HEALTH TECHNOLOGY ASSESSMENT

HEALTH TECHNOLOGY ASSESSMENT VOLUME 20 ISSUE 19 MARCH 2016 ISSN 1366-5278 A randomised pacebo-controed tria of ora and topica antibiotics for chidren with cinicay infected eczema in the community: the ChidRen with Eczema, Antibiotic Management (CREAM) study Nick A Francis, Matthew J Ridd, Emma Thomas-Jones, Victoria Shepherd, Christopher C Buter, Kerenza Hood, Chao Huang, Katy Addison, Mirea Longo, Charis Marwick, Mandy Wootton, Robin Howe, Amanda Roberts, Mohammed Inaam-u Haq, Vishnu Madhok and Frank Suivan on behaf of the CREAM team DOI 10.3310/hta20190

A randomised pacebo-controed tria of ora and topica antibiotics for chidren with cinicay infected eczema in the community: the ChidRen with Eczema, Antibiotic Management (CREAM) study Nick A Francis, 1* Matthew J Ridd, 2 Emma Thomas-Jones, 3 Victoria Shepherd, 3 Christopher C Buter, 1,4 Kerenza Hood, 3 Chao Huang, 3 Katy Addison, 3 Mirea Longo, 5 Charis Marwick, 6 Mandy Wootton, 7 Robin Howe, 7 Amanda Roberts, 8 Mohammed Inaam-u Haq, 3 Vishnu Madhok 9 and Frank Suivan 10 on behaf of the CREAM team 1 Cochrane Institute of Primary Care and Pubic Heath, Schoo of Medicine, Cardiff University, Cardiff, UK 2 Centre for Academic Primary Care, Nationa Institute for Heath Research Schoo of Primary Care Research, Schoo of Socia and Community Medicine, University of Bristo, Bristo, UK 3 South East Waes Trias Unit, Schoo of Medicine, Cardiff University, Cardiff, UK 4 Nuffied Department of Primary Care Heath Sciences, University of Oxford, Oxford, UK 5 Swansea Centre for Heath Economics, Swansea University, Swansea, UK 6 Popuation Heath Sciences, Schoo of Medicine, University of Dundee, Dundee, UK 7 Speciaist Antimicrobia Chemotherapy Unit, Pubic Heath Waes Microbioogy Cardiff, University Hospita Waes, Cardiff, UK 8 Centre of Evidence Based Dermatoogy, University of Nottingham, Nottingham, UK 9 Park House Surgery, Surrey, UK 10 Department of Famiy and Community Medicine and Daa Lana Schoo of Pubic Heath, North York Genera Hospita University of Toronto, Toronto, ON, Canada *Corresponding author Decared competing interests of authors: Professor Christopher C Buter received fees for acting in an advisory capacity to Aere and is supporting a study on which he is the chief investigator with diagnostic devices in the form of an unconditiona educationa grant. He is aso a Nationa Institute for Heath Research (NIHR) Efficacy and Mechanism Evauation board member. Professor Kerenza Hood is a member of the NIHR Cinica Trias Unit standing committee. Dr Mandy Wootton has decared that she received a speakers honoraria from Nordic Pharma Ltd (who manufacture fosfomycin).

Pubished March 2016 DOI: 10.3310/hta20190 This report shoud be referenced as foows: Francis NA, Ridd MJ, Thomas-Jones E, Shepherd V, Buter CC, Hood K, et a. A randomised pacebo-controed tria of ora and topica antibiotics for chidren with cinicay infected eczema in the community: the ChidRen with Eczema, Antibiotic Management (CREAM) study. Heath Techno Assess 2016;20(19). Heath Technoogy Assessment is indexed and abstracted in Index Medicus/MEDLINE, Excerpta Medica/EMBASE, Science Citation Index Expanded (SciSearch ) and Current Contents / Cinica Medicine.

Heath Technoogy Assessment HTA/HTA TAR ISSN 1366-5278 (Print) ISSN 2046-4924 (Onine) Impact factor: 5.027 Heath Technoogy Assessment is indexed in MEDLINE, CINAHL, EMBASE, The Cochrane Library and the ISI Science Citation Index. This journa is a member of and subscribes to the principes of the Committee on Pubication Ethics (COPE) (www.pubicationethics.org/). Editoria contact: nihredit@southampton.ac.uk The fu HTA archive is freey avaiabe to view onine at www.journasibrary.nihr.ac.uk/hta. Print-on-demand copies can be purchased from the report pages of the NIHR Journas Library website: www.journasibrary.nihr.ac.uk Criteria for incusion in the Heath Technoogy Assessment journa Reports are pubished in Heath Technoogy Assessment (HTA) if (1) they have resuted from work for the HTA programme, and (2) they are of a sufficienty high scientific quaity as assessed by the reviewers and editors. Reviews in Heath Technoogy Assessment are termed systematic when the account of the search appraisa and synthesis methods (to minimise biases and random errors) woud, in theory, permit the repication of the review by others. HTA programme The HTA programme, part of the Nationa Institute for Heath Research (NIHR), was set up in 1993. It produces high-quaity research information on the effectiveness, costs and broader impact of heath technoogies for those who use, manage and provide care in the NHS. Heath technoogies are broady defined as a interventions used to promote heath, prevent and treat disease, and improve rehabiitation and ong-term care. The journa is indexed in NHS Evidence via its abstracts incuded in MEDLINE and its Technoogy Assessment Reports inform Nationa Institute for Heath and Care Exceence (NICE) guidance. HTA research is aso an important source of evidence for Nationa Screening Committee (NSC) poicy decisions. For more information about the HTA programme pease visit the website: http://www.nets.nihr.ac.uk/programmes/hta This report The research reported in this issue of the journa was funded by the HTA programme as project number 09/118/03. The contractua start date was in June 2012. The draft report began editoria review in Juy 2015 and was accepted for pubication in November 2015. The authors have been whoy responsibe for a data coection, anaysis and interpretation, and for writing up their work. The HTA editors and pubisher have tried to ensure the accuracy of the authors report and woud ike to thank the reviewers for their constructive comments on the draft document. However, they do not accept iabiity for damages or osses arising from materia pubished in this report. This report presents independent research funded by the Nationa Institute for Heath Research (NIHR). The views and opinions expressed by authors in this pubication are those of the authors and do not necessariy refect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Heath. If there are verbatim quotations incuded in this pubication the views and opinions expressed by the interviewees are those of the interviewees and do not necessariy refect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Heath. Queen s Printer and Controer of HMSO 2016. This work was produced by Francis et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Pubished by the NIHR Journas Library (www.journasibrary.nihr.ac.uk), produced by Prepress Projects Ltd, Perth, Scotand (www.prepress-projects.co.uk).

