the vehicle. This clindamycin/tretinoin combination effectively treated both inflammatory and noninflammatory lesions with a convenient, once-daily application of a hydrogel. We thank the investigators of the Clindamycin/tretinoin Study Group (Appendix) as well as the subjects who participated in the study. REFERENCES 1. Gollnick H, Cunliffe W, Berson D, Dreno B, Finlay A, Leyden JJ, et al. Management of acne: a report from a global alliance to improve outcomes in acne. J Am Acad Dermatol 2003; 49(Suppl):S1-38. 2. Haider A, Shaw JC. Treatment of acne vulgaris. JAMA 2004;292:726-35. 3. Draelos ZK. Patient compliance: enhancing clinician abilities and strategies. J Am Acad Dermatol 1995;32(Suppl):S42-8.
80 Leyden, Krochmal, and Yaroshinsky
J AM ACAD DERMATOL JANUARY 2006
4. Berson DS, Chalker DK, Harper JC, Leyden JJ, Shalita AR, Webster GF. Current concepts in the treatment of acne: report from a clinical roundtable. Cutis 2003;72:4-13. 5. Zaghloul SS, Cunliffe WJ, Goodfield MJ. Objective assessment of compliance with treatments in acne. Br J Dermatol 2005; 152:1015-21. 6. Katsambas AD. Why and when the treatment of acne fails. What to do. Dermatology 1998;196:158-61. 7. Cambazard F. Clinical efficacy of Velac, a new tretinoin and clindamycin gel in acne vulgaris. J Eur Acad Dermatol Venereol 1998;11(Suppl 1):S20-7. 8. Richter JR, Bousema MT, De Boulle KLVM, Degreef HJ, Poli F. Efficacy of a fixed clindamycin 1.2%, tretinoin 0.025% gel formulation (Velac) in the topical control of facial acne lesions. J Dermatolog Treat 1998;9:81-90. 9. Richter JR, Forstrom LR, Kiistala UO, Jung EG. Efficacy of fixed 1.2% clindamycin, 0.025% tretinoin gel formulation (Velac) and a proprietary 0.025% tretinoin gel formulation (Aberela) in the topical control of facial acne. J Eur Acad Dermatol Venereol 1998;11:227-33. 10. Zouboulis CC, Derumeaux L, Decroix J, Maciejewska-Udziela B, Cambazard F, Stuhlert A. A multicentre, single-blind, randomised comparison of a fixed clindamycin/tretinoin gel formulation (Velac) applied once daily and a clindamycin lotion formulation (Dalacin T) applied twice daily in the topical treatment of acne vulgaris. Br J Dermatol 2000;143:498-505. 11. Leyden JJ. Open-label evaluation of topical antimicrobial and anti-acne preparations for effectiveness versus Propionibacterium acnes in vivo. Cutis 1992;49:8-11. 12. Webster GF, Leyden JJ, McGinley KJ, McArthur WP. Suppression of polymorphonuclear leukocyte chemotactic factor production in Propionibacterium acnes by subminimal inhibitory concentrations of tetracycline, ampicillin, minocycline, and erythromycin. Antimicrob Agents Chemother 1982;21:770-2. 13. Bergfeld WF. Topical retinoids in the management of acne vulgaris. J Drug Dev Clin Pract 1996;8:151-60. 14. Kligman AM, Mills OH, McGinley KJ, Leyden JJ. Acne therapy with tretinoin in combination with antibiotics. Acta Derm Venereol Suppl (Stockh) 1975;74:111-5. 15. Chalker DK, Lesher JL Jr, Smith JG Jr, Klauda HC, Pochi PE, Jacoby WS, et al. Efficacy of topical isotretinoin 0.05% gel in acne vulgaris: results of a multicenter, double-blind investigation. J Am Acad Dermatol 1987;17:251-4.
