HEALTH TECHNOLOGY ASSESSMENT

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1 HEALTH TECHNOLOGY ASSESSMENT VOLUME 22 ISSUE 24 MAY 2018 ISSN Continuous ow-dose antibiotic prophyaxis to prevent urinary tract infection in aduts who perform cean intermittent sef-catheterisation: the AnTIC RCT Robert Pickard, Thomas Chadwick, Yemi Ouboyede, Catherine Brennand, Aexander von Wiamowitz-Moeendorff, Doreen McCurg, Jennifer Wikinson, Laura Ternent, Hoy Fisher, Katherine Waton, Eaine McCo, Luke Vae, Ruth Wood, Mohamed Abde-Fattah, Pau Hiton, Mandy Fader, Simon Harrison, James Larcombe, Pau Litte, Anthony Timoney, James N Dow, Heather Armstrong, Nicoa Morris, Kerry Waker and Nikesh Thiruchevam DOI /hta22240

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3 Continuous ow-dose antibiotic prophyaxis to prevent urinary tract infection in aduts who perform cean intermittent sef-catheterisation: the AnTIC RCT Robert Pickard, 1 * Thomas Chadwick, 2 Yemi Ouboyede, 2 Catherine Brennand, 3 Aexander von Wiamowitz-Moeendorff, 3 Doreen McCurg, 4 Jennifer Wikinson, 3 Laura Ternent, 2 Hoy Fisher, 2 Katherine Waton, 5 Eaine McCo, 2 Luke Vae, 2 Ruth Wood, 3 Mohamed Abde-Fattah, 6 Pau Hiton, 7 Mandy Fader, 8 Simon Harrison, 9 James Larcombe, 10 Pau Litte, 11 Anthony Timoney, 12 James N Dow, 6 Heather Armstrong, 13 Nicoa Morris, 12 Kerry Waker 4 and Nikesh Thiruchevam 14 1 Institute of Ceuar Medicine, Newcaste University, Newcaste upon Tyne, UK 2 Institute of Heath and Society, Newcaste University, Newcaste upon Tyne, UK 3 Newcaste Cinica Trias Unit, Newcaste University, Newcaste upon Tyne, UK 4 Nursing, Midwifery and Aied Heath Professions Research Unit, Gasgow Caedonian University, Gasgow, UK 5 Department of Microbioogy, Newcaste upon Tyne Hospitas NHS Foundation Trust, Freeman Hospita, Newcaste upon Tyne, UK 6 Institute of Appied Heath Sciences, University of Aberdeen, Aberdeen, UK 7 Facuty of Medica Sciences, Newcaste University, Newcaste upon Tyne, UK 8 Heath Sciences, University of Southampton, Southampton, UK 9 Department of Uroogy, Mid-Yorkshire Hospitas NHS Trust, Pinderfieds Hospita, Wakefied, UK 10 Skerne Medica Centre, Sedgefied, UK 11 Primary Care and Popuation Sciences, University of Southampton, Southampton, UK 12 Bristo Uroogica Institute, North Bristo NHS Trust, Bristo, UK 13 Patient representative, no affiiation 14 Department of Uroogy, Cambridge University Hospitas NHS Foundation Trust, Cambridge, UK *Corresponding author Chief investigator