Heath Technoogy Assessment Editor-in-Chief Professor Hywe Wiiams Director, HTA Programme, UK and Foundation Professor and Co-Director of the Centre of Evidence-Based Dermatoogy, University of Nottingham, UK NIHR Journas Library Editor-in-Chief Professor Tom Waey Director, NIHR Evauation, Trias and Studies and Director of the HTA Programme, UK NIHR Journas Library Editors Professor Ken Stein Chair of HTA Editoria Board and Professor of Pubic Heath, University of Exeter Medica Schoo, UK Professor Andree Le May Chair of NIHR Journas Library Editoria Group (EME, HS&DR, PGfAR, PHR journas) Dr Martin Ashton-Key Consutant in Pubic Heath Medicine/Consutant Advisor, NETSCC, UK Professor Matthias Beck Chair in Pubic Sector Management and Subject Leader (Management Group), Queen s University Management Schoo, Queen s University Befast, UK Professor Aieen Carke Professor of Pubic Heath and Heath Services Research, Warwick Medica Schoo, University of Warwick, UK Dr Tessa Criy Director, Crysta Bue Consuting Ltd, UK Dr Peter Davidson Director of NETSCC, HTA, UK Ms Tara Lamont Scientific Advisor, NETSCC, UK Professor Eaine McCo Director, Newcaste Cinica Trias Unit, Institute of Heath and Society, Newcaste University, UK Professor Wiiam McGuire Professor of Chid Heath, Hu York Medica Schoo, University of York, UK Professor Geoffrey Meads Professor of Heath Sciences Research, Heath and Webeing Research and Deveopment Group, University of Winchester, UK Professor John Norrie Heath Services Research Unit, University of Aberdeen, UK Professor John Powe Consutant Cinica Adviser, Nationa Institute for Heath and Care Exceence (NICE), UK Professor James Raftery Professor of Heath Technoogy Assessment, Wessex Institute, Facuty of Medicine, University of Southampton, UK Dr Rob Riemsma Reviews Manager, Keijnen Systematic Reviews Ltd, UK Professor Heen Roberts Professor of Chid Heath Research, UCL Institute of Chid Heath, UK Professor Jonathan Ross Professor of Sexua Heath and HIV, University Hospita Birmingham, UK Professor Heen Snooks Professor of Heath Services Research, Institute of Life Science, Coege of Medicine, Swansea University, UK Professor Jim Thornton Professor of Obstetrics and Gynaecoogy, Facuty of Medicine and Heath Sciences, University of Nottingham, UK Pease visit the website for a ist of members of the NIHR Journas Library Board: www.journasibrary.nihr.ac.uk/about/editors Editoria contact: nihredit@southampton.ac.uk NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta20190 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 19 Abstract A randomised pacebo-controed tria of ora and topica antibiotics for chidren with cinicay infected eczema in the community: the ChidRen with Eczema, Antibiotic Management (CREAM) study Nick A Francis, 1* Matthew J Ridd, 2 Emma Thomas-Jones, 3 Victoria Shepherd, 3 Christopher C Buter, 1,4 Kerenza Hood, 3 Chao Huang, 3 Katy Addison, 3 Mirea Longo, 5 Charis Marwick, 6 Mandy Wootton, 7 Robin Howe, 7 Amanda Roberts, 8 Mohammed Inaam-u Haq, 3 Vishnu Madhok 9 and Frank Suivan 10 on behaf of the CREAM team 1 Cochrane Institute of Primary Care and Pubic Heath, Schoo of Medicine, Cardiff University, Cardiff, UK 2 Centre for Academic Primary Care, Nationa Institute for Heath Research Schoo of Primary Care Research, Schoo of Socia and Community Medicine, University of Bristo, Bristo, UK 3 South East Waes Trias Unit, Schoo of Medicine, Cardiff University, Cardiff, UK 4 Nuffied Department of Primary Care Heath Sciences, University of Oxford, Oxford, UK 5 Swansea Centre for Heath Economics, Swansea University, Swansea, UK 6 Popuation Heath Sciences, Schoo of Medicine, University of Dundee, Dundee, UK 7 Speciaist Antimicrobia Chemotherapy Unit, Pubic Heath Waes Microbioogy Cardiff, University Hospita Waes, Cardiff, UK 8 Centre of Evidence Based Dermatoogy, University of Nottingham, Nottingham, UK 9 Park House Surgery, Surrey, UK 10 Department of Famiy and Community Medicine and Daa Lana Schoo of Pubic Heath, North York Genera Hospita University of Toronto, Toronto, ON, Canada *Corresponding author FrancisNA@cardiff.ac.uk Background: Secondary skin infection is common during eczema exacerbations and many chidren are treated with antibiotics when this is suspected, athough there is itte high-quaity evidence to justify this practice. Objective: To determine the cinica effectiveness of ora and topica antibiotics, in addition to standard treatment with emoients and topica corticosteroids, in chidren with cinicay infected eczema. Design: Muticentre randomised, doube-bind, pacebo-controed tria. Setting: Genera practices and dermatoogy cinics in Engand, Waes and Scotand. Participants: Chidren (aged 3 months to < 8 years) with a diagnosis of eczema (according to U.K. Working Party definition) and cinica suspicion of infection. Interventions: (1) Ora fucoxaciin and topica pacebo; (2) topica fusidic acid (Fucidin, Leo Laboratories Limited) and ora pacebo; and (3) ora and topica pacebos, a for 1 week. Queen s Printer and Controer of HMSO 2016. This work was produced by Francis et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. vii