Appendix. List of participating investigators Dan K. Chalker, MD, PC 1505 Winter St #A Augusta, GA 30904 Sunil Dhawan Center for Dermatology Cosmetic and Laser Surgery 2557 Mowry Ave, Suite 34 Fremont, CA 94538 Boni Elewski University of Alabama at Birmingham Department of Dermatology The Kirklin Clinic 2000 6th Ave South Birmingham, AL 35233 Joseph Fowler Dermatology Specialists
444 S First St Louisville, KY 40202 David Fried Omega Medical Research 400 Bald Hill Rd Warwick, RI 02886 Toni Funicella DermResearch, Inc. 8140 N Mopac Building 3, Suite 120 Austin, TX 78759 Michael Gold Tennessee Clinical Research Center 2000 Richard Jones Rd, Suite 220 Nashville, TN 37215 J. John Goodman Radiant Research 2051 45th St, Suite 200 West Palm Beach, FL 33407 Carin Gribetz Mount Sinai School of Medicine Dermatology Department 5 E 98th St 12th Floor, Box 1048 New York, NY 10029 Jo Lynn Herzog Radiant Research 516 Brookwood Blvd., First Floor Birmingham, AL 35209 Terry M. Jones J&S Studies, Inc. 3201 University Dr East, Suite 475 Bryan, TX 77802 Sewon Kang University of Michigan Department of Dermatology 1618 Taubman Health Care Center Ann Arbor, MI 48109-0314 Alexa Kimball Stanford University Department of Dermatology 900 Blake Wilbur Dr, Room W022 Stanford, CA 94305-5334 William Ko Radiant Research Phoenix 333 W Thomas Rd, Suite 100 Phoenix, AZ 85013 Jim Leyden Ivy Labs 3401 Market St, Suite 226 Philadelphia, PA 19104
J AM ACAD DERMATOL
Leyden, Krochmal, and Yaroshinsky 81
VOLUME 54, NUMBER 1
Robert Loss Dermatology Associates of Rochester 100 White Spruce Blvd Rochester, NY 14623 Anne Lucky Dermatology Research Associates 7691 Five Mile Rd, Suite 312 Cincinnati, OH 45230 Steven Mings Radiant Research, Inc. 6565 W Emerald St Boise, ID 83704 Christopher Moeller Compliant Clinical Research, Inc. 250 N Rock Rd, Suite 340 Wichita, KS 67206 Eugene Monroe Advanced Healthcare Clinical Research Center 3003 W Good Hope Rd Milwaukee, WI 53209 Amy Morris Coastal Clinical Research, Inc. 100 Memorial Hospital Dr, Suite 3-B Mobile, AL 36608 Amy Paller Children’s Memorial Hospital Division of Dermatology 2300 Children’s Plaza #107 Chicago, IL 60614 John Proffitt Compliant Clinical Research, Inc. 11805 W 62nd Place, Suite 105 Shawnee, KS 66203 Toivo Rist Dermatology Associates of Knoxville 930 Emerald Ave, Suite 511 Knoxville, TN 37917 Alan Shalita SUNY Brooklyn 450 Clarkson Ave (Box 46) Brooklyn, NY 11203 Joel Shavin Gwinnett Clinical Research Center, Inc. 2383 Pate St Snellville, GA 30078 Linda Stein Henry Ford Health System Department of Dermatology,
Room W1604 2799 W Grand Blvd Detroit, MI 48202 Bruce Strober NYU Medical Center 560 First Ave H-158 New York, NY 10016 James Swan Northwestern University Department of Dermatology 675 N St Clair St, Suite 19-200 Chicago, IL 60611 Leonard Swinyer Dermatology Research Center 3920 South 1100 East, #210 Salt Lake City, UT 84124-1276 Marvin Tankel Atlantic Dermatologic Associates, LLP 10 Peninsula Blvd Lynbrook, NY 11563 Diane Thiboutot M. S. Hershey Medical Center Department of Dermatology 500 University Dr, UPC 2, Room 4300 Hershey, PA 17033-0850 Eduardo Tschen Academic Dermatology Associates 1203 Coal SE, Suite B Alburquerque, NM 87106-5239 Guy Webster Jefferson Medical College Department of Dermatology, Suite 740 833 Chestnut St Philadelphia, PA 19107 David Wilson The Education & Research Foundation 2602 Langhorne Rd Lynchburg, VA 24501-1672 Hector Wiltz FXM Research Corporation 11760 Bird Rd, Suite 451 Miami, FL 33175 John Wolf Jr Baylor College of Medicine, Baylor Dermatology 6560 Fannin, Suite 802 Houston, TX 77030
A
cne is a multifactorial disease involving pilosebaceous follicles. Excess sebum production and abnormal desquamation of follicular ep-
From the Department of Dermatology, University of Pennsylvania Hospital, Philadelphiaa; and Connetics Corporation, Palo Alto.b Supported by Connetics Corporation. Disclosure: Dr Leyden is a consultant and/or member of an advisory board or speaker’s bureau for Allergan, Medicis, Galderma, Dermik, Connetics, CollaGenex, Stiefel, Ortho, and Fujisawa. Drs Yaroshinsky and Krochmal are employees of Connetics Corporation, and each holds stock in Connetics. Accepted for publication April 13, 2005. Reprint requests: James J. Leyden, MD, KGL Skin Study Center, 505 Parkway, Broomall, PA 19008. E-mail: [email protected]. Published online November 25, 2005. 0190-9622/$32.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.04.046
ithelium provide an environment (microcomedo) in which Propionibacterium acnes proliferation occurs with noninflammatory comedones and inflammatory papules, pustules, and nodules as the clinical expression of these areas of pathophysiology. In a recent consensus conference, the combination of a topical retinoid and an antibiotic were recommended for the treatment of acne in a majority of patients.1,2 Until now these two classes of drugs had to be used separately because they were not readily formulated in one compound. The inconvenience of such a treatment regimen may reduce the chance for an optimal response because of poor compliance,3-6 particularly in the teenaged population. Recent advances in delivery vehicles now permit the combination of topical tretinoin and clindamycin in one formulation. We describe herein the results from two 12-week randomized, active 73
