Topical retinoids for acne vulgaris (Protocol)
`
`Naito A, Ovaisi A, Ovaisi S, Roberts IG
`
`THE COCHRANE
`COLLABORATION®
`
`This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane
`Library 2008, Issue 3
`
`http://www.thecochranelibrary.com
`
`( W!LEY
`
`s Since 1807
`
`Topical retinoids for acne vulgaris (Protocol)
`Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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`1 of 13
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`Almirall EXHIBIT 2029
`Anmeal v. Almirall
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`TABLE OF CONTENTS
`HEADER .......................................
`ABSTRACT ......................................
`BACKGROUND ....................................
`OBJECTIVES .....................................
`METHODS ......................................
`ACKNOWLEDGEMENTS ................................
`REFERENCES .....................................
`APPENDICES .....................................
`HISTORY .......................................
`CONTRIBUTIONS OF AUTHORS .............................
`DECLARATIONS OF INTEREST ..............................
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`[Intervention Protocol]
`Topical retinoids for acne vulgaris
`
`Ayumi NaitoI, Ayesha Ovaisi2, Shazia Ovaisi3, Ian G Roberts4
`
`1japan Green Medical Centre, London, UK. 2Business Management, hnperial College, Middlesex, UK. 3Department of General
`Practice, Northwick Park Hospital, Harrow, UK. 4Nutrition & Public Health Intervention Research Unit, London School of Hygiene
`& Tropical Medicine, London, UK
`
`Contact address: Ayumi Naito, Japan Green Medical Centre, Unit 7, Acton Mews, 310.328 Uxbridge Road, London, W3 9QN, UK.
`ayumi0709@hotmail.com.
`
`Editorial group: Cochrane Skin Group.
`Publication status and date: New, published in Issue 3, 2008.
`
`Citation: Naito A, Ovaisi A, Ovaisi S, Roberts IG. Topical retinoids for acne vulgaris. Cochrarle Database of Systematic Reviews 2008,
`Issue 3. Art. No.: CD007299. DOI: 10.1002/14651858.CD007299.
`
`Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`This is the protocol for a review and there is no abstract. The objectives are as follows:
`
`To assess the effects of topical retinoids in the treatment of acne.
`
`ABSTRACT
`
`Topical retinoids for acne vulgaris (Protocol) I
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`BACKGROUND
`
`Description of the condition
`
`c) hypercolonization of the pilosebaceous duct by the bacteria
`
`Prwionibacterium acnes (P.acne~9;
`
`d) direct or indirect inflammation due to the release of pro inflam-
`
`matory mediators from Eacnes resulting in an inmmne response
`
`Ache vulgaris (which we refer to as ache for the purpose of this
`
`(Millikan 2003).
`
`review) is a common skin disease of the pilosebaceous gland, which
`
`As well as these primary factors, some other factors such as genetic
`
`produces oil to keep the skin lubricated. Acne typically begins in
`
`factors, stress, diet, smoking, sex (male) and age (youth) have been
`
`puberty, affecting about 80% ofadolescents andyoung adults, but
`
`suggested to affect the ache condition (Haider 2004; Krautheim
`
`may also arise in adulthood, affecting 8% of those aged 25 to 34
`
`2004), however their relationships with ache have not been proven
`
`and 3% of those aged 35 to 44 (White 1998). It is estimated that
`
`so far. It has been suggested that ache treatment should be directed
`
`approximately 3.5 ntillion people with ache consult their family
`
`at these pathogenetic factors, and preferably be combined in order
`
`doctor annually in the UK (Purdy 2006) and in the US, about 40
`
`to target as many factors as possible (Gollnick 2003).
`
`to 50 ntillion people are affected by some form of ache (White
`
`1998). Ache lesions are most likely to occur on the face, neck,
`
`upper trunk (chest and back) and upper arms where there is a high
`
`Conventional treatments
`
`density ofpilosebaceous glands producing sebum. Ache lesions can
`
`Conventional ache treattnents work by either preventing the pi-
`
`often leave permanent marks, hyper-pigmentation, less frequently
`
`losebaceous duct from beconfing blocked at its follicular opening,
`
`hypertrophic scars, keloids and pitted scars (Longshore 2003).
`
`reducing the numbers of ache bacteria or controlling excess sebum
`
`production (Goulden 2003). Most treattnents work on a combi-
`
`nation of these factors. Many anti-ache drugs also have an anti-
`
`Impact
`
`inflammatory effect.
