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TherapeuTics for The clinician A Multicenter, Double-blind Study to Evaluate the Efficacy and Safety of 2 Treatments in Participants With Mild to Moderate Acne VulgarisZoe Diana Draelos, MD; Alan R. Shalita, MD; Diane Thiboutot, MD; Christian Oresajo, PhD; Margarita Yatskayer; Susanna Raab Acne treatment regimens have changed due to the peroxide (BPO) generally are regarded as safe and recent over-the-counter (OTC) switch of all pre- effective,1 which led to the movement from the scription benzoyl peroxide (BPO) topical prepara- prescription realm to the over-the-counter (OTC) tions. The elimination of prescription single-agent market. The movement has increased the need for BPO products means that dermatologists must quality OTC BPO preparations to use as sole therapy select from a variety of OTC formulations to utilize in individuals with mild acne and in combination the time-tested efficacy of BPO in the treatment with prescription therapy in individuals with mild to of mild to moderate acne. Our research compared moderate acne. Most of the BPO preparations previ-the efficacy and safety of an OTC BPO 5.5% ously sold in the OTC market were based on the acne Do Not Copy
formulation with lipohydroxy acid and tretinoin monograph,1 but efficacy testing was not commonly cream 0.025% with prescription clindamycin 1%– performed. The preparations were assumed to be effi-BPO 5% gel and tretinoin cream 0.025%. Parity cacious based on the active BPO ingredient, which was demonstrated between the 2 treatment regi- plays an important role in the treatment of acne. mens at 12 weeks. The most effective and most commonly used active ingredient in OTC acne preparations is BPO. Twenty-three percent of acne patients aged he paradigm for acne treatment has changed 13 to 27 years have used an OTC BPO product.2 since the US Food and Drug Administration Benzoyl peroxide is a member of the organic perox- determined that preparations with 10% benzoyl ide family consisting of 2 benzoyl groups joined by a peroxide group. It has many properties pertinent to Dr. Draelos is from the Department of Dermatology, Duke University acne including antibacterial, anti-inflammatory, and School of Medicine, Durham, North Carolina. Dr. Shalita is from the Department of Dermatology, State University of New York (SUNY), comedolytic effects.3 When BPO touches the skin, it Brooklyn. Dr. Thiboutot is from the Department of Dermatology, breaks down into benzoic acid and oxygen, neither Pennsylvania State University College of Medicine, Hershey. of which is problematic. It has antimicrobial proper- Dr. Oresajo, Ms. Yatskayer, and Ms. Raab are from L'Oréal USA, Inc, ties against Propionibacterium acnes as demonstrated Clark, New Jersey. by a log10 2 decrease in P acnes concentration follow- This study was sponsored by an unrestricted educational grant from La Roche-Posay Laboratoire Dermatologique. Dr. Draelos ing 2 days of topical BPO 5% application.4 However, received an educational grant from L'Oréal USA, Inc, and unlike topical antibiotics, BPO does not induce La Roche-Posay Laboratoire Dermatologique. Drs. Shalita and resistant organisms.5 Even a BPO cleanser can sup- Thiboutot are investigators for La Roche-Posay Laboratoire press the development of resistant organisms.6 Dermatologique. Dr. Oresajo, Ms. Yatskayer, and Ms. Raab are Benzoyl peroxide also acts as an anti-inflammatory employees of L'Oréal USA, Inc. Correspondence: Zoe Diana Draelos, MD, 2444 N Main St, agent by reducing oxygen radicals. Furthermore, High Point, NC 27262 ([email protected]).
its ability to reduce the P acnes population also VOLUME 89, JUNE 2012 287 Copyright Cutis 2012. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher.
Therapeutics for the Clinician reduces the activation of toll-like receptor 2 on the were masked to conceal their identity from both surface of monocytes, leading to reduced secretion the participants and the investigators. Following of proinflammatory cytokines such as tumor necrosis 12 weeks of product application, participants were factor , IL-1, and IL-8.7 This anti-inflammatory asked to discontinue their acne treatment and enter effect is perceived by the consumer as reduced red- a 4-week no-treatment phase known as a regression ness and pain.
phase to determine the degree of acne relapse.