74 Leyden, Krochmal, and Yaroshinsky
J AM ACAD DERMATOL JANUARY 2006
Table I. Investigator’s Static Global Assessment Scale Grade 0 Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Normal, clear skin with no evidence of acne vulgaris Skin almost clear: rare noninflammatory lesions present, with rare noninflamed papules (papules must be resolving and may be hyperpigmented, though not pink-red) requiring no further treatment in the investigator’s opinion Some noninflammatory lesions are present, with few inflammatory lesions (papules/ pustules only, no nodulocystic lesions) Noninflammatory lesions predominate, with multiple inflammatory lesions evident: several to many comedones and papules/pustules, and there may or may not be one small nodulocystic lesion Inflammatory lesions are more apparent: many comedones and papules/pustules, there may or may not be a few nodulocystic lesions Highly inflammatory lesions predominate: variable number of comedones, many papules/pustules and nodulocystic lesions
druge and vehicle-controlled clinical trials in which the combination of clindamycin (1%) and tretinoin (0.025%) in the hydrogel (Velac, Connetics Corporation, Palo Alto, Calif) was compared with tretinoin, clindamycin, and the vehicle in 2219 subjects.
METHODS Study population A total of 2219 male and female subjects at 37 US sites were enrolled in these two studies. To be included in the studies, subjects had to be 12 years or older with an Investigator’s Static Global Assessment (ISGA) score of 2 or higher, 17 to 40 facial inflammatory lesions (papules plus pustules) including nasal lesions, and 20 to 150 facial noninflammatory lesions (open and closed comedones), excluding nasal lesions (Table I). Informed consent documents were signed. Subjects were excluded if they (1) had any nodulocystic lesions at baseline; (2) had a history or presence of regional enteritis or inflammatory bowel disease and/or similar symptoms, known hypersensitivity or previous allergic reaction to any of the active components of the study medication, and/or current drug or alcohol abuse; (3) had a facial procedure (eg, chemical or laser peel, microdermabrasion) 2 weeks before or during the study, used any
investigational therapy, topical antiacne medications and/or systemic corticosteroids 4 weeks before study start and/or systemic retinoids 12 weeks before study start; (4) were pregnant, nursing, and/or using oral contraceptives with a specific antiandrogenic action or any oral contraceptive treatment initiated within 12 weeks before or during the study; and (5) concurrently or concomitantly used photosensitizers, neuromuscular blocking agents, medications reported to exacerbate acne, certain types of facial products, and/or tanning booths or sunbathing. Subjects were excluded for any other condition that in the judgment of the investigator would put the subject at unacceptable risk for participation in the study. Study design These two studies were randomized, doubleblind, active druge and vehicle-controlled, multicenter clinical studies of the combination of clindamycin (1%) and tretinoin (0.025%) solubilized in an alcoholfree hydrogel compared with clindamycin (1%) hydrogel, tretinoin (0.025%) hydrogel, and hydrogel alone (vehicle). Subjects were randomized to one of four parallel treatment groups in a 2:2:2:1 ratio (combination:clindamycin:tretinoin:vehicle) following a randomization list generated before enrollment. Each subject was assigned a subject number at enrollment, which defined the study drug assignment. Hydrogel treatments were packaged in blinded containers showing the subject number. The investigator, nurse/coordinator, patient, and Connetics personnel were all blinded as to subject treatment assignments. All treatments were administered once daily in the evening from baseline through week 12. Subjects were evaluated at baseline (week 0/day 1), week 2, week 4, week 8, and week 12. These two studies were powered on the basis of results of 6 European efficacy and safety studies comparing combination hydrogel to that of clindamycin and tretinoin.7-10 Allowing for a 20% rate of attrition, it was estimated that 847 subjects (242 in each active group and 121 in the vehicle group) would be required to establish superiority of the combination hydrogel to clindamycin hydrogel, tretinoin hydrogel, and the vehicle at the .05 significance level, with at least 80% power to detect a 10% difference in the reduction of total lesions. For the ISGA comparison, this sample size was calculated to be sufficient to establish superiority of the combination to the comparators at the .05 significance level with 80% power. The power of the pooled analysis including 2219 subjects was in excess of 90%. An institutional review board at each site approved the protocol used at that site.