`Although ache is not a life-threatening condition, it can cause However, a drawback of conventional treatments is that they are
`substantial morbidity. Ache and resulting scarring can have a psy- mostly palliative, in that they control the symptoms, rather than
`chological impact including lowered self-image and self-esteem,
`
`cure the condition. In fact, ache usually resolves as people grow
`
`social impairment and anger (Koo 1995). Even those with ntin-
`
`older, rather than because of treattnent. Widely used conven-
`
`imal ache experience psychological effects and for those people,
`
`tional treatments include retinoids, antibiotics and benzoyl per-
`
`the psychosocial burden may be the most significant problem with
`
`oxide. Oral contraceptives, which contain an estrogen and a pro-
`
`this disease. (Koo 1995) It has been shown that even clinically
`
`gesterone, may also be helpful in women (Arowojolu 2004). Oral
`
`nfild to moderate ache can be associated with higher rates of de-
`
`isotretinoin is the only ache treatment available that ntight be con-
`
`pression and suicidal thoughts than other chronic and disfiguring
`
`sidered curative, it is used in severe ache when standard treatment
`
`skin diseases (Gupta 1998). Adolescents, who are developing their
`
`has failed, but still a proportion of people do not respond, and
`
`self-identity and are undergoing rapid sexual maturation, are often
`
`a substantial nmnber of people relapse and require further treat-
`hormonally and emotionally unstable, so are particularly vulner- ment (Layton 1992; Leyden 1997). Oral isotretinoin also can very
`able to the psychological impact. Another group at risk of psy-
`
`rarely have psychiatric effects such as depression leading to suicide
`
`chological effects due to ache is women, aged 25 to 40, who face
`
`(Charakida 2004).
`
`such issues as motherhood, adult sexuality and career demands.
`
`Currently, there is an emerging interest in light therapies for ache.
`Ache can add an enormous burden to this group (Richard 2006). Many of these use the healing properties of light of different wave-
`Furthermore, it has been shown that there is more unemployment
`
`lengths and treattnents include lamps and lasers as well as photo-
`
`among adults with acne in the UK (Cunliffe 1986). In smnmary,
`
`dynamic therapy (Ross 2005; Rotunda 2004). Some researchers
`
`ache is an important condition and appropriate intervention is
`
`propose diverse light therapies as a new treatment, however, there
`
`essential to prevent complications such as ache scarring, psycho-
`
`have been few randontised trials of the effects of these treatments
`
`logical impacts and secondary impaired social function
`
`and outcomes of existing trials are contradictory (Mariwalla 2005).
`
`Although there may be some grounds to be cautiously optintistic
`
`Causes about the role of light, lasers and radio frequency devices in acne
`management, establishing further evidence is critical.
`
`It is not fully understood what causes acne. The acne lesion begins
`
`with the nticro-comedo, a nticroscopic precursor of all the acne
`
`lesions. A therapeutic goal therefore is to stop these lesions from
`
`forming (microcomedogenesis.) (Cunliffe 2003) It is believed that
`
`Description of the intervention
`
`the interaction of the following four factors contributes to the
`
`Topical retinoids, which in the past were prescribed mostly for
`
`development of acne:
`
`people with mainly comedonal acne, are now considered to be a
`
`a) excess build-up of keratin in the pilosebaceous follicles;
`
`first-line treattnent for all types of acne including inflammatory
`
`b) excessive sebum production;
`
`acne due to their anti-inflammatory actions (Gollnick 2003). De-
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`¯ 0.025%, 0.01%, 0.05%, 0.1%, and 0.4% cream;
`¯ 0.025% gel; a 0.05%, 0.1%, and 0.2% solution;
`¯ 0.1% lotion; a 0.05% ointment; 0.05% in compresses;
`¯ 0.1% gel microsphere: and a 0.025% polymer cream.
`
`pending on the severity of the acne, retinoids are used either alone
`as monotherapy or in combination with other topical and systemic
`drugs (Zaenglein 2006). Retinoids are also suitable for a mainte-
`nance treatment because they prevent micro-comedones, and thus
`new lesions from forming. (Goulden 2003; Zane 2006).
`Retinoids are a class of chemical compounds derived from vitamin Other reported problems include delayed and variable improve-
`A (retinol). There are three generations of retinoids which have ment, photosensitivity and exacerbation of acne after wvo to four
`different chemical structures:
`weeks "pustular flare" (demonstrated by the initial hydroalcoholic
`1. the non aromatics;
`fornmlation of tretinoin) (Krautheim 2004).