Benzoyl peroxide is capable of producing a 10% Assessments—A variety of assessments were made reduction of comedones in clinical trials.4 Higher- at baseline and weeks 2, 4, 8, and 12, with the regres- concentration BPO preparations were originally sion phase assessment at week 16 in all enrolled thought to provide superior antiacne effects; how- study participants. The 3 board-certified investiga- ever, it now appears that even BPO 2.5% is effective tors were asked to blindly assess the participants in improving acne.8 for tolerability (ie, erythema, edema, dryness, peel- Current trends in BPO formulations have ing) on a 4-point ordinal scale (0none; 1mild; focused on the use of less irritating hydrogel for- 2moderate; 3severe). In addition, lesion counts mulations and smaller particle size BPO.9 Raw BPO were performed of the entire face including the nose is a large particulate that is not water soluble. The for open comedones, closed comedones, papules, pus- bulk of BPO in most formulations remains on the tules, noninflammatory lesions, inflammatory lesions, surface of the stratum corneum. It is only the dis- and total lesions. The investigators also assessed the solved BPO that reaches target areas in the skin and facial skin for skin tone (clarity), skin smoothness, follicle where it is active in killing P acnes. Smaller skin brightness, appearance of pores, overall appear- particle size allows better skin coverage with less ance, and global acne assessment on a 10-point visual irritation, as it affords the opportunity to reduce analog scale with 0 indicating a favorable rating the concentration of BPO. Careful creative formu- and 9 indicating an unfavorable rating. Participant lation can minimize tolerability issues with OTC irritation assessments (stinging, tingling, itching, BPO formulations.
burning) also were captured on a 4-point ordinal We conducted a 12-week, multicenter, double- scale (0none; 1mild; 2moderate; 3severe) blind study to compare the efficacy and safety of and standardized facial photography was conducted 2 acne regimen treatments (randomized in a with a 3-point head restraint of the front, right, 1:1 ratio) in patients with mild to moderate and left face to document the presence of partici- acne. One treatment regimen included an pants at the research center. The photographs were OTC formulation containing BPO 5.5% with not used for any efficacy assessments, as images can- Do Not Copy
lipohydroxy acid applied twice daily and treti- not duplicate the accuracy of real-time acne counts.
noin cream 0.025% applied at bedtime. The Statistical Analysis—Data obtained from other treatment regimen consisted of pre- the efficacy and tolerability evaluations were col- scription clindamycin 1%–BPO 5% gel applied lected from all of the testing centers and statistically twice daily and tretinoin cream 0.025% applied compared between baseline and weeks 2, 4, 8, 12, and/or 16 using paired t tests or Wilcoxon signed rank tests. Changes from baseline were considered significant at .05. Mean percentage change from Study Design and Treatment—Sixty-six participants baseline was reported for all attributes. Paired t tests aged 18 to 50 years were enrolled in this multicenter, or Wilcoxon signed rank tests were applied to deter- double-blind, institutional review board–approved, mine the differences between the 2 treatments.
12-week study. There were 3 research sites: Dermatology Consulting Services, High Point, Results
North Carolina; State University of New York, Sixty-six participants were randomized and 60 par- Brooklyn; and Pennsylvania State University ticipants completed the trial. Of the 60 partici- College of Medicine, Hershey. Participants were pants, 26 received treatment A and generic tretinoin randomized to treatment A or treatment B in a cream 0.025% and 34 received treatment B and 1:1 ratio. Treatment A consisted of an OTC generic tretinoin cream 0.025%. The study popu- BPO 5.5% preparation with lipohydroxy acid lation was comprised of all ethnicities (32 white; applied twice daily and tretinoin cream 0.025% 6 Hispanic; 2 Asian; 26 black); there were 54 female applied at bedtime. Treatment B consisted of the participants and 12 male participants enrolled. Fol- commonly prescribed clindamycin 1%–BPO 5% gel lowing the 12-week active treatment period, treat- (BenzaClin) applied twice daily and tretinoin ment was discontinued. Participants refrained from cream 0.025% applied at bedtime. Product labels other acne treatments and were reexamined after the Copyright Cutis 2012. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher.
Therapeutics for the Clinician Table 1. Mean Scores on the Visual Analog Scale for Clinical Grading for Efficacy ParametersaParameterb Skin tone (clarity) Appearance of pores Treatment A Overall appearance aTreatment A consisted of benzoyl peroxide 5.5% with lipohydroxy acid applied twice daily and tretinoin cream 0.025% applied at bedtime.
Treatment B consisted of clindamycin 1%–benzoyl peroxide 5% gel applied twice daily and tretinoin cream 0.025% applied at bedtime.
bRated using the visual analog scale with 0 indicating a favorable rating and 9 indicating an unfavorable rating. 4-week regression phase to determine how long the a statistically significant reduction in noninflamma- Do Not Copy
acne was controlled following cessation of treatment. tory and inflammatory lesion counts at treatment A total of 57 participants completed the regression weeks 4, 8, and 12, and during the regression phase phase. The study was initiated in September 2010 and at week 16 as compared with baseline (P.05). was completed in August 2011.