Leyden, Krochmal, and Yaroshinsky 75
J AM ACAD DERMATOL VOLUME 54, NUMBER 1
Table II. Baseline demographics of the intent-to-treat population (N = 2219) No. of subjects Age Mean (range) #16 y [16 y Sex Male Female Race Asian Caucasian African American Hispanic Other Lesion counts, mean (SD) Total Inflammatory Noninflammatory ISGA 2 3 4 5
Combination hydrogel
Clindamycin hydrogel
Tretinoin hydrogel
Vehicle hydrogel
634
635
635
315
19.3 (12-49) 328 (52%) 306 (48%)
19.6 (11-54) 301 (47%) 334 (53%)
20.2 (11-81) 284 (45%) 351 (55%)
19.0 (12-56) 169 (54%) 146 (46%)
296 (47%) 338 (53%)
297 (47%) 338 (53%)
266 (42%) 369 (58%)
164 (52%) 151 (48%)
11 425 118 65 15
18 406 123 64 24
15 409 131 58 22
9 202 65 31 8
(2%) (67%) (19%) (10%) (2%)
(3%) (64%) (19%) (10%) (4%)
(2%) (64%) (21%) (9%) (3%)
(3%) (64%) (21%) (10%) (3%)
78.3 (32.2) 26.3 (7.4) 52.0 (28.8)
76.4 (30.5) 26.2 (7.5) 50.2 (28.2)
76.7 (30.5) 26.0 (7.2) 50.7 (27.7)
78.1 (31.2) 26.4 (7.0) 51.7 (29.3)
145 388 99 2
132 382 112 9
134 395 100 6
62 194 56 3
(23%) (61%) (16%) (0%)
(21%) (60%) (18%) (1%)
(21%) (62%) (16%) (1%)
(20%) (61%) (18%) (1%)
SD, Standard deviation.
Efficacy evaluation Efficacy data were collected at each visit. The efficacy analysis was conducted on the intent-to-treat population, which included all subjects who were randomized and given study medication. The primary efficacy end points were the percent reduction from baseline to week 12 (end of treatment) in lesion counts (total, inflammatory, and noninflammatory) and the proportion of subjects who had an ISGA score of 0 (clear) or 1 (almost clear) at week 12 (end of treatment). For subjects who discontinued treatment before week 12, the last observation was carried forward for all efficacy end points. The secondary end point was the time to 50% reduction in total lesion counts. The analysis plan was finalized before study completion and before study results were unblinded. The analysis plan specified analysis of each individual study as well as a pooled analysis of the two trials. Pooled analysis of the data was deemed appropriate because of the following similarities between the two trials: (1) subject populations, (2) study design, (3) study procedures and event schedules, (4) primary and secondary end points, (5) studies conducted in parallel and in similar geographic regions/climates, (6) identical investigators’ training materials, and (7) a single investigators’ meeting for both studies.
Statistical analyses A Cochran-Mantel-Haenszel test stratified by site was used to compare success rates (proportion of subjects with a score of 0 or 1 on the ISGA) across treatment groups. A parametric analysis of variance model was used to compare the percent reduction in lesion counts between the combination and clindamycin, combination and tretinoin, and combination and vehicle. A log-rank test was used to compare the time to 50% reduction in total lesion counts with each treatment. Values for P less than .05 were considered statistically significant. Safety evaluation Safety data were collected at each office visit. All enrolled subjects were included in the safety analysis.
RESULTS Baseline characteristics A total of 2219 subjects were enrolled at 37 investigative sites and randomly assigned to one of four study drug treatments: combination (n = 634), clindamycin (n = 635), tretinoin (n = 635), and vehicle (n = 315). All treatments were applied once daily in the evening. Baseline demographic data of enrolled subjects are summarized in Table II. Baseline characteristics across the 4 treatment groups
76 Leyden, Krochmal, and Yaroshinsky
J AM ACAD DERMATOL JANUARY 2006
Fig 1. Schematic profile of randomized controlled study.
Fig 2. Mean percent reduction (SE) in inflammatory lesion counts from baseline to week 12 (end of treatment; intentto-treat population). Asterisk, P # .0043 versus combination gel (parametric analysis of variance model with last observation carried forward).