`2. the mono aromatics;
`3. the poly aromatics.
`The new synthetic retinoids e.g. third generation retinoids bear
`little structural resemblance to retinol, but they still have the abil-
`ity to bind with retinoid receptors and are thus included in this
`family (Sardana 2003). Several types of topical retinoids are avail-
`able for acne treatment. The most common options in Europe or
`the US include tretinoin, isotretinoin, adapalene and tazarotene:
`in some countries, motretinide, retinaldehyde and beta-retinoyl
`glucuronide are also approved for acne treatment (Zane 2006).
`
`Isotretinoin
`
`Topical isotretinoin ( 13-cis retinoic acid) is considered to have
`similar effects to tretinoin on acne lesions. It is available as a 0.05%
`gel and a 0.01% cream (Krautheim 2004). It has very different
`effects from oral isotretinoin which exerts a sebum-suppressive
`effect (Karlsson 2003). Topical isotretinoin does not reduce sebum
`secretion.
`
`Adapalene
`
`How the intervention might work
`
`Adapalene, a naphthoic acid, is a third-generation retinoid. Studies
`have shown that it shares some of the biological characteristics of
`tretinoin (Cunliffe 1997; Cunliffe 2002). Some additional prop-
`erties such as increased chemical and light stability, rigidity, and
`high lipophilicity are purported to cause reduced risk of photo-in-
`stability and local skin irritation, possibly enhancing compliance.
`In addition, adapalene is not very well absorbed from the skin
`and is partitioned into the lipid environment of the pilosebaceous
`duct, the target area. It is available as a 0.1% gel, solution, and
`cream (Krautheim 2004; Millikan 2000).
`
`Topical retinoids have several mechanisms of action and address
`several of the four primary factors in acne pathogenesis. Topical
`retinoids regulate excess build-up of keratin in the pilosebaceous
`follicles by increasing epithelial turnover and thus normalize the
`shedding of the outer layers oftheskin. (Gollnick 1998; Zaenglein
`2006). They do not affect sebum production as oral retinoids do.
`Topical retinoids reduce free fatty acid levels in the micro-comedo
`and prevent the formation and inflammation of the comedone,
`Because of the altered follicular microclimate, retinoids enhance
`the penetration of other topical anti-acne agents such as antibacte- Tazarotene
`rial drugs and antibiotics (Thielitz 2001; Zaenglein 2006). Topical This third-generation retinoid belongs to a novel family of topical
`retinoids have been shown to affect inflammation directly by in-
`receptor-selective acetylenic retinoids. It is available as a gel or
`hibitingthereleaseofnmdiatorsthatregulateinflammationsuchas
`cream in 0.05% or 0.1% (0.1% concentration is approved for
`prostaglandins, leukotrienes and pro inflammatory cytokines and
`acne treatment in the US) and has light stability (Krautheim 2004;
`regulating the inmmne response (Wolf 2002; Zaenglein 2006). AI-
`Shalita 1999; Shalita 2004). Common local adverse events include
`though retinoids from different generations have different chem-
`dryness, peeling/flaking, itching, redness/erythenm, burning and
`ical structures, they share more or less the same mechanisms of
`skin irritation (Bershad 2002).
`action and target the micro-comedo.
`
`Types of Topical Retinoids (ABPI Medicines
`Motretinide is a second-generation mono-aromatic retinoid and
`Compendium 2008) is available as 0.1% cream and solution (Krautheim 2004).
`
`Motretinide
`
`Tretinoin
`
`Retinaldehyde
`
`Tretinoin and isotretinoin are first generation retinoids. One of Retinaldehyde (RAL) is transformed into all-trans-retinoic acid
`
`the major and early side effects oftretinoin (all-trans retinoic acid)
`
`(tretinoin), and its biological activity has been found to be qual-
`
`which limit their use is dose-related skin irritation associated with
`
`itatively identical to that of retinoic acid (RA) (Didierjean 1999;
`
`its hydroalcoholic vehicle. To address this problem, various for-
`
`Sorg 1999). It has been demonstrated that in vitro, RAL unlike the
`
`mations and concentrations are now available as;
`
`first-generation ’parent’ natural retinoids such as retinoic acid or
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`Topical retinoids for acne vulgaris (Protocol)
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`retinol, has a significant direct antibacterial activity against gram-
`positive bacteria including 1).aches. This activity is probably due to
`its chemical structure: the aldehyde group in the isoprenoic lateral
`chain (Pechere 2002).
