Topical Preparations for the Treatment of Mild-to-moderate Acne Vulgaris

Systematic Review and Network Meta-analysis

B. Stuart; E. Maund; C. Wilcox; K. Sridharan; G. Sivaramakrishnan; C. Regas; D. Newell; I. Soulsby; K.F. Tang; A.Y. Finlay; H.C. Bucher; P. Little; A.M. Layton; M. Santer

Disclosures

The British Journal of Dermatology. 2021;185(3):512-525. 

In This Article

Materials and Methods

Protocol and Registration

The study was conducted and is reported in line with the PRISMA-NMA guideline[15] and was preregistered on PROSPERO (CRD42019135570).

Public and Patient Involvement

Prior to undertaking this study, we convened a 'patient panel' of 10 people with current/former acne. We discussed the research question and how we might measure 'effectiveness' and 'adverse events'. The patient panel felt strongly that a participant-reported outcome should be the primary measure; it was their own assessment of their acne that mattered most to them, not the assessment of a clinician. The patient panel also helped to decide on the scope of the review, stressing the importance of understanding whether prescribed topical medications actually worked. The panel saw little value in including medications not currently available to them in the UK. One member of the patient panel joined the study team and is a coauthor of this article.

Search Strategy and Information Sources

We searched the Cochrane Central Register of Controlled Trials, MEDLINE and Embase, from inception to June 2020, for relevant journal articles, conference abstracts and systematic reviews (Appendix S1; see Supporting Information). Our search was not limited by language. We also searched the World Health Organization International Clinical Trials Registry for relevant registered trials; we hand-searched references from included papers and relevant systematic reviews for additional relevant trials and we contacted experts and pharmaceutical companies to find any unpublished trials.

Study Selection

We included randomized controlled trials but excluded split-face and split-body trials owing to concerns about contamination, quasirandomized trials and any nonrandomized designs.

Two reviewers independently screened all titles, abstracts and full papers, using the eligibility criteria below, with any disagreements resolved through discussion. We obtained and assessed full papers or conference abstracts for inclusion in the review only if they were written in English. However, we kept a record of papers not written in English whose title and abstract were potentially relevant for inclusion in future updates.

Eligibility Criteria

Population. We included all trials where participants had mild-to-moderate acne (as defined by trial authors), regardless of age, sex, setting or previous treatments. We included trials in which there were mixed populations of acne severity, provided ≤ 50% of participants had severe acne. We excluded trials in which severity was not reported, or where it was unclear from the source material whether the trial was randomized.

We excluded trials in which all participants had truncal acne only, were diagnosed with rosacea, unusual forms of acne, chloracne, acne inversa, acne fulminans, neonatal acne, infantile acne, occupational acne, drug-induced acne and acne specifically associated with endocrinopathies, including polycystic ovary syndrome, had previously received oral isotretinoin, or were only using the trial treatment as maintenance therapy directly following another acne treatment.

Intervention

This review compares topical preparations for mild/moderate acne described in the NICE CKS or European guidelines. The list was refined by a panel of dermatologists, general practitioners and patients for relevance to clinical practice and patient needs. Treatment regimens available in the UK at any dose, formulation or duration were included. Preparations no longer manufactured or available in the UK, or studies comparing different strengths or dosages of the same preparation were excluded (Box 1).

The comparator was placebo/vehicle or any treatment regimen, dose, or duration for the topical treatments listed in Box 1.

The primary outcomes were:

  • proportion of participants self-reporting moderate or better global improvement in acne

  • proportion of participants withdrawing from trial or cessation of trial medication owing to adverse events.

The secondary outcomes were:

  • change in mean total lesion count from baseline as assessed by an investigator

  • proportion of participants rated 'clear' or 'almost clear' on the Investigator's Global Assessment (IGA) scale of acne severity

  • proportion of participants rated as having at least a two-grade improvement from baseline on the IGA scale of acne severity

  • change in quality of life from baseline (assessed using a validated instrument such as Skindex-16, Skindex-29 or Cardiff Acne Disability Index)

  • reduction in Cutibacterium acnes strains

  • total number of adverse events

  • participant satisfaction with treatment.

Data Collection and Data Items

A data extraction form was developed in Excel and piloted on two randomly selected papers to ensure consistency. Data available in graph format only were not extracted. Data extraction was performed by one reviewer and checked by a second reviewer.

All outcomes were reported in the medium term, defined as 5–16 weeks (with closest data point to 16 weeks used), with planned sensitivity analysis for short-term (2–4 weeks) and long-term (from 17 weeks to 12 months) outcomes. Trial arms that reported different strengths or dosages of the same medication were pooled.

Risk of Bias in Individual Studies

Risk of bias was assessed using the Cochrane Risk of Bias Tool, covering patient allocation sequence generation, allocation concealment, blinding and selective outcome reporting.[16]

Statistical Analyses

The network geometry has been presented graphically and describes the number of included interventions and the extent to which there are trials comparing different pairs of interventions.[17,18]

The network meta-analysis was performed using a frequentist approach with a version of the R package netmeta, implemented in MetaInsight.[19] We anticipated heterogeneity between trials and therefore used random effects models and a common variance approach.[20] Equal heterogeneity across all comparators was assumed and a consistency model was adopted.

For continuous outcomes, the effects were summarized using mean difference if included trials used the same outcome metric or using standardized mean difference if trials reported different outcome metrics. Continuous outcomes were modelled using normal likelihood, and dichotomous outcomes were modelled using binomial likelihood models to produce odds ratios (ORs). A reduced weights approach was used to account for correlation between arms in multiarm trials.[21] Ranking of treatments was undertaken using the P-Score approach.[22]

We used the design-by-treatment test to evaluate global inconsistency, and node splitting was used to examine inconsistency between direct and indirect effects, with a P-value < 0·05 considered to be suggestive of conflicting evidence.[19]

Confidence in Evidence

The confidence in the evidence across trials was assessed using the Confidence in Network Meta-Analysis (CINeMA) approach[23] and ratings were conducted in the CINeMA app.[23,24]

CINeMA considers the following six domains: within-study bias, reporting bias, indirectness, imprecision, heterogeneity and incoherence. These domains are rated as 'no concerns', 'some concerns' or 'major concerns', with the exception of reporting bias, which is rated as 'suspect' or 'undetected'. Judgements are then summarized across these six domains as 'very low', 'low', 'moderate' or 'high' confidence for each treatment comparison.[23]

Comparisons were considered to have suspected risk of reporting bias if all or most of the comparisons were from industry-funded trials. Indirectness was downgraded for comparisons that were poorly connected in the network. For imprecision, the threshold was set at an odds ratio of 1·5 for binary comparisons and a difference of 10 for lesion counts based on discussion.

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