Health Technology Assessment 2005; Vol 9: number 1
Executive SummaryView/Download full monograph in Adobe Acrobat format (0.98 mbytes)
M Ozolins,1* EA Eady,2 A Avery,1 WJ Cunliffe,3 C ONeill,4 NB Simpson5 and HC Williams1
1 Departments of Dermatology, General Practice and Economics, University of
2 School of Biochemistry and Microbiology, University of Leeds, UK
3 Department of Dermatology, Leeds General Infirmary, Leeds, UK
4 School of Policy Studies, University of Ulster, Newtownabbey, UK
5 Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
* Corresponding author
Acne is one of the most common skin disorders in young people. Having acne can give rise to feelings of embarrassment, loss of self-esteem and depression, as well as physical symptoms (such as soreness and pain) associated with individual lesions. Most people with acne are treated in primary care. GPs have at least 30 different acne preparations to choose from, which can be prescribed singly or in combination, yet there are virtually no good comparative data to guide them or their patients to make the best choice in terms of efficacy, cost-effectiveness, compliance, tolerability and overall patient satisfaction. Antibiotic resistance in the bacteria implicated in acne pathogenesis (Propionibacterium acnes and Propionibacterium granulosum) may be associated with a reduction in clinical efficacy, and some antibiotic preparations may be more likely to promote resistance than others.
This study therefore sought to determine:
The study was a randomised controlled clinical trial using parallel comparative groups and a pragmatic design with intention-to-treat analysis. Initially, 11 groups were to be compared, but major recruitment difficulties and high dropout rates prompted an early decision in consultation with the HTA Executive to restrict the study to just five treatment groups. Because matched placebos would have been prohibitively expensive to produce, blinding of study participants was only partially achieved. Assessors were blinded to the intervention status of participants.
Primary care practices and colleges in and around the cities of Nottingham and Leeds, and one practice in Stockton-on-Tees, England.
Participants were 649 people aged 1239 years, all of whom had mild to moderate inflammatory acne of the face. Those with exclusively truncal or comedonal acne were excluded from the study. All acne treatments (oral and topical) were stopped for 4 weeks before the study.
Study participants were randomised into one of the following five treatment groups:
In addition to comparing the treatments, these five interventions were specifically chosen to answer the following additional questions for the NHS:
The two primary outcome measures were:
Secondary outcome measures included three other measures of acne severity: the Burke and Cunliffe grade (a pictorial assessment method), assessor global assessment of the participant, and a new acne severity score that combined an assessment of inflamed lesions, non-inflamed lesions and redness in each of four areas of the face. Disability and effects on quality of life were assessed using the Short Form 36 questionnaire, the Dermatology Life Quality Index and the Dermatology Quality of Life Scales. Local irritation was assessed by both participant and assessor and indirectly by the use of moisturisers. The proportion of participants for whom the worst aspect of their acne had improved was also recorded, as were re-referral rates after treatment completion. Other adverse events and dropout rates were recorded at each visit.
Bacterial skin colonisation with propionibacteria resistant to erythromycin, clindamycin or the tetracyclines was estimated at baseline and on all subsequent visits using a semi-quantitative scoring method to derive data on both prevalence and population density.
The best response rates were seen with two of the topical regimens (erythromycin plus benzoyl peroxide administered separately o.d. or in a combined proprietary formulation b.d.), compared with benzoyl peroxide alone, oxytetracycline (500 mg b.d.) and minocycline (100 mg o.d.), although treatment differences were small. The percentage of participants with at least moderate improvement was 53.8% for minocycline (the least effective) and 66.1% for the combined erythromycin/benzoyl peroxide formulation (the most effective); the adjusted odds ratio for these two treatments was 1.74 [95% confidence interval (CI) 1.04 to 2.90]. Similar efficacy rankings were obtained using lesion counts, acne severity scores and global rating by assessor. Benzoyl peroxide was the most cost-effective and minocycline the least cost-effective regimen for treating mild to moderate inflammatory acne of the face (ratio of means 12.3; difference in means −0.051 units/£, 95% CI −0.063 to −0.039). The efficacy of oxytetracycline was similar to that of minocycline, but at approximately one-seventh of the cost. For all regimens, the largest reductions in acne severity were recorded in the first 6 weeks (around 4550% of participants with at least moderate improvement). Reductions in disability scores using the Dermatology Quality of Life Scales were largest for both topical erythromycin-containing regimens and minocycline. All treatments showed antibacterial activity in vivo. The two topical erythromycin-containing regimens produced the largest reductions in the prevalence and population density of cutaneous propionibacteria, including antibiotic-resistant variants, and these were equally effective in participants with and without erythromycin-resistant propionibacteria. The clinical efficacy of both tetracyclines was compromised in participants colonised by tetracycline-resistant propionibacteria. None of the regimens promoted an overall increase in the prevalence of antibiotic-resistant strains. Systemic adverse events were more common with the two oral antibiotics. Local irritation was more common with the topical treatments, particularly benzoyl peroxide. Residual acne was present in most participants (95%) at the end of the study.
