Topical Benzoyl Peroxide for Acne (Protocol)

Topical benzoyl peroxide for acne (Protocol)

Yang Z, Zhang Y, Lazic Mosler E, Li H, Hu J, Zhang Y, Liu J, Zhang Q

This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2014, Issue 6 http://www.thecochranelibrary.com

Topical benzoyl peroxide for acne (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER...... 1 ABSTRACT ...... 1 BACKGROUND ...... 1 OBJECTIVES ...... 3 METHODS ...... 3 ACKNOWLEDGEMENTS ...... 6 REFERENCES ...... 7 ADDITIONALTABLES...... 9 APPENDICES ...... 12 CONTRIBUTIONSOFAUTHORS ...... 16 DECLARATIONSOFINTEREST ...... 16 SOURCESOFSUPPORT ...... 17

Zhirong Yang1,2, Yuan Zhang3, Elvira Lazic Mosler4, Hang Li5, Jing Hu1, Yanchang Zhang6, Jia Liu7, Qian Zhang8

1Centre for Evidence Based Medicine and Clinical Research, Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China. 2Shantou-Oxford Clinical Research Unit, Shantou University Medical College, Shantou, Guang- dong, China. 3Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada. 4Department for Dermatology and Venereology, General Hospital “Dr. Ivo Pediši ”, Sisak, Croatia. 5Dermatologic Department, Peking University First Hospital, Beijing, China. 6Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA. 7Department of Geriatric Neurology, Chinese PLA General Hospital, Beijing, China. 8c/o Cochrane Skin Group, The University of Nottingham, Nottingham, UK

Contact address: Zhirong Yang, [email protected].

Editorial group: Cochrane Skin Group. Publication status and date: New, published in Issue 6, 2014.

Citation: Yang Z, Zhang Y, Lazic Mosler E, Li H, Hu J, Zhang Y, Liu J, Zhang Q. Topical benzoyl peroxide for acne. Cochrane Database of Systematic Reviews 2014, Issue 6. Art. No.: CD011154. DOI: 10.1002/14651858.CD011154.

ABSTRACT

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of benzoyl peroxide for acne.

BACKGROUND to severe acne constitutes 15% to 20% of all cases (Bhate 2013; Dréno 2010; Law 2010; Wei 2010). Girls are likely to suffer from acne earlier than boys (Archer 2012), but boys appear to be more Description of the condition susceptible to the disease (Halvorsen 2011). Acne may decrease with age, but 64% of people aged 20 to 29 years and 43% of Acne vulgaris is a common, chronic inﬂammatory disease of pi- people aged 30 to 39 years may still have visible acne (Bhate 2013; losebaceous units. It is characterised by increased sebum produc- Schäfer 2001). Globally, acne is the second most disabling skin tion and the formation of comedones, erythematous papules, pus- disease after eczema (Murray 2012). tules and nodules, which may lead to scarring (Archer 2012). For an explanation of the terminology used throughout the text, please refer to the glossary in Table 1. Pathogenesis Multiple factors are involved in the development of acne. An in- Epidemiology creased level of androgens at puberty, greater sebum production Acne vulgaris affects nearly all adolescents and adults at some time and abnormal hyperproliferation of keratinocytes leads to the de- in their lives (Webster 2002). It is estimated that up to 40 to 50 velopment of small microscopic lesions called microcomedones. In million individuals in the USA have acne, with an 85% prevalence this lipid-rich and anaerobic environment Propionibacterium acnes in those aged 12 to 24 years (Bhate 2013; White 1998). Moderate (P. acnes), which is present in normal follicles, proliferates abnor-