ABSTRACT Main outcome measures: Patient-Orientated Eczema Measure (POEM) at 2 weeks (assessing subjective severity in the week foowing treatment). Resuts: We randomised 113 chidren (36 to ora antibiotic, 37 to topica antibiotic and 40 to pacebo), which was fewer than our revised target sampe size of 282. A tota of 103 (92.0%) chidren had one or more cinica features suggestive of infection and 78 (69.6%) chidren had Staphyococcus aureus cutured from a skin swab. Ora and topica antibiotics resuted in a 1.52 [95% confidence interva (CI) 1.35 to 4.40] and 1.49 (95% CI 1.55 to 4.53) increase (worse subjective severity) in POEM score at 2 weeks, reative to pacebo and controing for baseine POEM score. Eczema Area and Severity Index (objective severity) scores were aso higher (worse) in the intervention groups, at 0.20 (95% CI 0.12 to 0.52) and 0.42 (95% CI 0.09 to 0.75) for ora and topica antibiotics, respectivey, at 2 weeks. Anayses of impact on the famiy, quaity of ife, daiy symptom scores, and onger-term outcomes were a consistent with the finding of no or imited difference and a trend towards worse outcomes in the intervention groups. Sensitivity anayses, incuding adjusting for compiance and imputation for missing data, were consistent with the main findings. Concusions: Our data suggest that ora and topica antibiotics have no effect, or a harmfu effect, on subjective eczema severity in chidren with cinicay infected eczema in the community. The CIs around our estimates excude a meaningfu beneficia effect (pubished minima cinicay important difference for POEM is 3.4). Athough most patients in this tria had features suggestive of infection and S. aureus on their skin, participants primariy had mid moderate eczema and those with signs of more severe infection were often excuded. Cinicians shoud consider avoiding ora and topica antibiotic use in chidren with suspected infected eczema in the community who do not have signs of severe infection. Further research shoud seek to understand how best to encourage the use of topica steroids and imit use of antibiotics in those with eczema fares without signs of severe infection, as we as deveoping toos to better phenotype eczema fares, in order to better define a popuation that may benefit from antibiotic treatment. Tria registration: European Union Drug Reguating Authorities Cinica Trias (EudraCT) number 2011-003591-37 and Current Controed Trias ISRCTN96705420. Funding: The Nationa Institute for Heath Research Heath Technoogy Assessment programme. viii NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta20190 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 19 Contents List of tabes List of figures List of abbreviations Pain Engish summary Scientific summary xiii xv xvii xix xxi Chapter 1 Introduction 1 Infected eczema 1 Use of antimicrobia treatments for eczema 2 Summary 2 Chapter 2 Methods 3 Summary of study design 3 Tria objectives 5 Primary objective 5 Secondary objectives 5 Setting 5 Site recruitment 5 Participant seection 6 Incusion criteria 6 Excusion criteria 6 Participant recruitment 6 Informing parents of potentiay eigibe chidren about the tria 6 Identification of potentiay eigibe chidren 6 Tria Torrent recruitment software 7 Informed consent 7 Randomisation, binding and unbinding 8 Withdrawa and oss to foow-up 8 Tria interventions 8 Treatments 9 Treatment arms 9 Tria procedures 10 Training 10 Data coection 10 Coection of swab sampes 12 Safety monitoring 13 Data management and monitoring 13 Data entry 13 Data quaity 13 Data ceaning 13 Data storage and retention 13 Research governance 14 Queen s Printer and Controer of HMSO 2016. This work was produced by Francis et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. ix