Fig 3. Mean percent reduction (SE) in noninflammatory lesion counts from baseline to week 12 (end of treatment; intent-to-treat population). Asterisk, P # .0004 versus combination gel (parametric analysis of variance model with last observation carried forward).
were not statistically different. Approximately half the subjects were 16 years of age or younger. At baseline, the mean number of total lesions (inflammatory and noninflammatory) was 77.3 per subject. The 12-week treatment period was completed by 1902 subjects (85.7%). Reasons for discontinuation included subject request, adverse experiences, noncompliance, and disease progression (Fig 1).
(Table II). From baseline to week 12 (end of treatment), the percentage reduction in the combination group was significantly higher than in each of the other 3 treatment groups (P \.005; Fig 2). Noninflammatory lesion counts. At baseline, the mean number of noninflammatory lesions was 51.1 (Table II). From baseline to week 12 (end of treatment), the percentage reduction in the combination group was significantly higher than in each of the other 3 treatment groups (P # .0004; Fig 3). Total lesion counts. At baseline, the mean number of total (inflammatory and noninflamma-
Efficacy Inflammatory lesion counts. At baseline, the mean number of inflammatory lesions was 26.2
J AM ACAD DERMATOL
Leyden, Krochmal, and Yaroshinsky 77
VOLUME 54, NUMBER 1
Fig 4. Mean percent reduction (SE) in total lesion counts from baseline to week 12 (end of treatment; intent-to-treat population). Asterisk, P # .0001 versus combination gel (parametric analysis of variance model with last observation carried forward).
Fig 5. Kaplan-Meier curve of the time to 50% reduction in subject’s total lesion counts.
tory) lesions was 77.3 (Table II). From baseline to week 12 (end of treatment), the percentage reduction in the combination group was significantly higher than in each of the other 3 treatment groups (P # .0001; Fig 4). The median time to 50% reduction in total lesion counts was 8 weeks with combination, which was significantly faster than with clindamycin (12 weeks; P \.0001), with tretinoin (12 weeks; P \ .001), and with vehicle (median time not reached; P \ .0001). A Kaplan-Meier analysis of the cumulative percentage of subjects with a 50% reduction in lesion counts at each time point is shown in Fig 5. ISGA scale. At baseline, subjects were required to have an ISGA score of 2 or greater (Table II). Approximately 75% of subjects had a score of 3 or greater. By week 12, the number of subjects who met the criteria for success, grade 0 to grade 1 (Table I), in the combination group was significantly higher than in each of the other 3 treatment groups (P \ .0001; Fig 6). An example of the improvement attained in a typical subject is shown in Fig 7.
Fig 6. Investigator’s Static Global Assessment (ISGA): Percentage of subjects with clear or almost clear skin (success) at week 12 (end of treatment; intent-to-treat population). Asterisk, P # .0001 versus combination gel (Cochran-Mantel-Haenszel test [a = .05] stratified by site with last observation carried forward).
Consistency. When the results reported in the preceding paragraphs as combined data were evaluated as two separate clinical trials, the results were similar across both trials for all primary end points. In each study, 12 comparisons were made between combination treatment and the other 3 treatment groups (clindamycin, tretinoin, and vehicle) with regard to the 4 primary end points (inflammatory, noninflammatory, total lesions, and ISGA score). In one study all 12 comparisons were statistically significant in favor of the combination treatment, and in the other study 11 of 12 were statistically significant in favor of the combination. Table III presents the P values for the primary end points from each individual study. Safety The combination hydrogel was well tolerated, as were the clindamycin hydrogel and tretinoin hydrogel. No adverse experiences were seen in 1943 subjects (87.6%). The most common adverse experiences were at the application site and included dryness, desquamation, burning, erythema, pruritus, sunburn, and irritation. Table IV summarizes the incidences of treatment-related adverse experiences by treatment group. Other application site adverse experiences that occurred in more than one subject included irritation, rash, pigmentation, pain, and swelling. An application site adverse experience was the cause for study withdrawal in 27 subjects (1.2%), including burning in 6 subjects, dryness in 4, rash in 4, and other in 13. Aggravation of depression was the cause for one subject to withdraw. Of those subjects who withdrew because of an adverse experience, 60.7% were in the tretinoin group, and the
78 Leyden, Krochmal, and Yaroshinsky
J AM ACAD DERMATOL JANUARY 2006
Fig 7. Images of typical patient at baseline (A) and after treatment with combination hydrogel at week 12 (B).