Topical benzoyl peroxide for acne (Protocol) 1 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. mally. Conventionally, it is believed that abnormal colonisation be action primarily against comedones (retinoids and salicylic acid) of P. acnes initiates the production of inflammatory and chemo- or against inflammatory lesions (antibacterials and antibiotics). tactic mediators, which drives the inflammatory processes (Brown Benzoyl peroxide is an oxidising agent that is bactericidal for 1998; Burkhart 1999; Cunliffe 2000; Gollnick 2003). There is P. acnes. Besides its primary bactericidal effect on P. acnes, it also evidence suggesting the involvement of inflammation at all also has mild anti-inflammatory, as well as comedolytic activity the stages of acne development (Jeremy 2003; Tanghetti 2013), (Patel 2010; Strauss 2007). Treatment of acne vulgaris with ben- and the exact sequence of events and the interaction between these zoyl peroxide alone or in combination with other topical treat- events and other possible factors (genes, diet, smoking, sunlight, ments (antibiotics, retinoid, salicylic acid or zinc) at concentra- etc.) remains unclear (Williams 2012). tions of 2% to 5% is the standard of care for mild to moderate acne (Bojar 1994; Dutil 2010; Gollnick 2003; Lookingbill 1997; Strauss 2007). The most common fixed-combination products Diagnosis and outcome measures containing benzoyl peroxide are clindamycin with benzoyl peroxide, erythromycin with benzoyl peroxide and adapalene with Clinical diagnosis of acne is usually straightforward. The condition benzoyl peroxide (Layton 2009; Taylor 2004). Besides benzoyl tends to affect the face (99%), the back (60%) and the chest (15%) peroxide, other potentially efficient over-the-counter agents for (Archer 2012), where the lesions are comedones (whiteheads and acne treatment include azelaic acid, alpha-hydroxy acids, resor- blackheads), which are non-inflamed lesions (Simpson 2008). In- cinol, sulphur and zinc, but evidence of their effectiveness from flammatory lesions such as papules, pustules, nodules and cysts randomised controlled clinical trials and studies comparing their may develop after the non-inflamed lesions (Layton 2010). Papules efficacy with other topical treatments is still lacking. and pustules are superficial lesions 5 mm or less in diameter, but There is also an increasingly wide range of non-drug-based ap- they may evolve into deep pustules or nodules in more severe forms proaches that have been developed for treating acne, among of the disease. In conglobate acne, suppurative nodules can extend which low-concentration chemical peels with glycolic, salicylic deeply and over larger areas, forming exudative sinus tracts and or trichloroacetic acid are beneficial for the reduction of come- tissue destruction, resulting in extensive and disfiguring scarring. dones (Kempiak 2008; Rendon 2010). In addition, comedo ex- Classification of acne severity at the time of diagnosis is important tractions, light electrocautery, electrofulguration and cryotherapy because guidelines for subsequent treatment are based on the sever- present other therapeutic options for comedonal acne. In addition, ity of disease (Nast 2012; Strauss 2007; Thiboutot 2009). Acne acne can be treated by photodynamic therapy, utilising topical 5- can be assessed and subsequently classified from two perspectives: aminolevulinic acid together with various light sources (e.g. blue, as objective disease activity based on measurement of the visible red, intense pulsed) or lasers (e.g. pulsed dye, 635 nm red diode), signs of acne by an investigator, or as a patient assessment of the as well as methyl aminolevulinate plus red light. Blue or intense impact on their quality of life (Nast 2012). More than 25 acne pulsed light alone and lasers such as the pulsed dye, the 1320 nm assessment scales have been described and they are inconsistently neodymium:YAG and especially the 1450 nm diode may be of used across different trials (Lehmann 2002). This does not allow therapeutic benefit for inflammatory acne (Rai 2013). For deep, a direct comparison of the results of separate trials (Nast 2012; inflamed nodules and cysts, intralesional injections of corticos- Zarchi 2012). Additionally, grading is a subjective measure that teroids, such as triamcinolone acetate, are beneficial (Levine 1983; may vary from one dermatologist to another (Ramli 2012). In Strauss 2007). clinical trials, assessment of the severity of acne before and after Commercially available over-the-counter preparations of benzoyl the intervention is essential to determine the therapeutic effect peroxide include gels, creams, lotions, soaps and washes, rang- (Zarchi 2012). Grading and lesion counting appear to be most ing from 2.5% to 10% in concentration (Strauss 2007; Zaenglein frequently used for this purpose (Zarchi 2012), as is described in 2006). The choice of vehicle depends largely on skin type and the the revised Leeds acne grading system, which includes numeri- person’s preference (Brown 1998). Irritant dermatitis (erythema, cal grading systems for the back and chest as well as for the face scaling, burning and itching) is the primary limitation of benzoyl (Lehmann 2002). peroxide for some people; this primarily occurs within the first few days of treatment but generally subsides with continued use (Gollnick 2003; Sagransky 2009). However, when in contact with Description of the intervention hair, clothing and other fabrics benzoyl peroxide can cause bleach- ing (Bojar 1995; Sagransky 2009). Treatments for acne target the pathophysiological processes and a wide range of topical and systemic treatments are currently available (Katsambas 2004). Topical therapies, including benzoyl per- How the intervention might work oxide, tretinoin, antibiotics and salicylic acid, can be used for non- inflammatory comedones or mild to moderate inflammatory acne Benzoyl peroxide acts through three fundamental mechanisms: it (Strauss 2007; Thiboutot 2009). The underlying mechanism can is bactericidal to P.acnes, it has mild comedolytic and anti-inflam-