CONTENTS Outcome measures 14 Primary outcome measure 14 Secondary outcome measures 14 Statistica considerations 15 Sampe size cacuation 15 Anaysis 15 Main anaysis 15 Secondary anayses 15 Economic anayses 16 Sensitivity anayses and process measures 17 Patient and pubic invovement 18 Summary of changes to the study 18 Chapter 3 Resuts 19 Sites 19 Participants 20 Baseine characteristics 21 Objective assessment of cinica features 22 Primary outcomes 23 Secondary outcomes 25 Subjective severity at 4 weeks and 3 months 25 Objective eczema severity 26 Impact on the famiy 26 Quaity of ife 26 Daiy symptom scores 26 Microbioogy 27 Adverse effects 30 Parenta-reported NHS consutations 30 Medication use during foow-up 30 Time off work 30 Sensitivity anayses, process measures and post-hoc anayses 35 Medication adherence 35 Parenta views about use of treatment 36 Use of topica corticosteroids 36 Regiona variation 36 Missing data 36 Subgroup anaysis by presence of Staphyococcus aureus on the skin at baseine 36 Chapter 4 Vaidation of the Atopic Dermatitis Quaity of Life preference-based index 39 Introduction 39 Methods 40 Study popuation 40 Data coection 40 Hypotheses testing 40 Statistica anaysis 40 Resuts 40 Correation between scores 42 Discriminant vaidity of the preference-based Atopic Dermatitis Quaity of Life Index 42 Change of preference-based Atopic Dermatitis Quaity of Life Index scores over time 45 Participants feedback on the preference-based ADQoL questionnaire 45 Discussion 46 Concusions 47 x NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta20190 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 19 Chapter 5 Study chaenges 49 Manufacture and suppy of tria treatments 49 Contracts and research and deveopment approvas 49 Recruitment of sites 50 Actions taken to improve recruitment at site eve 51 November 2013 (4 months into the study recruitment) 51 Apri 2014 (9 months into the study recruitment) 51 June 2014 (11 months into the study recruitment) 51 Incidence of infected eczema 52 Defining eigibiity 53 Attrition between identification and recruitment 53 Amendment of incusion and excusion criteria 54 Recruitment barriers at site 55 Tria Torrent 55 Consutation time 55 Chaenges to assessment and data coection 56 Enabing factors 56 Research nurse support and advice 56 Record of treatment use and adherence 56 Strategies empoyed to try and improve recruitment 57 Concusion 57 Chapter 6 Discussion and concusions 59 Summary of main resuts 59 Strengths and imitations 59 Generaisabiity 60 Interpretation 61 Concusions 62 Impications for heath care 62 Recommendations for research 63 Acknowedgements 65 References 69 Appendix 1 Tria Torrent 75 Appendix 2 Atopic Dermatitis Quaity of Life Index: preference-based index questionnaire 77 Appendix 3 Factor anaysis on tota daiy symptoms score 79 Appendix 4 Compier-average causa effect anaysis for key secondary outcomes 81 Queen s Printer and Controer of HMSO 2016. This work was produced by Francis et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xi

DOI: 10.3310/hta20190 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 19 List of tabes TABLE 1 Treatment arms 9 TABLE 2 Summary of data coection 11 TABLE 3 Characteristics of recruiting and non-recruiting practices 20 TABLE 4 Baseine characteristics 21 TABLE 5 Baseine symptom severity scores 22 TABLE 6 Objective assessment of cinica features 22 TABLE 7 Effect of ora and topica antibiotics on subjective and objective eczema severity, famiy impact and quaity of ife at 2 weeks, 4 weeks and 3 months 24 TABLE 8 Tota symptom score correation 26 TABLE 9 Area under the curve by treatment group for daiy tota symptom score 27 TABLE 10 Presence of S. aureus on the skin at baseine and foow-up by treatment group and overa 28 TABLE 11 Presence of resistant S. aureus on the skin at baseine and foow-up by treatment group and overa 28 TABLE 12 Presence of resistant S. aureus in the nose at baseine and foow-up by treatment group and overa 29 TABLE 13 Presence of resistant S. aureus in the mouth at baseine and foow-up by treatment group and overa 29 TABLE 14 Adverse events as recorded in the daiy symptom diary 30 TABLE 15 Heath-care consutations in the foow-up period 31 TABLE 16 Cost of contacts with primary and secondary care-based heath professionas at 4 weeks and from weeks 5 to 12 32 TABLE 17 Eczema-reated prescriptions by study group and overa, for the first 3 months 33 TABLE 18 Eczema-reated drug costs from over the 3 months foowing recruitment 33 TABLE 19 Cost of time off from work at 4 weeks and from weeks 5 to 12 34 TABLE 20 Adherence to study medication by treatment group 35 TABLE 21 Mean weight of remaining IMP by study group and overa 35 Queen s Printer and Controer of HMSO 2016. This work was produced by Francis et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xiii