`
`Types of outcome measures
`
`Primary outcomes
`
`Retinoyl Beta-Glucuronide
`
`(i) Partidpamt’s global assessment ofchamge
`Retinoyl beta-glucuronide (RBG) is a naturally occurring, biolog- We expect this to be recorded on a Likert or Likert-like scale. The
`ically active metabolite of Vitamin A (Retinol). It shares several
`participant’s assessment may be done with or without the aid of
`properties with Vitamin A but is considered to be less toxic (Barua
`photographs or a mirror.
`1997).
`
`Why it is important to do this review
`
`Acne is one of the most common skin diseases. Although it is not
`life-threatening, it is a chronic condition and can cause substantial
`morbidity. Appropriate intervention is therefore required and a
`variety of treatments are available. Topical retinoids are now used
`as a first-line treatment for most forms ofacne. They are also being
`used as part of maintenance therapy. In the face of an increasing
`prevalence of antibiotic resistant strains of P.acnes (i.e.P.acnes do
`not respond to conventional antibiotics), topical retinoids have the
`potential to minimize antibiotic use in acne. A systematic review
`is hence required to determine both the efficacy and the safety of
`topical retinoids in acne treatment.
`
`(ii) Investigator assessed change in lesion count
`
`The change or percentage change, compared to baseline, in the
`number of:
`superficial inflamed lesions (papules or pustules or both, SILs);
`non-inflamed lesions (blackheads or whiteheads or both, NILs);
`nodules and cysts (for nodulocystic acne only).
`If the above data are not available, then we will record the change
`or percentage change, compared to baseline, in the number of SILs
`and NILs or combined count of all lesion type, as enumerated by
`a physician or trained assessor.
`Where lesion counts have been weighted, combined and converted
`into a severity index we shall use the lesion counts in preference
`to the derived values, where given.
`
`Secondary outcomes
`
`O B J E C T I V E S
`
`(iii) Investigator-assessed change in acne severity
`To assess the effects of topical retinoids in the treatment of acne. The change in acne severity, compared to baseline, using:
`A published grading scale;
`A severity index derived from the lesion count (if count data is not
`given).
`
`M E T H O D S
`
`Criteria for considering studies for this review
`
`Types of studies
`
`All randomised controlled trials (RCTs).
`
`Types of participants
`
`Anyone with acne of any severity as diagnosed by a health practi-
`tioner. The definition of acne includes comedonal, papulopustu-
`lar, polymorphic and nodulocystic.
`
`(iv) Investigator’s global assessment of change
`
`We expect this to be recorded on a Likert or Likert-like scale.
`The investigator’s global assessnlent will be ignored if it was done
`without the aid of baseline photographs.
`
`(v) Changes in Quality of life
`
`As assessed using a validated instrument (generic, dermatology
`specific, disease specific, DLQI or patient-generated index).
`
`Adverse outcomes
`
`Types of interventions
`
`This review will consider a wide range of different topical retinoids
`and we cannot prespecify which are the most important or corn-
`Studies that examined topical retinoids at any dose, percentage, mon adverse events. Therefore we shall document the incidence
`form and duration compared to no treatment, placebo, other active
`and severity of all recorded local and systemic adverse events, at
`therapy or another retinoid,
`any time point, in all the included studies. We shall use the system
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`organ classes (SOCs) defined in medDRA release 10.1. (MedDRA Ongoing Trials
`2008)
`
`We shall search for ongoing trials in:
`
`Economic data
`
`Data relating to costs will not be reported but we will address cost
`implications in the discussion,
`
`Timing of outcome assessment
`
`¯ the metaRegister of Controlled Trials (www.controlled-
`trials.corn);
`¯ the US National Institutes of Health trials registry on
`www.clinicaltrials.gov;
`¯ the Australian Clinical Trials Registry on www.actr.org.au;
`¯ the World Health Organisation portal on www.who.int/
`trialsearch;
`¯ the Ongoing Skin Trials Register on
`www.nottingham.ac.uk/ongoingskintrials.
`
`Data that has been recorded for less than four weeks will be con-
`sidered to reflect short-term benefit and will be analysed separately
`from data that was recorded for longer than three months, which
`we consider to reflect the minimum time period to capture any
`longer-term benefit. The end point closest to two weeks (one to
`four weeks) will be used for short-term benefit and the endpoint
`closest to ten weeks (± two weeks) will be used for long-term ben-
`efit. The long-term data will be considered the primary endpoint
`but we shall consider the short-term data in order to detect rapid We shall attempt to find unpublished studies by contacting authors
`of published trials and through searching grey literature sources.