Topical benzoyl peroxide for acne (Protocol) 2 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. matory properties (Dutil 2010; Patel 2010; Strauss 2007), and it is increase anger and anxiety (Layton 2010). Acne itself induces lipophilic, concentrating inside the sebaceous follicles to produce stress, which may also exacerbate the condition (Archer 2012). benzoic acid and reactive oxygen species. By oxidising bacterial Furthermore, acne episodes impose a financial burden on health- proteins, benzoyl peroxide can inhibit protein and nucleotide syn- care providers as well as the person themselves: an acne episode thesis, and mitochondrial activity (Dutil 2010; Fakhouri 2009; costs a total of USD 690 on average, ranging from USD 360 to Krakowski 2008). The response to benzoyl peroxide appears to USD 870 (Gamble 2012; Yentzer 2010). The average cost of a 30- be rapid; it has been shown that significant reductions in surface day supply of a topical treatment depends on the drugs, but ranges and follicular micro-organisms may be obtained after 48 hours from USD 21 to more than USD 100, while generic benzoyl per- treatment with 5% benzoyl peroxide in aqueous gel (Bojar 1995), oxide costs USD 21 to USD 60 per 30-day course of treatment and clinical improvement has been noted as early as five days after (Gamble 2012; Krakowski 2008). The annual direct cost of acne beginning treatment (James 2005). A novel finding is the report management is over USD 2.5 billion and among skin diseases it of a significant reduction in P.acnes within 20 hours of a single ap- ranks second only to the cost of treating skin ulcers and wounds plication of 5% benzoyl peroxide in solution, which implies that (Bickers 2006). the vehicle in topical therapy is important (Ramirez 2006). Multiple treatments for acne have been developed, among which Nowadays, the development of fixed-concentration combinations topical benzoyl peroxide has been recommended for the first-line of agents is the basis of topical treatment of acne. Combinations treatment of mild or moderate acne. of benzoyl peroxide with topical antibiotics or retinoids exert a Evidence from two recently published systematic reviews assess- synergistic effect, allowing several pathogenic factors to be targeted ing the use of benzoyl peroxide for treating acne was insufficient by a single product, which makes them an ideal choice from the to inform clinical practice (Mohd Nor 2012; Seidler 2010). One point of efficacy, tolerability, compliance and decreased bacterial compared the efficacy of 5% benzoyl peroxide, clindamycin with resistance (Gamble 2012). a range of concentrations between 1% and 1.2%, 5% benzoyl Resistance to P. acnes, which commonly develops during peroxide with salicylic acid and a combination of benzoyl perox- monotherapy with topical antibiotics, has not been reported with ide with clindamycin (Seidler 2010). The other focused only on benzoyl peroxide because of its direct toxicity to P.acnes, which is benzoyl peroxide-containing products but restricted the length of due to its ability to inhibit bacterial protein and nucleotide synthe- follow-up to at least six weeks (Mohd Nor 2012). Neither review sis, metabolic pathways and mitochondrial activity (Dutil 2010). gave details about the search strategies they used, nor was it clear This mechanism allows benzoyl peroxide to be used as a long-term whether their outcomes of interest were defined a priori. Further, therapy for acne, either as monotherapy or in combination with there was no third author in either review to act as an arbiter if topical antibiotics, without the hazard of the development of bac- there was a dispute when extracting data from the studies or eval- terial resistance. However, any relationship between skin coloni- uating study quality. sation with antibiotic-resistant P. acnes and treatment outcomes A comprehensive and transparent assessment of the efficacy and remains unclear. safety of topical benzoyl peroxide treatment for acne is important Besides topical antibiotics, topical retinoids (adapalene and and this is what we plan to do in our Cochrane review. We will not tazarotene) are frequently used as combination therapy with ben- apply any restriction on the concentration of benzoyl peroxide or zoyl peroxide. Retinoids regulate the differentiation and prolif- the length of follow-up. We hope to provide sufficient evidence to eration of keratinocytes, and have an anti-inflammatory effect inform physicians when treating people with this skin condition. (Chivot 2005; Williams 2012). However, because benzoyl peroxide oxidises retinoids if applied simultaneously, it has been suggested that it should be used in the morning and the retinoid at night to minimise any possible interaction (Gollnick 2003; Kraft OBJECTIVES 2011). However, modern formulations allow the stable combination of topical retinoids and benzoyl peroxide (Tan 2009). To assess the effects of benzoyl peroxide for acne.