LIST OF TABLES TABLE 22 Use of topica corticosteroids by treatment group 37 TABLE 23 Baseine data for compete cases and those missing 2-week foow-up POEM scores 38 TABLE 24 Effect of ora and topica antibiotics by presence of S. aureus on skin 38 TABLE 25 Answers provided and missing data for each question 41 TABLE 26 Missing data according to chid s sex 41 TABLE 27 Description of the ADQoL scores at each time point 42 TABLE 28 Spearman s correation between ADQoL and condition-specific heath outcome measures used in the study 43 TABLE 29 Spearman s correation of ADQoL scores with IDQoL scores (parenta competed) 44 TABLE 30 Spearman s correation of ADQoL scores with CDLQI scores 44 TABLE 31 Frequency and comparison of ADQoL scores at 2 weeks by cinica improvement as refected by the POEM score 44 TABLE 32 Standardised response mean at each time window 45 TABLE 33 Ease of competion of the preference-based ADQoL questionnaire 46 TABLE 34 Compier-average causa effect anaysis on POEM scores at 4 weeks and 3 months 81 TABLE 35 Compier-average causa effect anaysis on EASI scores at 2 weeks and 4 weeks 81 TABLE 36 Compier-average causa effect anaysis on DFI scores at 2 weeks, 4 weeks and 3 months 82 TABLE 37 Compier-average causa effect anaysis on IDQoL scores at 2 weeks, 4 weeks and 3 months 82 TABLE 38 Compier-average causa effect anaysis CDLQI scores at 2 weeks, 4 weeks and 3 months 83 xiv NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta20190 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 19 List of figures FIGURE 1 Study schema and participant fow diagram 4 FIGURE 2 Site recruitment fow diagram 19 FIGURE 3 Consoidated Standards of Reporting Trias fow diagram 20 FIGURE 4 Baseine, week 2, week 4 and 3-month POEM scores for each treatment group 25 FIGURE 5 Daiy tota symptom score for each treatment group over 4 weeks 27 FIGURE 6 Box pot of ADQoL at each time point 42 FIGURE 7 Preference-based ADQoL scores change over time 45 Queen s Printer and Controer of HMSO 2016. This work was produced by Francis et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xv

DOI: 10.3310/hta20190 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 19 List of abbreviations ADQoL ANCOVA CACE Atopic Dermatitis Quaity of Life Index anaysis of covariance compier-average causa effect IMP ITT MCID investigationa medicina product intention to treat minima cinicay important difference CDLQI Chidren s Dermatoogy Life Quaity Index MHRA Medicines and Heathcare products Reguatory Agency CI CNA CREAM confidence interva coistin and naidixic acid ChidRen with Eczema, Antibiotic Management NICE POEM QALY Nationa Institute for Heath and Care Exceence Patient-Orientated Eczema Measure quaity-adjusted ife-year CRF case report form R&D research and deveopment DFI Dermatitis Famiy Impact SAE serious adverse event EASI Eczema Area and Severity Index SD standard deviation EMR eectronic medica record SEWTU South East Waes Trias Unit EQ-5D GP HRQoL IDQoL European Quaity of Life-5 Dimensions genera practitioner heath-reated quaity of ife Infant s Dermatoogy Quaity of Life instrument SMPU SRM TCS TT St Mary s Pharmaceutica Unit standardised response mean topica corticosteroid Tria Torrent Queen s Printer and Controer of HMSO 2016. This work was produced by Francis et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xvii

DOI: 10.3310/hta20190 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 19 Pain Engish summary Eczema affects about one in five chidren in the UK. It tends to come and go, and fare-ups are sometimes triggered by infection. Many doctors give antibiotics for fares, but there is not much evidence to show whether or not they hep. The antibiotics can be given as a cream or by mouth. The ChidRen with Eczema, Antibiotic Management study was designed to find out if antibiotics hep improve eczema severity in chidren with infected eczema fares. A tota of 113 chidren aged < 8 years, with infected eczema, joined the study. Most chidren had reativey mid or moderate fares. The bacterium Staphyococcus aureus (which causes skin infections) was found on most chidren s skin. Every chid was given one of three treatments for 1 week: 1. ora antibiotics and pacebo cream 2. antibiotic cream and pacebo ora treatment; or 3. doube pacebo treatment. A chidren aso received standard eczema treatment with steroid creams/emoients. We coected detais about the chid s eczema and their genera heath, eczema severity, daiy symptoms, quaity of ife and impact on the famiy. We found that patients in a groups improved by 2 weeks, but patients in both antibiotic groups had sighty worse eczema scores than the pacebo group. The difference may have occurred by chance but we can be fairy confident that antibiotics do not reduce eczema severity by a worthwhie amount. They may even make it worse. We concude that most chidren with ess severey infected eczema shoud not be given antibiotics as ong as standard treatment (steroid creams/emoients) is offered. Queen s Printer and Controer of HMSO 2016. This work was produced by Francis et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xix

DOI: 10.3310/hta20190 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 19 Scientific summary Background Eczema affects approximatey 20% of chidren in the UK. Eczema is a reapsing remitting condition and a significant proportion of eczema fares wi be treated with antibiotics. Staphyococcus aureus has ong been known to be more prevaent on the skin of patients with eczema, and is found in higher densities in peope with more severe eczema. This has ed to a wide range of therapies and products intended to reduce the presence of S. aureus with the aim of reducing the severity and frequency of eczema fares. However, evidence for the effectiveness of these interventions is imited. A Cochrane systematic review pubished in 2008 (and an update pubished by the same authors in 2010) found that most studies were sma and at high risk of bias, and that the resuts were conficting. Ony three previous studies have evauated the effects of ora antibiotics in eczema, and ony one of these (33 chidren) invoved cinicay infected eczema, and this found no significant difference in eczema severity at foow-up. There was a simiar ack of cear evidence with regard to topica antibiotics, or indeed any antimicrobia agents, eading the authors of the review to concude that Their continued use shoud be questioned in such situations, unti better and onger-term studies show cear evidence of cinica benefit (Bath-Hexta FJ, Birnie AJ, Ravenscroft JC, Wiiams HC. Interventions to reduce Staphyococcus aureus in the management of atopic eczema: an updated Cochrane review. Br J Dermato 2010;163:12 26). This is important not ony because of the need to identify effective treatments for chidren with eczema, but aso to reduce the use of ineffective treatments currenty being prescribed. Widespread use of antimicrobias contributes to the deveopment of antimicrobia resistance and exposes chidren to possibe harms from adverse effects, so it is justifiabe ony where there is cear evidence of benefit. Objectives The main aim of this study was to evauate the cinica effectiveness of ora and topica antibiotics in chidren in the community with cinicay suspected infected eczema. The objectives were to assess the effects of ora and topica antibiotics, in addition to standard treatment with emoients and topica corticosteroids (TCSs), on: short-term (2 weeks) subjective eczema severity (primary) onger-term (4 weeks and 3 months) subjective eczema severity short- and onger-term objective eczema severity impact on the famiy, quaity of ife and daiy symptoms. In addition to: comparing ora and topica antibiotic treatments in terms of short- and ong-term effects, adverse effects, parent preference and effect on prevaence of coonisation/infection with resistant organisms vaidating a new condition-specific preference-based measure of heath for chidren describing the prevaence of antibiotic resistance in isoates at baseine and foow-up in those who received ora and topica antibiotics and pacebo. Queen s Printer and Controer of HMSO 2016. This work was produced by Francis et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xxi