Table III. P value of each end point for the two studies individually End point
Study
Combination vs clindamycin
Combination vs tretinoin
Combination vs vehicle
Total lesion counts
One Two One Two One Two One Two
\.0001 .0001 .0503 .0306 \.0001 \.0001 .0002 .0441
\.0001 .0034 \.0001 .0041 .0065 .0121 \.0001 .0108
\.0001 \.0001 \.0001 \.0001 \.0001 \.0001 \.0001 \.0001
Inflammatory lesion counts Noninflammatory lesion counts ISGA
remaining subjects were in the combination group. There were no serious adverse experiences that were related to treatment. Most treatment-related adverse experiences were mild or moderate. Those that were considered severe occurred in the combination and tretinoin treatment groups and included application site burning (2 and 3 subjects, respectively), application site desquamation (3 and 3 subjects, respectively), application site dryness (2 and 1 subjects, respectively), application site erythema (4 and 1 subjects, respectively), application site pruritus (1 and 3 subjects, respectively), application site rash (0 and 1 subjects, respectively), application site swelling (1 and 0 subjects, respectively), and application site vesicles (1 and 0 subjects, respectively).
DISCUSSION These two randomized, double-blind, active drugand vehicle-controlled, multicenter clinical trials compared a combination of clindamycin and tretinoin with each agent alone and vehicle applied once daily for 12 weeks in subjects with grade 2 to grade 5 acne vulgaris (Table I). At the end of treatment, 37% of subjects treated with the combination had clear or almost clear skin as assessed with the ISGA scale; this compares favorably with 27%, 25%, and 14% of subjects achieving this result on clindamycin, tretinoin, and vehicle, respectively. The combination was effective in treating both inflammatory and noninflammatory lesions. In fact, 12 comparisons were made between the combination treatment group and
Leyden, Krochmal, and Yaroshinsky 79
J AM ACAD DERMATOL VOLUME 54, NUMBER 1
Table IV. Incidence of treatment-related adverse experiences (N = 2219) Combination hydrogel
No. of subjects Subjects with treatment-related adverse experience Subjects who withdrew due to adverse experience Application site dryness Application site desquamation Application site burning Application site erythema Application site pruritus Application site sunburn Application site irritation
Clindamycin hydrogel
Tretinoin hydrogel
Vehicle hydrogel
634 119 (19%)
635 34 (5%)
635 107 (17%)
315 16 (5%)
11 (2%)
0 (0%)
17 (3%)
0 (0%)
48 47 41 33 21 5 3
3 2 5 3 6 3 1
57 51 40 35 24 9 6
(9%) (8%) (6%) (6%) (4%) (1%) (1%)
12 2 3 6 7 5 1
(2%) (\1%) (\1%) (1%) (1%) (1%) (\1%)
(8%) (7%) (6%) (5%) (3%) (1%) (\1%)
(1%) (1%) (2%) (1%) (2%) (1%) (\1%)
Subjects reporting a particular adverse experience more than once are counted only once for that adverse experience. Treatment-related experiences are dened as denitely, probably, or possibly related to the study drug.
the other three treatment groups (clindamycin, tretinoin, vehicle) with regard to the 4 primary end points (inflammatory, noninflammatory, and total lesion counts and ISGA score), and all 12 were statistically significant in favor of the combination. In addition, the response time (time to 50% reduction in total lesion counts) was significantly shorter with the combination (8 weeks) as compared with either agent alone (12 weeks) or vehicle. These results were consistent with those of smaller clinical studies of the combination clindamycin/tretinoin hydrogel conducted in Europe.7-10 The present studies substantially expand our understanding of the combination hydrogel by including comparisons with the active ingredients alone and vehicle and by including a much larger study population. Clindamycin is a commonly prescribed topical antibiotic for the treatment of acne and improves symptoms of acne by reducing levels of P acnes and decreasing inflammation.11,12 Topical tretinoin is a commonly prescribed topical retinoid for the treatment of acne and has been for more than 30 years. Tretinoin normalizes follicular desquamation13,14 and slows the desquamation process.15 The development of a hydrogel to stabilize these two efficacious drugs in one formulation at room temperature made it possible to treat multiple causes of acne vulgaris with one product. This may translate into better therapeutic adherence and better outcomes. As with any combination topical product containing retinoids and antibiotics, the disadvantage is that there is a fixed concentration of the two agents, and the flexibility of multiple concentrations of a retinoid is lost. In addition, the flexibility of removing exposure to the antibiotic is gone. The 3 active treatments evaluated in this study were well tolerated, with 88% of subjects showing no
adverse experiences at all. In those subjects treated with tretinoin, 8% developed dryness, 6% had burning, 5% had erythema, and 3% withdrew. In the clindamycin and vehicle groups, 1% to 2% of subjects developed these signs and there were no withdrawals. In the combination group, 2% withdrew, and the rates of dryness and erythema were similar to those seen with tretinoin. Overall, the incidence of irritation and application site reactions in the combination and tretinoin alone groups over the 12-week treatment period was low. This may be a result of formulating the medications in the alcoholfree hydrogel. Further studies are warranted to explore this observation.