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5 Decared competing interests of authors: Robert Pickard reports grants from the Nationa Institute for Heath Research (NIHR) during the conduct of the study. Thomas Chadwick reports grants from the NIHR Heath Technoogy Assessment (HTA) programme during the conduct of the study and outside the submitted work. Katherine Waton reports grants from NIHR during the conduct of the study. Eaine McCo reports grants from the NIHR HTA programme during the conduct of the study and from the NIHR Journas Library outside the submitted work. From 2013 to 2016 she was an editor for the NIHR Programme Grants for Appied Research (PGfAR) series, with a fee paid to her empoying organisation. Luke Vae reports that he is a member of the NIHR HTA Cinica Evauation and Trias pane and is co-director of NIHR Research Design Service North East. Mohamed Abde-Fattah reports grants from Bard Medica UK (Crawey, UK), Asteas Pharma Inc. (Tokyo, Japan), Coopast (Humebæk, Denmark), Pfizer Inc. (New York, NY, USA), Advanced Medica Soutions [(AMS) Winsford, UK] and Ethicon Inc. (Somervie, NJ, USA) outside the submitted work and is a member of the HTA Interventiona Procedures pane. Pau Hiton reports a grant from the NIHR HTA programme during the conduct of the study and grants from the Wiiam Harker Foundation and Webeing of Women outside the submitted work. He was a member of the Nationa Institute for Heath and Care Exceence (NICE) Interventiona Procedures Advisory Committee (2002 7), NIHR Evauation, Trias and Studies Coordinating Centre (NETSCC)-HTA Therapeutic Procedures Pane (2007 8) and NETSCC-HTA Cinica Evauations and Trias Prioritisation Group ( ). He chaired the NICE deveopment group for cinica guideine on urinary incontinence in women (2004 7). Mandy Fader reports grants from NIHR (reference number RP-PG ) and from the Sma Business Research Initiative grant outside the submitted work. Simon Harrison reports grants from the NIHR HTA programme (reference number 11/72/01) during the conduct of the study. James Larcombe reports grants from the NIHR HTA programme during the conduct of the study and is a member of the HTA Eective and Emergency Speciaist Care pane. Pau Litte reports that he is director of PGfAR and editor-in-chief of the PGfAR pubication in the NIHR Journas Library. James N Dow is a member of the HTA Genera Board. Nikesh Thiruchevam reports grants from Asteas, non-financia support from Asteas and persona fees from Coopast outside the submitted work. Pubished May 2018 DOI: /hta22240 This report shoud be referenced as foows: Pickard R, Chadwick T, Ouboyede Y, Brennand C, von Wiamowitz-Moeendorff A, McCurg D, et a. Continuous ow-dose antibiotic prophyaxis to prevent urinary tract infection in aduts who perform cean intermittent sef-catheterisation: the AnTIC RCT. Heath Techno Assess 2018;22(24). Heath Technoogy Assessment is indexed and abstracted in Index Medicus/MEDLINE, Excerpta Medica/EMBASE, Science Citation Index Expanded (SciSearch ) and Current Contents / Cinica Medicine.

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7 Heath Technoogy Assessment HTA/HTA TAR ISSN (Print) ISSN (Onine) Impact factor: Heath Technoogy Assessment is indexed in MEDLINE, CINAHL, EMBASE, The Cochrane Library and the Carivate Anaytics Science Citation Index. This journa is a member of and subscribes to the principes of the Committee on Pubication Ethics (COPE) ( Editoria contact: journas.ibrary@nihr.ac.uk The fu HTA archive is freey avaiabe to view onine at Print-on-demand copies can be purchased from the report pages of the NIHR Journas Library website: 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 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: This report The research reported in this issue of the journa was funded by the HTA programme as project number 11/72/01. The contractua start date was in September The draft report began editoria review in August 2017 and was accepted for pubication in January 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 and Socia Care. 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 and Socia Care. Queen s Printer and Controer of HMSO This work was produced by Pickard et a. under the terms of a commissioning contract issued by the Secretary of State for Heath and Socia Care. 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 ( produced by Prepress Projects Ltd, Perth, Scotand (

8 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 EME Programme, UK NIHR Journas Library Editors Professor Ken Stein Chair of HTA and EME Editoria Board and Professor of Pubic Heath, University of Exeter Medica Schoo, UK Professor Andrée Le May Chair of NIHR Journas Library Editoria Group (HS&DR, PGfAR, PHR journas) Dr Martin Ashton-Key Consutant in Pubic Heath Medicine/Consutant Advisor, NETSCC, UK Professor Matthias Beck Professor of Management, Cork University Business Schoo, Department of Management and Marketing, University Coege Cork, Ireand Dr Tessa Criy Director, Crysta Bue Consuting Ltd, UK Dr Eugenia Cronin Senior Scientific Advisor, Wessex Institute, UK Dr Peter Davidson Director of the NIHR Dissemination Centre, University of Southampton, UK Ms Tara Lamont Scientific Advisor, NETSCC, UK Dr Catriona McDaid Senior Research Feow, York Trias Unit, Department of Heath Sciences, University of York, UK Professor Wiiam McGuire Professor of Chid Heath, Hu York Medica Schoo, University of York, UK Professor Geoffrey Meads Professor of Webeing Research, University of Winchester, UK Professor John Norrie Chair in Medica Statistics, University of Edinburgh, 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 Great Ormond Street 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 Professor Martin Underwood Director, Warwick Cinica Trias Unit, Warwick Medica Schoo, University of Warwick, UK Pease visit the website for a ist of members of the NIHR Journas Library Board: Editoria contact: journas.ibrary@nihr.ac.uk NIHR Journas Library