`onset of improvement, which may be important for good adher-
`We will attempt to obtain the summary Basis of Approval for each
`ence to medication (compliance).
`of the three topical anti-acne U.S.A. ED.A. approved drugs.
`
`Searching other resources
`
`Unpublished and Grey literature
`
`Search methods for identification of studies
`
`Reference lists
`
`Electronic searches for any references to randontised controlled trials.
`
`We will search the bibliographies of included and excluded studies
`
`We shall search for relevant published trials in:
`
`Language
`
`No language restrictions will be imposed and translations will be
`sought where necessary.
`
`¯ Cochrane Skin Group Specialised Register, the Cochrane
`Central Register of Controlled Trials in The Cachrane Library
`(last update);
`¯ MEDLINE (OVID) (from 2003):
`Adverse Effects
`¯ EMBASE (OVID) (from 2005);
`¯ AMED (Allied and Complementary Medicine, from 1985); We shall not conduct a separate search for adverse events, but we
`¯ CINAHL (from 1980);
`shall include any adverse events that have been reported in the
`¯ PsycInfo (from 1872);
`included studies.
`¯ LILACS (Latin American and Caribbean Health Science
`Information database, from 1982);
`¯ CISCOM (Centralised Information Service for
`Complementary Medicine);
`¯ ISI Science Citation Index (on BIDS) ISI web of science.
`
`Data collection and analysis
`
`Selection of studies
`
`We have devised a search strategy for MEDLINE (OVID) which
`Two authors (AN and SO) will screen electronic records for po-
`can be viewed in Appendix 1. This is a draft strategy which will
`tentially eligible trials and will obtain the full text of these trials
`be adapted to include additional search terms where necessary and
`for further examination. The same wvo authors will independently
`will be modified for the other databases listed. The UK Cochrane
`Centre has an ongoing project to systematically search MEDLINE
`assess potentially eligible trials for inclusion with disagreements
`and EMBASE for reports of trials which are then included in
`resolved by discussion between the two reviewers. If the disagree-
`the Cochrane Central Register of Controlled Trials. Searching has ment cannot be resolved by discussion, a third author will resolve
`the discrepancy. When there are ntissing data in trial reports, we
`currently been completed in MEDLINE to 2003 and in EMBASE
`to 2005. Further searching of MEDLINE will be undertaken for will attempt to contact the trial authors to obtain that data. We
`this review by the Cochrane Skin Group to cover the years that will list the studies that can only be excluded after reading the full
`have not been searched by the UKCC.
`text in the ’Characteristics of excluded studies’ table.
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`Data extraction and management
`
`such as the lesion counts, means and standard deviations will be
`
`Two authors (AN and SO) will independently extract the data us-
`
`ing a specially designed data extraction form. Discussion, as well
`
`as involvement of a third member, will resolve any discrepancies in
`
`opinion. We will attempt to contact trial authors for unreported
`
`data. For the participant’s and investigator’s global assessments of
`
`improvement, the authors will translate reported changes in acne
`
`severity into the proportion of participants with improvement
`
`recorded. In both cases, the ’denominators’ will be the numbers
`
`randomly allocated to treatment and control groups. For each di-
`
`chotomous outcome we will estimate risk ratios (RR) and 95%
`
`confidence intervals (CI) and for continuous outcomes we will
`
`estimate weighted mean diffbrences (WMD) and 95% confidence
`
`intervals. The results will also be expressed as numbers needed
`
`to treat (NNT) where appropriate, for a range of plausible event
`
`greater than minimal. By minimal we mean anything greater than
`
`rates.
`
`the first category of improvement on a Likert scale, or greater than
`
`50% improvement from baseline on a continuous scale. For the
`
`purpose of calculating clinical efficacy, we shall regard categories
`
`relating to greater than minimal improvement as a treatment suc-
`
`cess. All other outcomes will be expressed as the actual or percent-
`
`age change from baseline,
`
`Assessment of risk of bias in included studies
`
`Unit of analysis issues
`
`Where there are multiple intervention groups within a trial, we
`
`shall make pairwise comparisons of topical retinoids versus no
`
`treatment, placebo, other conventional treatment or another top-
`
`ical retinoid. We shall analyse cross-over trials using data from the
`
`first phase only and pooled, where possible, with parallel design
`
`studies. We shall exclude non-randomised controlled studies and
`
`The quality assessment will include an evaluation of the following
`
`cluster randomised controlled trials but these may be commented
`
`components for each included study, since there is some evidence
`
`on in the discussion.