Why it is important to do this review METHODS Effective treatment of this condition is important. Acne is a common skin disease in adolescence, which can cause psychological harm to an individual and the possibility of long-term scarring. It Criteria for considering studies for this review is also an economic burden. More than half of people with acne may experience shame, em- barrassment, anxiety, lack of conﬁdence and impaired social con- Types of studies tact (Bach 1993; Cunliffe 1986; Jowett 1985). Severe acne may

Topical benzoyl peroxide for acne (Protocol) 3 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. We will consider randomised controlled trials (RCTs) with a paral- 3. Change in quality of life (assessed with a validated lel or cross-over design eligible for our review. We will only include instrument such as Skindex-16, Skindex-29 or Cardiff Acne the ﬁrst-phase data from cross-over trials, because of the possibility Disability Index). of the effect of the acne interventions carrying over to subsequent 4. Reduction in P. acnes strains (total and resistant). periods. 5. Total number of adverse events.

Types of participants We will consider participants with a clinical diagnosis by a health- Search methods for identification of studies care practitioner of acne vulgaris on the face or trunk, regardless We aim to identify all relevant randomised controlled trials (RCTs) of age, gender, severity, setting and previous treatment. We will regardless of language or publication status (published, unpub- exclude studies where individuals were diagnosed with rosacea, lished, in press or in progress). chloracne, acne inversa, infantile acne, occupational acne, drug- induced acne and acne associated with polycystic ovary syndrome. Electronic searches Types of interventions We will search the following databases for relevant trials: We will include any treatment regimen of benzoyl peroxide (in- • the Cochrane Skin Group Specialised Register; cluding wash-off and leave-on), dose, duration and vehicle (includ- • the Cochrane Central Register of Controlled Trials ing gel, cream, lotion, etc.) used alone or as any fixed-combination (CENTRAL) in The Cochrane Library; product containing benzoyl peroxide, compared with placebo, no • MEDLINE via OVID (from 1946); treatment or other active topical treatments (such as retinoids, an- • EMBASE via OVID (from 1974); and tibiotics, azelaic acid, salicylic acid, etc.). We will consider compar- • LILACS (Latin American and Caribbean Health Science isons between different formulations and concentrations of ben- Information database, from 1982). zoyl peroxide, if available. We will allow other co-interventions if they were offered equivalently to both groups of the trial. We have devised a draft search strategy for randomised controlled trials (RCTs) for MEDLINE (OVID), which is displayed in Appendix 1. We will use this as the basis for search strategies Types of outcome measures for the other databases listed. We will consider short-term (less than four weeks), medium-term (four or more weeks and less than eight weeks) and long-term (eight weeks or more) follow-up periods for each outcome. Trials registers We will search the following trials registers: Primary outcomes • metaRegister of Controlled Trials (www.controlled- 1. Participant global self assessment of acne improvement. trials.com); • 2. Withdrawal due to adverse effects. US National Institutes of Health Ongoing Trials Register ( www.clinicaltrials.gov); • Australian New Zealand Clinical Trials Registry ( Secondary outcomes www.anzctr.org.au); 1. Change in lesion counts (total, inflamed and non-inflamed, • World Health Organization International Clinical Trials separately). We will define a clinically significant total lesion Registry Platform (www.who.int/trialsearch); and count as more than 10 lesions. According to the number of the • EU Clinical Trials Register (www.clinicaltrialsregister.eu/). lesions, acne severity is graded as follows: mild acne (fewer than 20 comedones, fewer than 15 inflammatory lesions or total lesion count fewer than 30); moderate acne (20 to 100 Searching other resources comedones, 15 to 50 inflammatory lesions or total lesion count 30 to 125); severe acne(more than five cysts, total comedone count more than 100, total inflammatory count more than 50 or total lesion count more than 125) (Lehmann 2002). References from published studies 2. The percentage of participants rated ’clear’ or ’almost clear’ We will check the bibliographies of included primary studies and on the Investigator’s Global Assessment (IGA) scale of acne related (systematic) reviews to identify further references to rele- severity. vant trials.