SCIENTIFIC SUMMARY Methods We undertook a muticentre, doube-binded, individuay randomised, pacebo-controed tria in genera practices and dermatoogy cinics in Engand, Waes and Scotand. A tota of 91 genera practices and 4 dermatoogy cinics participated, of which 32 (35%) and one (25%), respectivey, recruited participants. Cinicians in participating centres opportunisticay identified chidren (aged 3 months to < 8 years) consuting who had eczema (as defined by U.K. Working Party) that was cinicay suspected of being infected. Recent use of antibiotics (past week) or (very) potent TCSs (2 days), suspected eczema herpeticum, significant comorbid iness, severe infection and aergy to study medication were a excusion criteria. Eigibe chidren were then seen by a research nurse within the next 72 hours for further eigibiity assessment, provision of informed consent, baseine data coection and provision of study medication. Participants were randomised to one of three study arms: ora antibiotic and topica pacebo (ora antibiotic); topica antibiotic and ora pacebo (topica antibiotic); or ora and topica pacebos (contro). Randomisation was conducted by study pharmacies using pre-prepared aocation ists using bock randomisation stratified by site and peniciin aergy status. Study medication packs were identica (with taste- and coour-matched pacebos). Participants, research nurses and cinica team were binded to the aocation. The interventions under evauation were fucoxaciin suspension or erythromycin suspension for those with peniciin aergy (dose according to age according to British Nationa Formuary guidance), and fusidic acid cream (Fucidin, Leo Laboratories Limited), appied three times a day, a for 1 week. In addition, a chidren were prescribed hydrocortisone 1% for use on the face and cobetastone butyrate 0.05% (or another moderate-strength TCS) for use on other parts of the body. Outcomes were measured at 2 and 4 weeks via visits from a research nurse and at 3 months via a posta questionnaire and swabs. In addition, we conducted a review of each patient s primary care medica record for the 3 months foowing randomisation. The primary outcome was a comparison of Patient-Orientated Eczema Measure (POEM; assesses subjective eczema severity over the preceding week) at 2 weeks between each active intervention group and the contro (pacebo/pacebo) group. Other outcomes incuded objective eczema measured using the Eczema Area and Severity Index (EASI), famiy impact using the Dermatitis Famiy Impact instrument, quaity of ife using the Infant s Dermatoogy Quaity of Life instrument or the Chidren s Dermatoogy Life Quaity Index, heath utiity status using a new preference-based disease-specific measure [Atopic Dermatitis Quaity of Life Index (ADQoL)], daiy symptoms, medication use, adverse effects, parenta views about treatment, consutations and microbioogy (presence of S. aureus and β-haemoytic streptococci on the skin and in the nose and mouth at baseine, 2 weeks and 3 months, and resistance in isoates at each time point). We panned to recruit 137 participants per treatment arm to have 90% power to detect difference of 3 in POEM scores. After 9 months of recruitment at a sower than anticipated rate, we used data from the first 69 participants to check the assumptions of the sampe size cacuation. This resuted in us using a smaer standard deviation (SD) for baseine POEM (SD 5.3) and a correation between baseine and week 2 POEM scores (SD 0.27) that resuted in an amended sampe size cacuation of 94 patients per arm. After 113 patients had been recruited a decision was made by the Heath Technoogy Assessment programme to terminate the tria eary due to sow recruitment. Resuts We randomised 113 chidren (36 to ora antibiotic, 37 to topica antibiotic and 40 to pacebo). Four chidren were recruited from dermatoogy cinics, the rest from primary care. Ony three chidren had peniciin aergy, and none of these was randomised to the ora antibiotic arm, so no chid received active ora erythromycin. We were abe to foow up 101 (89.4%) chidren at 2 weeks, 98 (86.7%) at 4 weeks and 74 (65.5%) at 3 months, and conduct a 3-month notes review for 97 (85.8%) participants. xxii NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta20190 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 19 Participants had a mean age of 3.1 (SD 2.1) years, 54% were femae, 80.5% were white, 74.6% had a fare that had asted for 14 days and 92.0% reported having one or more of weeping, crusting, pustues or painfu skin as a symptom at baseine. One hundred participants had their cinica features recorded objectivey by a research nurse (47 by photographs and 53 by competing a questionnaire directy whie examining the patient). Of these, 30.0%, 10.1%, 6.8% and 53.0% had moderate or severe crusting, weeping, pustues or erythema, respectivey. Mean baseine POEM scores were 13.42, 14.62 and 16.90 in the contro, ora antibiotic and topica antibiotic groups, respectivey. POEM scores at 2 weeks after correcting for baseine scores were higher (worse severity) in the ora antibiotic and topica antibiotic groups by 1.52 [95% confidence interva (CI) 1.35 to 4.40] and 1.49 (95% CI 1.55 to 4.53) than in the contro group. The ower bands of the CIs ( 1.35 and 1.55) are ess than the pubished minima cinicay important difference for POEM of 3.0, and therefore these resuts suggest that the interventions do not resut in cinicay meaningfu benefit in this popuation. EASI (objective severity) scores were aso higher (worse) in the intervention groups [by 0.20 (95% CI 0.12 to 0.52) and 0.42 (95% CI 0.09 to 0.75) for ora and topica antibiotics, respectivey] at 2 weeks. Anayses of impact on the famiy, quaity of ife, daiy symptom scores, and onger-term outcomes were a consistent with the finding of no or imited difference and a trend towards worse outcomes in the intervention groups. Daiy tota symptom scores improved over the first 7 days and then stabiised in a three groups. There was no difference in area under the curve between the three groups. Cuture of baseine skin swabs resuted in isoation of S. aureus from 69.6% of patients. By 2 weeks and 3 months this had reduced to 44.4% (95% CI 34.5% to 54.4%) and 36.1% (95% CI 24.7% to 47.5%), respectivey. Less than 10% of isoates were resistant to fucoxaciin at a time points and in a groups. A tota of 26.9% of S. aureus isoates from the skin were resistant to fusidic acid at baseine. This had increased to 31.1% overa (and 72.7% in the topica antibiotic group) by 2 weeks but decreased to 15.4% overa by 3 months. There were no significant between-group differences in reported adverse effects. New rash (17.5%) and diarrhoea (15.5%) were the most commony reported adverse events. Overa, participants reported taking 61.3% of ora antibiotic (or matched pacebo) doses and using 81.8% of topica antibiotic (or matched pacebo) appications. A compier-average casua effect anaysis to adjust for adherence produced resuts that were very simiar to the main anaysis. During the first 2 weeks, 55 patients used hydrocortisone 1% and 70 patients used cobetastone butyrate 0.05% (or another moderate-strength TCS). Participants appied a mean of 7.5 (SD 5.4) and 7.1 (SD 3.6) appications per week, respectivey, and there were no significant differences between groups. During the 3-month foow-up period, 74% and 11% of participants reported one or more primary care and secondary care consutations, respectivey. Sensitivity anayses, incuding adjusting for region and imputing missing data, produced simiar resuts to the main anayses. A post-hoc subgroup anaysis by presence of S. aureus on the skin or not found evidence of harm or no effect in those with S. aureus [increase in POEM of 2.20 (95% CI 1.06 to 5.50) and 1.79 (95% CI 1.67 to 5.25) for ora and topica antibiotics, respectivey] and wide CIs that incuded benefit, no effect and harm in those with negative cutures. Most parents reported that the ADQoL was easy to answer and refected the impact of eczema on their chid. Some parents of younger chidren found it difficut to answer, and other parents woud have iked additiona response options to accommodate heath status in between those currenty presented in the questionnaire. Correations with other heath outcome measures used in the study were significant, in the right direction and of moderate strength. The instrument showed good discriminate vaidity at 2 weeks and sensitivity to change was moderate for the change between baseine and 2 weeks. Queen s Printer and Controer of HMSO 2016. This work was produced by Francis et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xxiii