The response of mild to moderate inflammatory acne to antimicrobial treatment in the community is not optimal. Only around half to two-thirds of trial participants reported at least a moderate improvement over an 18-week study period; extending treatment beyond 12 weeks increased overall benefit slightly. Around one-quarter of participants dropped out when using such treatments, and 55% sought further treatment after 18 weeks. Most improvement was seen within the first 6 weeks.
Perhaps the single most important finding of this study is that the topical antimicrobial therapies performed at least as well as oral antibiotics in terms of clinical efficacy. Benzoyl peroxide was the most cost-effective and minocycline the least cost-effective therapy for facial acne. The efficacy of all three topical regimens was not compromised by pre-existing propionibacterial resistance. In addition to causing fewer systemic adverse events, topical preparations are less likely to induce resistance in other common bacteria, a finding that may be important for reducing the more widespread problem of bacterial resistance in the community. These findings need to be tempered by the fact that topical therapy can be more difficult to use for truncal acne, and the cost of treatment is directly related to the size of the area treated.
Even though benzoyl peroxide was the most cost-effective treatment, it was associated with a greater frequency and severity of local irritant reactions. The results suggest that the use of a combination of topical benzoyl peroxide and erythromycin gives rise to less irritation and better quality of life. There was little difference between erythromycin plus benzoyl peroxide administered separately and the combined proprietary formulation in terms of efficacy or local irritation, except that the former was nearly three times more cost-effective. The data on cost-effectiveness, and outcomes in patients with resistant propionibacterial floras, did not support the first line use of minocycline for mild to moderate inflammatory acne of the face.
Although this trial has helped to inform the selection of antimicrobial treatment for mild to moderate inflammatory acne of the face, prescribers are still faced with a lack of good quality evidence to help them to make informed decisions about many other aspects of acne management, such as choosing between antimicrobials and other types of treatment, how to manage truncal acne, when and how to combine treatments, whether and when to refer for oral isotretinoin, and the extent to which patient characteristics such as ethnicity or social class modulate outcomes. A small number of high-quality acne trials is needed to address the key issues for prescribers and patients as opposed to manufacturers and regulators. There is a need for more research on trial methodology and agreement between those who fund trials upon some degree of standardisation with respect to the selection and use of outcome measures. This study has shown how difficult it is capture all aspects of acne with a single measure, but also that the use of multiple measures is not an ideal solution. Three priority areas for clinical research in acne are:
Ozolins M, Eady EA, Avery A, Cunliffe WJ, ONeill C, Simpson NB, et al. Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne. Health Technol Assess 2005;9(1).
The research findings from the NHS R&D Health Technology Assessment (HTA) Programme directly influence key decision-making bodies such as the National Institute for Clinical Excellence (NICE) and the National Screening Committee (NSC) who rely on HTA outputs to help raise standards of care. HTA findings also help to improve the quality of the service in the NHS indirectly in that they form a key component of the National Knowledge Service that is being developed to improve the evidence of clinical practice throughout the NHS.
The HTA Programme was set up in 1993. Its role is to ensure that high-quality research information on the costs, effectiveness and broader impact of health technologies is produced in the most efficient way for those who use, manage and provide care in the NHS. Health technologies are broadly defined to include all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care, rather than settings of care.
The HTA programme commissions research only on topics where it has identified key gaps in the evidence needed by the NHS. Suggestions for topics are actively sought from people working in the NHS, the public, consumer groups and professional bodies such as Royal Colleges and NHS Trusts.
Research suggestions are carefully considered by panels of independent experts (including consumers) whose advice results in a ranked list of recommended research priorities. The HTA Programme then commissions the research team best suited to undertake the work, in the manner most appropriate to find the relevant answers. Some projects may take only months, others need several years to answer the research questions adequately. They may involve synthesising existing evidence or designing a trial to produce new evidence where none currently exists.
Additionally, through its Technology Assessment Report (TAR) call-off contract, the HTA Programme is able to commission bespoke reports, principally for NICE, but also for other policy customers, such as a National Clinical Director. TARs bring together evidence on key aspects of the use of specific technologies and usually have to be completed within a limited time period.
Criteria for inclusion in the HTA monograph series
Reports are published in the HTA monograph series if (1) they have resulted from work commissioned for the HTA Programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors.
Reviews in Health Technology Assessment are termed systematic when the account of the search, appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others.
The research reported in this monograph was commissioned by the HTA Programmeas project number 94/48/03. As funder, by devising a commissioning brief, the HTA Programme specified the research question and study design. The authors have been wholly responsible for all data collection, analysis and interpretation and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.
The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme or the Department of Health.
Editor-in-Chief: Professor Tom Walley
Series Editors: Dr Peter Davidson, Professor John Gabbay, Dr Chris Hyde, Dr Ruairidh Milne, Dr Rob Riemsma and Dr Ken Stein
Managing Editors: Sally Bailey and Caroline Ciupek
© 2005 Crown Copyright Top ^