Topical benzoyl peroxide for acne (Protocol) 4 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Unpublished literature Assessment of risk of bias in included studies We will try to identify unpublished studies and grey literature via Independently, two review authors (ZY, YCZ) will perform as- correspondence with authors and pharmaceutical companies. sessment of risk of bias using the Cochrane Collaboration tool (Higgins 2011). If necessary, we will resolve any disagreement through discussion with a third review author (YZ). Adverse effects We will assign ’low’, ’high’ or ’unclear’ risk of bias for each of the We will not perform a separate search for adverse effects of the tar- following ’Risk of bias’ domains based on the judgement criteria get intervention. However, from the included studies we identify, (Higgins 2011)(Appendix 2): we will critically examine data on adverse effects and the methods 1. random sequence generation; used to collect these. 2. allocation concealment; 3. blinding of participants and personnel; 4. blinding of outcome assessment; Data collection and analysis 5. incomplete outcome data; 6. selective outcome reporting; We plan to include at least one ’Summary of findings’ table in 7. other sources of bias. our review. In this we will summarise the primary outcomes for the most important comparison. If we feel there are several major comparisons or that our findings need to be summarised for dif- Measures of treatment effect ferent populations we will include further ’Summary of findings’ We will express dichotomous outcomes as risk ratios (RR), with tables 95% confidence intervals (CIs). We will express continuous outcomes as mean differences (MD), with 95% CIs. If continuous Selection of studies outcomes are measured with different methodology across studies, we will use standardised mean differences (SMD) with 95% CIs. Two authors (YZ, ELM) will examine the titles and abstracts of We will treat metric scales (ordinal data outcomes) as continuous each reference retrieved in the search to determine those potentially outcomes. related to our review. Based on this first assessment, we will then obtain the full text of these articles to ascertain further whether they will be included in our review. Throughout this process we Unit of analysis issues will select studies independently and resolve any disagreement by We will include cross-over trials; however, only the first phase of referring to a third author (ZY). We will record the reasons for intervention will be included, as we expect that interventions for exclusion of each study and draw a PRISMA flow-chart of study acne may have a lasting effect and there is minimal data on the selection (Liberati 2009; Moher 2009). effectiveness of wash-out periods for the treatment. In the case of within-participant studies, where different treatments have been allocated to different body parts, we will consider the body part as Data extraction and management a unit of analysis. Using standard data extraction templates (Appendix 2), two authors (ZY, JH) will independently extract the data from the full text of eligible studies, with any disagreements being resolved by Dealing with missing data a third author (HL). We will compile the following information We will contact the authors of the included trials to acquire missing from the included studies: information (Appendix 3). We will conduct ITT analysis where 1. publication details (e.g. year, country, authors); data are available, in which case we will analyse all participants 2. study design; in the group to which they were allocated, regardless of whether 3. setting, inclusion and exclusion criteria; or not they received the allocated intervention. When we fail to 4. population characteristics (e.g. age, severity of the acne); obtain missing data for ITT analysis, we will use the method of 5. details of the intervention (e.g. regimen, concentration, last observation carried forward for continuous data if available. duration, co-interventions); For dichotomous data we will conduct sensitivity analysis based 6. outcome measures and corresponding data; on consideration of ’best case’ and ’worst case’ scenarios (Gamble 7. dropouts; 2005). 8. length of follow-up; and 9. type of data analyses (e.g. intention-to-treat (ITT), modified ITT). Assessment of heterogeneity We will use this information to populate the ’Characteristics of We will assess statistical heterogeneity using the I² statistic. When Included Studies’ table for each included study (Appendix 2). the I² statistic is greater than 80%, which indicates substantial

Topical benzoyl peroxide for acne (Protocol) 5 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. heterogeneity, we will only make a narrative description rather We will perform exploratory subgroup meta-analyses (if each sub- than undertake any meta-analysis. When the I² statistic is greater group includes at least three studies) to assess whether the treat- than 50%, we will explore the potential sources of heterogeneity ment effects are different between subgroups. If there are fewer through pre-speciﬁed subgroup analyses, which we have suggested than three studies within each subgroup, we will only conduct in Subgroup analysis and investigation of heterogeneity. a narrative analysis for the treatment effects. Possible subgroups could be as follows: • Disease factors at baseline Assessment of reporting biases ◦ Site (face versus trunk) We will generate funnel plots using the log of the effect measure for ◦ Severity (mild versus moderate versus severe) the individual studies by its standard error to assess reporting bias • Treatment factors for each primary outcome, if more than 10 studies are included ◦ Concentration in the meta-analysis. Additionally, we will perform Egger’s test for ◦ Vehicle the assessment publication bias (Egger 1997). ◦ Co-intervention (with versus without co- interventions)