9 DOI: /hta22240 HEALTH TECHNOLOGY ASSESSMENT 2018 VOL. 22 NO. 24 Abstract Continuous ow-dose antibiotic prophyaxis to prevent urinary tract infection in aduts who perform cean intermittent sef-catheterisation: the AnTIC RCT Robert Pickard, 1 * Thomas Chadwick, 2 Yemi Ouboyede, 2 Catherine Brennand, 3 Aexander von Wiamowitz-Moeendorff, 3 Doreen McCurg, 4 Jennifer Wikinson, 3 Laura Ternent, 2 Hoy Fisher, 2 Katherine Waton, 5 Eaine McCo, 2 Luke Vae, 2 Ruth Wood, 3 Mohamed Abde-Fattah, 6 Pau Hiton, 7 Mandy Fader, 8 Simon Harrison, 9 James Larcombe, 10 Pau Litte, 11 Anthony Timoney, 12 James N Dow, 6 Heather Armstrong, 13 Nicoa Morris, 12 Kerry Waker 4 and Nikesh Thiruchevam 14 1 Institute of Ceuar Medicine, Newcaste University, Newcaste upon Tyne, UK 2 Institute of Heath and Society, Newcaste University, Newcaste upon Tyne, UK 3 Newcaste Cinica Trias Unit, Newcaste University, Newcaste upon Tyne, UK 4 Nursing, Midwifery and Aied Heath Professions Research Unit, Gasgow Caedonian University, Gasgow, UK 5 Department of Microbioogy, Newcaste upon Tyne Hospitas NHS Foundation Trust, Freeman Hospita, Newcaste upon Tyne, UK 6 Institute of Appied Heath Sciences, University of Aberdeen, Aberdeen, UK 7 Facuty of Medica Sciences, Newcaste University, Newcaste upon Tyne, UK 8 Heath Sciences, University of Southampton, Southampton, UK 9 Department of Uroogy, Mid-Yorkshire Hospitas NHS Trust, Pinderfieds Hospita, Wakefied, UK 10 Skerne Medica Centre, Sedgefied, UK 11 Primary Care and Popuation Sciences, University of Southampton, Southampton, UK 12 Bristo Uroogica Institute, North Bristo NHS Trust, Bristo, UK 13 Patient representative, no affiiation 14 Department of Uroogy, Cambridge University Hospitas NHS Foundation Trust, Cambridge, UK *Corresponding author robert.pickard@newcaste.ac.uk Chief investigator Background: Peope carrying out cean intermittent sef-catheterisation (CISC) to empty their badder often suffer repeated urinary tract infections (UTIs). Continuous once-daiy, ow-dose antibiotic treatment (antibiotic prophyaxis) is commony advised but knowedge of its effectiveness is acking. Objective: To assess the benefit, harms and cost-effectiveness of antibiotic prophyaxis to prevent UTIs in peope who perform CISC. Design: Parae-group, open-abe, patient-randomised 12-month tria of aocated intervention with 3-monthy foow-up. Outcome assessors were bind to aocation. Setting: UK NHS, with recruitment of patients from 51 sites. Queen s Printer and Controer of HMSO This work was produced by Pickard et a. under the terms of a commissioning contract issued by the Secretary of State for Heath and Socia Care. 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

10 ABSTRACT Participants: Four hundred and four aduts performing CISC and predicted to continue for 12 months who had suffered at east two UTIs in the previous year or had been hospitaised for a UTI in the previous year. Interventions: A centra randomisation system using random bock aocation set by an independent statistician aocated participants to the experimenta group [once-daiy ora antibiotic prophyaxis using either 50 mg of nitrofurantoin, 100 mg of trimethoprim (Kent Pharmaceuticas, Ashford, UK) or 250 mg of cefaexin (Sandoz Ltd, Hozkirchen, Germany); n = 203] or the contro group of no prophyaxis (n = 201), both for 12 months. Main outcome measures: The primary cinica outcome was reative frequency of symptomatic, antibiotic-treated UTI. Cost-effectiveness was assessed by cost per UTI avoided. The secondary measures were microbioogicay proven UTI, antimicrobia resistance, heath status and participants attitudes to antibiotic use. Resuts: The frequency of symptomatic antibiotic-treated UTI was reduced by 48% using prophyaxis [incidence rate ratio (IRR) 0.52, 95% confidence interva (CI) 0.44 to 0.61; n = 361]. Reduction in microbioogicay proven UTI was simiar (IRR 0.49, 95% CI 0.39 to 0.60; n = 361). Absoute reduction in UTI episodes over 12 months was from a median (interquartie range) of 2 (1 4) in the no-prophyaxis group (n = 180) to 1 (0 2) in the prophyaxis group (n = 181). The resuts were unchanged by adjustment for days at risk of UTI and the presence of factors giving higher risk of UTI. Deveopment of antimicrobia resistance was seen more frequenty in pathogens isoated from urine and Escherichia coi from periana swabs in participants aocated to antibiotic prophyaxis. The use of prophyaxis incurred an extra cost of 99 to prevent one UTI (not incuding costs reated to increased antimicrobia resistance). The emotiona and practica burden of CISC and UTI infuenced we-being, but heath status measured over 12 months was simiar between groups and did not deteriorate significanty during UTI. Participants were generay unconcerned about using antibiotics, incuding the possibe deveopment of antimicrobia resistance. Limitations: Lack of binding may have ed participants in each group to use different threshods to trigger reporting and treatment-seeking for UTI. Concusions: The resuts of this arge randomised tria, conducted in accordance with best practice, demonstrate cear benefit for antibiotic prophyaxis in terms of reducing the frequency of UTI for peope carrying out CISC. Antibiotic prophyaxis use appears safe for individuas over 12 months, but the emergence of resistant urinary pathogens may prejudice onger-term management of recurrent UTI and is a pubic heath concern. Future work incudes onger-term studies of antimicrobia resistance and studies of non-antibiotic preventative strategies. Tria registration: Current Controed Trias ISRCTN and EudraCT Funding: This project was funded by the Nationa Institute for Heath Research Heath Technoogy Assessment programme and wi be pubished in fu in Heath Technoogy Assessment Vo. 22, No. 24. See the NIHR Journas Library website for further project information. viii NIHR Journas Library