SCIENTIFIC SUMMARY Concusions The ChidRen with Eczema, Antibiotic Management study is the argest tria to date to evauate the effect of ora and topica antibiotic treatment for cinicay infected eczema in chidren, and the ony tria to be conducted in primary care, where most peope with eczema are treated. We used pragmatic incusion criteria, based around cinica suspicion of infection, and interventions that are commony used in routine cinica practice. Athough the study had to cose before reaching its recruitment target, and the CIs around our main effect sizes incude the nu and are wider than if we had recruited to target, we have provided strong evidence of ack of meaningfu cinica benefit from either ora or topica antibiotics in this popuation. One of the chaenges that contributed to recruitment probems was the ack of a cear definition of infected eczema, and uncear equipoise among some cinicians and parents around the roe of antibiotics in chidren with infected eczema. For this reason, our resuts may not be abe to be generaised to a chidren with suspected infected eczema. Nevertheess, a participants had cinicay suspected infected eczema, and the majority had features cassicay associated with infection as we as a positive cuture for S. aureus. Therefore, we beieve that for the majority of patients seen in primary care with a cinica suspicion of infection, antibiotics can be safey withhed as ong as adequate treatment with emoients and TCSs are provided and appropriate safety-netting is put in pace. Tria registration This tria is registered as European Union Drug Reguating Authorities Cinica Trias (EudraCT) number 2011-003591-37 and Internationa Standard Randomised Controed Tria Number (ISRCTN) 96705420. Funding Funding for this study was provided by the Heath Technoogy Assessment programme of the Nationa Institute for Heath Research. xxiv NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta20190 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 19 Chapter 1 Introduction Eczema is one of the most common disorders of chidhood. 1,2 It affects > 20% of chidren in most deveoped countries, 3 and up to 35% of chidren in the UK. 4 The prevaence appears to be increasing, 4 particuary in the deveoping word. 2 Of those affected, 45% deveop symptoms within the first 6 months of ife and 85% by the age of 5 years. 5 The annua treatment cost for chidren in the UK with eczema aged 1 5 years was 47M in 1995 6. 6 Athough not aways recognised by heath-care professionas as a serious medica condition, 7 eczema has a significant impact on the quaity of a chid s ife and that of their famiy; the more severe the eczema, the greater the effect. 8 For the chid, eczema can adversey infuence their emotiona and socia deveopment 9 and may predispose them to psychoogica difficuties. 10 One study found that eczema resuted in a greater impairment of quaity of ife than other skin conditions, incuding urticaria and acne, and that generaised eczema resuted in greater impairment in quaity of ife than rena disease, cystic fibrosis, asthma, epiepsy and diabetes. 11 The predominant symptom of itching causes seep disturbance in over 60% of chidren with eczema, 12 and chidren with eczema have more seep probems, a ower quaity of ife, and higher eves of attention deficit hyperactivity disorder and oppositiona behaviour than chidren who do not have eczema. 13 Preiminary evidence suggests that the disease is associated with ong-term behavioura and neurocognitive deficits, and that disturbed seep may contribute to this. 14 Disturbed seep aso has an impact on other members of the famiy, and parents of chidren with eczema report stress and socia isoation. 5 The appication of eczema treatments can resut in confict between parents and their chidren, and this can aso affect famiy reationships and drain the carers physica and emotiona resources. 15,16 In addition, there are significant burdens for famiies of chidren suffering with eczema. For exampe, parents report having to take time off work and financia oss as a resut of caring for their chid. 6 Infected eczema Eczema is a reapsing remitting condition, yet there is considerabe uncertainty about the cause of fares. 17 19 Eczema often resuts in skin that is dry, red, itchy, broken and sore, and can ead to a breakdown of the skin barrier. This makes the skin susceptibe to trigger factors such as irritants and aergens, as we as microbia coonisation and infections. 20 Staphyococcus aureus has ong been known to be more prevaent on the skin of patients with eczema. The organism can be isoated from up to 90% of patients with eczema 21,22 compared with between 5% and 25% of heathy subjects. 21,23 Furthermore, more severe eczema is associated with higher densities of the organisms 21,23,24 and more resistant strains. 25 There is evidence that a number of factors contribute to this propensity for coonisation and infection, incuding dysreguation of the adaptive immune response, reduced antimicrobia peptide eves, diminished recruitment of ces to the skin, to-ike receptor defects and epiderma barrier abnormaities. 26 The exact roe of S. aureus in the maintenance or exacerbation of eczema is not cear. However, there is increasing evidence for the roe of toxins with superantigenic properties (superantigens). 26 Queen s Printer and Controer of HMSO 2016. This work was produced by Francis et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. 1