Data synthesis We expect that clinical heterogeneity will exist across included Sensitivity analysis studies, mainly because of the various tools for grading acne and If possible (at least three studies are included in meta-analysis), we various concentrations and vehicles of benzoyl peroxide, which will perform exploratory sensitivity analyses to examine the treat- may introduce differences in treatment effects across studies. ment effects by excluding studies of low methodological quality Therefore we will use a random-effects model a priori for data (more than three items rated ’high risk’ or ’unclear risk’ using the synthesis of all the outcomes. Cochrane Collaboration tool for assessing risk of bias). For dichotomous outcomes, we will pool risk ratios (RR) and corresponding 95% conﬁdence intervals (CI) from individual studies. For continuous outcomes, we will pool the mean difference (MD) and corresponding 95% CIs from individual studies. In case of ACKNOWLEDGEMENTS continuous outcomes measured with different outcome scales, we will calculate and pool standardised mean differences (SMD) with Many thanks to Laura Prescott, Finola Delamere and Hywel 95% CIs from individual studies. Williams for providing us with useful suggestions on the title reg- We will only make direct comparisons between topical benzoyl istration and the development of the protocol. Many thanks to peroxide (alone or in combination) and placebo, no treatment and Trials Search Co-ordinator, Liz Doney, for helping us revise and other active topical treatments (alone or in combination); indirect establish the search strategy. Many thanks also to other members comparisons are not suitable because we expect that an assumption of the Cochrane Skin Group and all the peer reviewers who con- of consistency is invalid in the current therapeutic ﬁeld of acne. We tributed to our protocol. will not include outcomes that are not considered in our review, The Cochrane Skin Group editorial base wishes to thank Robert but which a study has evaluated, in the analyses but will describe Dellavalle who was the Cochrane Dermatology Editor for this them in a narrative way. protocol; Matthew Grainge and Esther van Zuuren who were the Statistical and Methods Editors, respectively; the clinical referee, Anne Eady; and the consumer referee, who wishes to remain Subgroup analysis and investigation of heterogeneity anonymous.

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ADDITIONAL TABLES

Table 1. Glossary of unfamiliar terms

Term Deﬁnition

Acne inversa A chronic disease of the apocrine glands occurring mainly in the axillae and the groin regions. It is caused by poral occlusion with secondary bacterial infection, evolving into abscesses which eventually rupture. The chronic phase is characterised by ulcers, sinus tracts, ﬁstulas, ﬁbrosis and scarring

Acne vulgaris Chronic acne involving mainly the face, chest and shoulders, which is common in adolescents, and characterised by the intermittent formation of discrete papular and/or pustular lesions, sometimes resulting in scarring

Alpha-hydroxy acids Organic acids, such as glycolic, lactic, citric and mandelic acid, containing a hydroxyl group bonded to the carbon atom adjacent to the carboxylic acid group. They are used in skin care preparations for their exfoliating properties

Androgens A steroid hormone, such as testosterone or androsterone, which controls the development and main- tenance of masculine characteristics. They stimulate sebaceous glands to grow and produce sebum, and therefore cause acne

Azelaic acid Azelaic acid is a natural material that kills bacteria in the skin and decreases the production of keratin. It is used to treat and prevent mild and moderate acne that is caused by bacteria

Bacterial resistance The ability of bacteria to resist the effects of an antibiotic

Benzoyl peroxide An organic compound in the peroxide family used for acne treatment. It works as a peeling agent. It increases skin turnover, clearing pores and reducing the bacterial count (speciﬁcally P.acnes) as well as acting directly as an antimicrobial agent

Clindamycin A lincosamide antibiotic, commonly used for topical treatment of acne

Colonisation The presence of bacteria on a body surface (like on the skin, mouth, intestines or airway) without causing disease in the person

Comedone A blocked pore in the form of a yellow or black bump or plug on the skin

Comedolytic The term used to describe a product or medication that inhibits the formation of comedones. Comedolytic products work by helping the skin to shed more effectively, keeping the pores from becoming plugged

Corticosteroids Any of a class of steroid hormones formed in the cortex of the adrenal gland or chemically similar synthesised hormones that have anti-inﬂammatory properties

Cyst A closed sac, having a distinct membrane compared to the nearby tissue, which may contain air, ﬂuids or semi-solid material

Cytokines A diverse group of soluble molecules important for cell signalling in the generation of an immune response, where they act as intercellular mediators or signalling molecules

Drug-induced acne Acne caused or exacerbated by several types of drugs, such as antiepileptics, halogens and steroids

Differentiation The process by which a less specialised cell becomes a more specialised cell

Eczema An acute or chronic non-contagious inﬂammation of the skin, often caused by allergy and characterised by itching, scaling and blistering