CONCLUSIONS The results of these two randomized, controlled clinical trials demonstrate that the fixed combination of clindamycin and tretinoin was well tolerated and resulted in significantly greater improvements in acne vulgaris than either drug alone or the vehicle. This clindamycin/tretinoin combination effectively treated both inflammatory and noninflammatory lesions with a convenient, once-daily application of a hydrogel. We thank the investigators of the Clindamycin/tretinoin Study Group (Appendix) as well as the subjects who participated in the study. REFERENCES 1. Gollnick H, Cunliffe W, Berson D, Dreno B, Finlay A, Leyden JJ, et al. Management of acne: a report from a global alliance to improve outcomes in acne. J Am Acad Dermatol 2003; 49(Suppl):S1-38. 2. Haider A, Shaw JC. Treatment of acne vulgaris. JAMA 2004;292:726-35. 3. Draelos ZK. Patient compliance: enhancing clinician abilities and strategies. J Am Acad Dermatol 1995;32(Suppl):S42-8.
80 Leyden, Krochmal, and Yaroshinsky
J AM ACAD DERMATOL JANUARY 2006
4. Berson DS, Chalker DK, Harper JC, Leyden JJ, Shalita AR, Webster GF. Current concepts in the treatment of acne: report from a clinical roundtable. Cutis 2003;72:4-13. 5. Zaghloul SS, Cunliffe WJ, Goodfield MJ. Objective assessment of compliance with treatments in acne. Br J Dermatol 2005; 152:1015-21. 6. Katsambas AD. Why and when the treatment of acne fails. What to do. Dermatology 1998;196:158-61. 7. Cambazard F. Clinical efficacy of Velac, a new tretinoin and clindamycin gel in acne vulgaris. J Eur Acad Dermatol Venereol 1998;11(Suppl 1):S20-7. 8. Richter JR, Bousema MT, De Boulle KLVM, Degreef HJ, Poli F. Efficacy of a fixed clindamycin 1.2%, tretinoin 0.025% gel formulation (Velac) in the topical control of facial acne lesions. J Dermatolog Treat 1998;9:81-90. 9. Richter JR, Forstrom LR, Kiistala UO, Jung EG. Efficacy of fixed 1.2% clindamycin, 0.025% tretinoin gel formulation (Velac) and a proprietary 0.025% tretinoin gel formulation (Aberela) in the topical control of facial acne. J Eur Acad Dermatol Venereol 1998;11:227-33. 10. Zouboulis CC, Derumeaux L, Decroix J, Maciejewska-Udziela B, Cambazard F, Stuhlert A. A multicentre, single-blind, randomised comparison of a fixed clindamycin/tretinoin gel formulation (Velac) applied once daily and a clindamycin lotion formulation (Dalacin T) applied twice daily in the topical treatment of acne vulgaris. Br J Dermatol 2000;143:498-505. 11. Leyden JJ. Open-label evaluation of topical antimicrobial and anti-acne preparations for effectiveness versus Propionibacterium acnes in vivo. Cutis 1992;49:8-11. 12. Webster GF, Leyden JJ, McGinley KJ, McArthur WP. Suppression of polymorphonuclear leukocyte chemotactic factor production in Propionibacterium acnes by subminimal inhibitory concentrations of tetracycline, ampicillin, minocycline, and erythromycin. Antimicrob Agents Chemother 1982;21:770-2. 13. Bergfeld WF. Topical retinoids in the management of acne vulgaris. J Drug Dev Clin Pract 1996;8:151-60. 14. Kligman AM, Mills OH, McGinley KJ, Leyden JJ. Acne therapy with tretinoin in combination with antibiotics. Acta Derm Venereol Suppl (Stockh) 1975;74:111-5. 15. Chalker DK, Lesher JL Jr, Smith JG Jr, Klauda HC, Pochi PE, Jacoby WS, et al. Efficacy of topical isotretinoin 0.05% gel in acne vulgaris: results of a multicenter, double-blind investigation. J Am Acad Dermatol 1987;17:251-4.