`
`that these are associated with biased estimates of treatment effect
`
`(Juni 2001):
`
`(a) the method of generation of the randomisation sequence;
`
`Dealing with missing data
`
`(b) the method of allocation conceahnent - it will be considered
`
`If participant drop-out leads to missing data we shall conduct an
`
`’adequate’ if the assignment could not be foreseen;
`
`intention-to-treat analysis. We shall contact trial authors or spon-
`
`(c) who was not aware (blinded) and aware (not blinded) of treat-
`
`sors of studies less than 15 years old to provide missing statistics
`
`ment allocation (participants, clinicians, outcome assessors) if this
`
`such as standard deviations. For dichotomous outcomes such as
`
`is appropriate;
`
`the participant’s and investigator’s global assessments of improve-
`
`(d) how many participants were lost to follow up in each arm, and ment (which translated into the proportion of participants with
`improvement greater than minimal." treatment success), we shall
`
`whether reasons for losses were adequately reported;
`
`(e) whether all participants were analysed in the groups to which
`
`regard participants with missing outcome data as treatment fail-
`
`they were originally randomised (intention to treat principle),
`
`ures and include these in the analysis. For continuous outcomes,
`
`In addition we shall report on:
`
`we shall carry forward the last recorded value for participants with
`
`(f) the degree of certainty that the participants have acne;
`
`missing outcome data.
`
`(g) the baseline assessment of the participants for age, sex, duration,
`
`location and severity of acne;
`
`(h) drug identity, source, dose, duration of treatment, and ade-
`
`quacy of instructions;
`
`Assessment of heterogeneity
`
`We shall assess statistical heterogeneity using 12. If 12 is less than
`
`(i) whether outcome measures were described and their assessment
`
`80% we shall synthesise data using meta-analysis techniques.
`
`was standardised;
`
`(j) the use and appropriateness of statistical analyses, where tabu-
`
`lated data cannot be extracted from the original publication.
`We shall record information on all these components in a Table We shall test publication bias by the use of a funnel plot when
`adequate data are available for similar types of interventions or for
`of Quality Criteria. We shall also summarise the general quality
`
`Assessment of reporting biases
`
`of all the studies,
`
`a similar active component.
`
`Measures of treatment effect
`
`Data synthesis
`
`For studies with a similar comparison of interventions, in the ab-
`For dichotomous outcomes such as the participant’s and investi-
`sence of clinical heterogeneity we shall perform a meta-analysis to
`gator’s global assessments of improvement (which translate into
`calculate a weighted treatment effect across trials, using a random-
`the proportion of participants with improvement greater than
`effbcts model. Where it is not possible to perform a meta-analysis
`minimal; treatment success), numbers of outcomes in treatment
`and control groups will be recorded. For continuous outcomes we shall summarise the data for each trial.
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`Subgroup analysis and investigation of heterogeneity
`
`We shall explore any observed heterogeneity. We specify a priori
`that the following factors may account for any observed hetero-
`geneity: quality of included studies, disease severity, and dosage
`and duration of treatment. We shall perform further subgroup
`analysis if adequate information is given. The groups will be dif-
`ferent types of acne (comedonal, papulopustular, polymorphic,
`nodular, persistent or late onset) and the age of participants (child
`or adult) as described by the trial authors.
`
`Sensitivity analysis
`
`We plan to conduct sensitivity analyses to examine the effects of
`excluding poor quality studies, defined as those with a moderate
`or high risk of bias as described in the Cochrane Handbook of
`Systematic Reviews of Interventions (Higgins 2008)
`
`Adverse outcomes
`
`We shall record:
`a) the appropriateness of the methods used to detect adverse
`events;
`b) the adequacy of reporting.
`We shall describe the information qualitatively.
`
`Other
`
`Where there is uncertainty, we shall contact the trial authors for
`clarification. A consumer is part of the review team to increase the
`relevance and readability of the final review.
`
`ACKNOWLEDGEMENTS
`
`The Cochrane Skin Group would like to thank the following peo-
`ple who were external refrees for this protocol: Robert Dellavalle
`(key editor), Jim Leyden (content expert), Mike Clarke (statisti-
`cal and methods editor), Anne Lyddiat (consumer) and Raphael
`Freitas de Souza (consumer).
`
`REFERENCES
`
`Additional references
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`Topical retinoids for acne vulgaris (Protocol)
`Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
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