Erythema Blanching reddening of the skin due to local vasodilatation

Erythromycin A macrolide antibiotic, commonly used for topical treatment of acne

Chloracne An acneiform eruption due to exposure to chlorine compounds

Hypercolonisation Abnormal increase in the number of bacteria otherwise normally present on a body surface without causing disease in the person

Infantile acne Acne which presents at the age of two to six months and persists until the age of three to four years

Keratinisation The process of keratin production in order to form an epidermal barrier in stratiﬁed squamous epithelial tissue

Microcomedones Microscopic comedones, not visible to the naked eye

Nodule A deep skin-seated dome-shaped solid lump

Occupational acne Acne causes by exposure to extraneous agents or adverse conditions in a working environment. The agents and conditions that most commonly cause problems are: oils, tars or excessive humidity

Papule Small, solid, raised lesion, usually dome-shaped

Pilosebaceous unit The hair follicle and sebaceous gland

Polycystic ovarian syndrome A condition caused by the imbalance of female sex hormones. It is associated with absence of ovulation resulting in irregular menstrual cycles and infertility, insulin resistance causing obesity, as well as high levels of masculinising hormones causing excessive hair growth and acne

Pustule A visible collection of pus

Reactive oxygen species Chemically reactive molecules containing oxygen. Increased levels of reactive oxygen species may result in signiﬁcant damage to cell structures, which is called an oxidative stress

Resorcinol A dihydroxy benzene compound used in many acne treatment products. It helps prevent comedones by removing buildup of dead skin cells

Retinoids A class of chemical compound related chemically to vitamin A, topically used for acne treatment due to the way they regulate the epithelial cell growth

Rosacea A chronic dermatitis of the face, especially of the nose and cheeks, characterised by a red or rosy coloration, caused by dilation of capillaries, and the appearance of acne-like pimples

Sebaceous glands Glands that produce sebum and deliver it to the surface of the skin. They are larger and greater in number on the face and upper parts of the trunk, which makes these the acne-prone areas

Sebum An oily substance produced by the sebaceous glands of the skin. Its main function is to protect and waterproof the hair and skin. Oily skin and acne are the result of excessive sebum production

Scar The ﬁbrous tissue replacing normal tissues destroyed by injury, disease or surgery

Sodium sulphacetamide A sulphonamid antibiotic used topically for ﬁghting bacteria on the skin in the treatment of acne, dandruff and seborrhoeic dermatitis

Tetracycline A broad-spectrum antibiotic synthesised from chlortetracycline or derived from certain micro-organisms of the genus Streptomyces

Topical therapy A medication in the form of a cream, foam, gel, lotion or ointment, which is applied to body surfaces in order to treat ailments

APPENDICES

Appendix 1. MEDLINE (OVID) search strategy 1. exp Acne Vulgaris/ 2. acne.mp. 3. 1 or 2 4. exp Benzoyl Peroxide/ 5. benzoyl peroxide$.ti,ab. 6. peroxide dibenzoyl.ti,ab. 7. dibenzoyl peroxide.ti,ab. 8. benzoyl superoxide.ti,ab. 9. panoxyl.ti,ab. 10. diphenylglyoxal superoxide.ti,ab. 11. benzoperoxide.ti,ab. 12. or/4-11 13. randomized controlled trial.pt. 14. controlled clinical trial.pt. 15. randomized.ab. 16. placebo.ab. 17. clinical trials as topic.sh. 18. randomly.ab. 19. trial.ti. 20. 13 or 14 or 15 or 16 or 17 or 18 or 19 21. exp animals/ not humans.sh. 22. 20 not 21 23. 3 and 12 and 22

Methods Study design: parallel/cross-over design Duration of follow-up:

Participants Inclusion criteria: Exclusion criteria: Diagnostic criteria: Treatment before study: Sex: [male %] Age: [mean (SD)/range years, or as reported] Sites of acne: Duration of acne: [mean/range years (SD), or as reported] Severity of acne and corresponding criteria of judgement:

Interventions Topical treatment: Combination: yes (specify)/no Regimen: wash-off/leave-on Concentration: Vehicle: gel/cream/lotion/other (specify) Dose: Duration: Co-interventions:

Control Topical treatment: no treatment/placebo/active treatments (specify) Regimen: wash-off/leave-on Concentration: Vehicle: gel/cream/lotion/other (specify) Dose: Duration: Co-interventions:

Outcomes Deﬁnition: Time point of measurement: Number of event (percentage) in each group: Effect size:

Study details Study period: Country: Setting: Number of study centres: Study terminated before regular end (for beneﬁt/because of adverse events): yes/no

Publication details Language of publication: Funding: commercial/non-commercial/other funding Publication status: full article/journal supplement/conference paper/other (specify)

Stated aim for study Quote from publication: “...”