Treatment B showed a statistically significant reduc- Efficacy—The mean ordinal scores for the tion in open comedones at week 2 (P.05) that was investigator efficacy assessment are summarized in not observed with treatment A; however, treatment A Table 1. There was statistically significant improve- showed a statistically significant reduction in pus- ment compared with baseline in all scores for both acne tules at week 2 (P.05) that was not seen with treatment regimens at weeks 4, 8, and 12 (P.05). treatment B. Again, parity was established by the Statistically significant improvement was main- 2 treatments from week 4 onward.
tained for both groups compared with baseline at Tolerability—Tables 3 and 4 summarize the toler- the end of the 4-week no-treatment regression phase ability assessments of both treatment formulations. (P.05). Some differences between treatment A Treatment B produced a statistically significant and treatment B were noted at week 2. Treatment B increase in investigator-assessed erythema compared showed statistically significant improvement in skin with baseline at week 2 (P.042) that was not brightness (P.05). Treatment B also showed a sta- seen in treatment A. Compared with baseline, tistically significant reduction in the appearance of a statistically significant increase in dryness and pores at week 2 when evaluated by the investigator peeling was noted in both treatment A and (P.05), while treatment A did not reach statisti- treatment B as expected during the early phases cal significance. Parity between the 2 treatments of retinization (dryness: week 2, P.004 and was established from week 4 onward compared P.001, respectively; peeling: week 2, P.001 and with baseline.
P.002, respectively; week 4, P.039 and P.013, Mean scores of facial lesion counts are summa- respectively). By week 12, increase in dryness rized in Table 2. Both treatment regimens produced and peeling had resolved when assessed by the VOLUME 89, JUNE 2012 289 Copyright Cutis 2012. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher.
Therapeutics for the Clinician Table 2. Mean Scores on Facial Lesion CountsaParameter Week 2 Week 4 Week 8 Week 12 Week 16 Inflammatory lesions aTreatment A consisted of benzoyl peroxide 5.5% with lipohydroxy acid applied twice daily and tretinoin cream 0.025% applied at bedtime.
Treatment B consisted of clindamycin 1%–benzoyl peroxide 5% gel applied twice daily and tretinoin cream 0.025% applied at bedtime.
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investigator. In addition, no increase in erythema formulations, which can be recommended by derma- was present as the facial skin had adapted to the tologists and other healthcare providers. Many OTC formulations exist that can be purchased through The participant-assessed tolerability presented mass merchandisers, direct sales, and infomercial in Table 4 showed a statistically significant increase marketing, yet few have been tested against prescrip- with both treatment A and treatment B in sting- tion counterparts in treatments that include tretinoin ing (both P.001), tingling (P.007 and P.001, cream 0.025%. Because dermatologists frequently respectively), itching (P.027 and P.007, respec- combine the antibacterial benefits of BPO with the tively), and burning (both P.001) compared with benefits of tretinoin to target noninflammatory and baseline at week 2. The symptoms persisted at inflammatory lesions, this regimen seemed worth- week 4, with the exception of an insignificant dif- while to study in participants with mild to moderate ference in itching in both treatments and in tingling acne. The OTC BPO and prescription BPO formu- for treatment A when compared with baseline. lations demonstrated parity for efficacy and toler- Participant-assessed irritation had largely resolved ability when used in a treatment regimen containing by week 8 in both groups. tretinoin cream 0.025%. Both BPO products were of The data demonstrated parity between the 2 treat- similar particle size and composition.
ments for investigator-assessed and participant- There are several unique attributes of the OTC BPO formulation that merit further discussion. The BPO 5.5% formulation used in treatment A contained other antiacne ingredients, such as sali- The recent movement of all single-agent BPO cylic acid and lipohydroxy acid. Salicylic acid is products from the prescription realm to the OTC an antiacne active ingredient that can be used realm has created a need for quality OTC BPO in concentrations up to 2% according to the Copyright Cutis 2012. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher.
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olerability (Investigator Assessed) es of Objective T VOLUME 89, JUNE 2012 291 Copyright Cutis 2012. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher.
Therapeutics for the Clinician consisted of clindam applied at bedtim Do Not Copy
ice daily and tretinoin cream applied at bedtim ith lipohydroxy acid applied tw olerability (Participant Assessed) ice daily and tretinoin cream es of Subjective T consisted of benzoyl peroxide 5.5% ith baseline.
ated on a 4-point scale (0 Copyright Cutis 2012. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher.
Therapeutics for the Clinician US Food and Drug Administration acne monograph.1 improvement. This formulation has the additive ben- It is a colorless, crystalline, oil-soluble, phenolic efit of lipohydroxy acid, which may provide enhanced compound originally derived from the willow comedolytic effects over the BPO alone.
tree.10 Salicylic acid, a -hydroxy acid also known as 2-hydroxybenzenecarboxylic acid, can penetrate REFERENCES
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