INTRODUCTION Use of antimicrobia treatments for eczema Despite cear evidence for a reationship between eczema and the presence of S. aureus, there is a ack of carity about what constitutes infection and when antibiotic treatments are ikey to confer benefit. 27 A recenty updated Cochrane review 28 of antimicrobia interventions for peope with eczema, which incuded 26 studies and 1229 participants, found that most studies were sma and of poor quaity, and that athough there was evidence that interventions reduced the presence of S. aureus on the skin, none of the studies showed any meaningfu cinica benefit from antibiotics or other antimicrobia interventions, for either cinicay infected or non-infected eczema. The authors concuded that Their continued use shoud be questioned in such situations, unti better and onger-term studies show cear evidence of cinica benefit. 28 This is important not ony because of the need to identify effective treatments for chidren with eczema, but aso to reduce the use of ineffective treatments currenty being prescribed. Cinica experts estimate that chidren in the UK experience approximatey 900,000 eczema fares a year, and that approximatey 40% of them are treated with topica antibiotics. 29 Widespread use of antimicrobias is a key contributor to the deveopment of antimicrobia resistance and exposes chidren to possibe harms from adverse effects. Therefore, use of antibiotics is ony justifiabe where there is cear evidence of benefit. Topica antibiotics may be preferabe to systemic treatment, as they maximise the effective doses at the site of infection whie minimising the systemic effects. However, the prevaence of resistant strains of skin bacteria is steadiy increasing and cases of aergy or skin sensitisation are not uncommon. 30,31 Fusidic acid resistance has been shown to be reated to high eves of use, for exampe. 32 Therefore, once a decision is made to prescribe antibiotic treatment, it is uncear whether topica or ora antibiotics are most effective and which cause the east coatera damage to the microbiome in terms of driving resistance. Summary Eczema has a negative impact on the quaity of ife of paediatric patients and their famiies. Ora and topica antibiotics are widey used to treat cinicay infected eczema in primary care and yet there is insufficient evidence to be sure whether this estabished practice either heps or harms patients and, if antibiotics hep, which route (topica or ora) does most good, causes east harm and is preferred by parents. Therefore, there is a cear need to identify whether or not ora and topica antibiotics confer meaningfu benefit to chidren with cinicay infected eczema. The ChidRen with Eczema, Antibiotic Management (CREAM) study aims to benefit patients with eczema (and their famiies), as we as heping to address the important issue of antibiotic use and resistance, by addressing this gap in the evidence. 2 NIHR Journas Library www.journasibrary.nihr.ac.uk