Notes Abbreviations:

Risk of bias table

Bias Criteria for judgement Authors’ judgement Support for judgement

Random sequence generation Low risk: any one of the follow- Quote from publication: “...” (selection bias) ing random sequence genera- Comment: ... tions: a random number table, a computer random number gen- erator, coin tossing, shufﬂing cards or envelopes, throwing dice, drawing of lots, or min- imisation High risk: any one of non- random sequence generations (other methods except those suggested as low risk) Unclear risk: insufﬁcient information to permit judgement of ’low risk’ or ’high risk’

Allocation concealment (selec- Low risk: allocation based on Quote from publication: “...” tion bias) any one of the following meth- Comment: ... ods: central allocation, sequen- tially numbered drug contain- ers of identical appearance, se- quentially numbered, opaque, sealed envelopes High risk: allocation based on any other methods (other methods except those suggested as low risk) Unclear risk: insufﬁcient information to permit judgement of ’low risk’ or ’high risk’

Blinding of participants and Low risk: blinding of partici- Quote from publication: “...” personnel (performance bias) pants and key study personnel, Comment: ... and unlikely that the blinding could be broken High risk: no blinding or incomplete blinding, or blinding of participants and key study

personnel could be broken Unclear risk: insufﬁcient information to permit judgement of ’low risk’ or ’high risk’

Blinding of outcome assess- Low risk: blinding of outcome Quote from publication: “...” ment (detection bias) assessment and unlikely that the Comment: ... blinding could be broken High risk: no blinding or incomplete blinding, or blinding of outcome assessment could be broken Unclear risk: insufﬁcient information to permit judgement of ’low risk’ or ’high risk’

Incomplete outcome data (at- Low risk: any one of the fol- Quote from publication: “...” trition bias) lowing situations: no missing Comment: ... outcome data, missing outcome data (proportion of loss of follow-up ≤ 10%) balanced in numbers across intervention groups with similar reasons, or missing data have been imputed using data complement or ITT High risk: any other situation except those suggested above Unclear risk: insufﬁcient information to permit judgement of ’low risk’ or ’high risk’

Selective reporting (reporting Low risk: the study protocol is Comment: ... bias) available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the protocol have been reported in the pre-specified way High risk: any other situation except those suggested above Unclear risk: insufficient information to permit judgement of ’low risk’ or ’high risk’

Other sources of bias We will assess the baseline char- Comment: ... acteristics (e.g. age, gender, duration, location, severity, previous treatment) imbalance between groups

Low risk: no statistical signifi- cance (P ≥ 0.05) of baseline imbalance for each characteristic High risk: statistical signifi- cance (P < 0.05) of baseline imbalance for each characteristic Unclear risk: insufficient information to permit judgement of ’low risk’ or ’high risk’

Appendix 3. Survey of authors providing information on trials

Characteristic Study author contacted Study author replied Study author asked for Study author provided Study ID additional information data

Study 1

Study 2

Study 3

Footnotes n: no; y: yes

CONTRIBUTIONSOFAUTHORS ZY was the contact person with the editorial base. ZY co-ordinated the contributions from the co-authors and wrote the final draft of the protocol. ZY, YZ, ELM and JH worked on the methods sections. ZY, HL, ELM and JL drafted the clinical sections of the background and responded to the clinical comments of the referees. ZY, YZ and YCZ responded to the methodological and statistical comments of the referees. All the authors contributed to writing the protocol. QZ was the consumer co-author and checked the protocol for readability and clarity. She also ensured that the outcomes are relevant to consumers. ZY is the guarantor of the final review. Disclaimer The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health, UK.

Topical benzoyl peroxide for acne (Protocol) 16 Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. DECLARATIONSOFINTEREST Zhirong Yang: Nothing to declare. Yuan Zhang: Nothing to declare. Elvira Lazic Mosler: Nothing to declare. Hang Li: Nothing to declare. Jing Hu: Nothing to declare. Yanchang Zhang: Nothing to declare. Jia Liu: Nothing to declare. Qian Zhang: Nothing to declare.

SOURCES OF SUPPORT

Internal sources • Peking University Health Science Center, China. • Shantou-Oxford Clinical Research Unit, China.

External sources • Cochrane Skin Group, UK. • The National Institute for Health Research (NIHR), UK. The NIHR, UK, is the largest single funder of the Cochrane Skin Group.