Appendix. List of participating investigators Dan K. Chalker, MD, PC 1505 Winter St #A Augusta, GA 30904 Sunil Dhawan Center for Dermatology Cosmetic and Laser Surgery 2557 Mowry Ave, Suite 34 Fremont, CA 94538 Boni Elewski University of Alabama at Birmingham Department of Dermatology The Kirklin Clinic 2000 6th Ave South Birmingham, AL 35233 Joseph Fowler Dermatology Specialists
444 S First St Louisville, KY 40202 David Fried Omega Medical Research 400 Bald Hill Rd Warwick, RI 02886 Toni Funicella DermResearch, Inc. 8140 N Mopac Building 3, Suite 120 Austin, TX 78759 Michael Gold Tennessee Clinical Research Center 2000 Richard Jones Rd, Suite 220 Nashville, TN 37215 J. John Goodman Radiant Research 2051 45th St, Suite 200 West Palm Beach, FL 33407 Carin Gribetz Mount Sinai School of Medicine Dermatology Department 5 E 98th St 12th Floor, Box 1048 New York, NY 10029 Jo Lynn Herzog Radiant Research 516 Brookwood Blvd., First Floor Birmingham, AL 35209 Terry M. Jones J&S Studies, Inc. 3201 University Dr East, Suite 475 Bryan, TX 77802 Sewon Kang University of Michigan Department of Dermatology 1618 Taubman Health Care Center Ann Arbor, MI 48109-0314 Alexa Kimball Stanford University Department of Dermatology 900 Blake Wilbur Dr, Room W022 Stanford, CA 94305-5334 William Ko Radiant Research Phoenix 333 W Thomas Rd, Suite 100 Phoenix, AZ 85013 Jim Leyden Ivy Labs 3401 Market St, Suite 226 Philadelphia, PA 19104
J AM ACAD DERMATOL
Leyden, Krochmal, and Yaroshinsky 81
VOLUME 54, NUMBER 1
Robert Loss Dermatology Associates of Rochester 100 White Spruce Blvd Rochester, NY 14623 Anne Lucky Dermatology Research Associates 7691 Five Mile Rd, Suite 312 Cincinnati, OH 45230 Steven Mings Radiant Research, Inc. 6565 W Emerald St Boise, ID 83704 Christopher Moeller Compliant Clinical Research, Inc. 250 N Rock Rd, Suite 340 Wichita, KS 67206 Eugene Monroe Advanced Healthcare Clinical Research Center 3003 W Good Hope Rd Milwaukee, WI 53209 Amy Morris Coastal Clinical Research, Inc. 100 Memorial Hospital Dr, Suite 3-B Mobile, AL 36608 Amy Paller Children’s Memorial Hospital Division of Dermatology 2300 Children’s Plaza #107 Chicago, IL 60614 John Proffitt Compliant Clinical Research, Inc. 11805 W 62nd Place, Suite 105 Shawnee, KS 66203 Toivo Rist Dermatology Associates of Knoxville 930 Emerald Ave, Suite 511 Knoxville, TN 37917 Alan Shalita SUNY Brooklyn 450 Clarkson Ave (Box 46) Brooklyn, NY 11203 Joel Shavin Gwinnett Clinical Research Center, Inc. 2383 Pate St Snellville, GA 30078 Linda Stein Henry Ford Health System Department of Dermatology,
Room W1604 2799 W Grand Blvd Detroit, MI 48202 Bruce Strober NYU Medical Center 560 First Ave H-158 New York, NY 10016 James Swan Northwestern University Department of Dermatology 675 N St Clair St, Suite 19-200 Chicago, IL 60611 Leonard Swinyer Dermatology Research Center 3920 South 1100 East, #210 Salt Lake City, UT 84124-1276 Marvin Tankel Atlantic Dermatologic Associates, LLP 10 Peninsula Blvd Lynbrook, NY 11563 Diane Thiboutot M. S. Hershey Medical Center Department of Dermatology 500 University Dr, UPC 2, Room 4300 Hershey, PA 17033-0850 Eduardo Tschen Academic Dermatology Associates 1203 Coal SE, Suite B Alburquerque, NM 87106-5239 Guy Webster Jefferson Medical College Department of Dermatology, Suite 740 833 Chestnut St Philadelphia, PA 19107 David Wilson The Education & Research Foundation 2602 Langhorne Rd Lynchburg, VA 24501-1672 Hector Wiltz FXM Research Corporation 11760 Bird Rd, Suite 451 Miami, FL 33175 John Wolf Jr Baylor College of Medicine, Baylor Dermatology 6560 Fannin, Suite 802 Houston, TX 77030