11 DOI: /hta22240 HEALTH TECHNOLOGY ASSESSMENT 2018 VOL. 22 NO. 24 Contents List of tabes List of figures List of boxes List of abbreviations Pain Engish summary Scientific summary xiii xv xvii xix xxi xxiii Chapter 1 Introduction (background and objectives) 1 Scientific background 1 Cean intermittent sef-catheterisation 1 Prevaence of use of cean intermittent sef-catheterisation in the UK 1 Recurrent urinary tract infection among peope using intermittent catheterisation 1 Evidence for use of antibiotic prophyaxis 2 Antibiotic stewardship 2 Summary with impications for tria design 3 Aims and objectives 3 Primary objectives 3 Secondary objectives 3 Chapter 2 Methods 5 Summary of tria design 5 Sites 5 Participants 5 Consent procedures 8 Randomisation 8 Progress in tria 8 Participant expenses 9 Withdrawa of participants 9 Patient and pubic Invovement 9 Outcome measurement 9 Primary cinica outcome 9 Secondary outcomes 10 Microbioogica outcomes 11 Data coection 11 Summary 11 Tria events 11 Data handing and record keeping 12 Detais of tria medication 12 Panned interventions 12 Antibiotic prophyaxis (experimenta) 12 No prophyaxis 14 Queen s Printer and Controer of HMSO This work was produced by Pickard et a. under the terms of a commissioning contract issued by the Secretary of State for Heath and Socia Care. 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

12 CONTENTS Standard care for both groups 14 Deivery of interventions 14 Funding of tria intervention 14 Sampe size cacuation 15 Statistica anaysis 15 Tria progress and monitoring 16 Sources of bias 16 Microbioogica methods 17 Definition of end of tria 18 Compiance and withdrawa 18 Assessment of adherence 18 Data monitoring, quaity contro and assurance 18 Tria fow chart 19 Ethics and governance 20 Tria registration and protoco avaiabiity 20 Serious adverse event reporting 21 Chapter 3 Resuts 23 Recruitment 23 Participant fow 23 Baseine data 23 Numbers anaysed 28 Outcomes 29 Primary cinica outcome 29 Secondary outcomes 29 Chapter 4 Economic evauation 51 Introduction 51 Methods 51 NHS resource use and costs to the participant and their main caregiver 51 Derivation of costs 52 Estimation of effects 54 Anaysis of costs and benefits 54 Comparative incrementa anayses of costs and outcomes between tria groups 56 Missing data 56 Sensitivity anaysis 56 Resuts 57 Response rates 57 Resource use and costs 58 Outcomes 60 Economic evauation 61 Concusion 67 Summary 67 Chapter 5 Quaitative study 69 Introduction 69 Methods 69 Design 69 Participant recruitment and samping 69 Data coection 69 Anaysis of the interviews 71 x NIHR Journas Library

13 DOI: /hta22240 HEALTH TECHNOLOGY ASSESSMENT 2018 VOL. 22 NO. 24 Resuts 71 Impact of cean intermittent sef-catheterisation and urinary tract infection on quaity of ife 71 Views on antibiotics 73 Adherence to the AnTIC tria aocation (prophyaxis and no prophyaxis) 74 Discussion 75 Summary of findings and impications 75 Strengths and imitations of the quaitative study 77 Concusion 77 Chapter 6 Discussion 79 Statement and interpretation of resuts 79 Strengths and imitations 80 Generaisabiity 82 Chapter 7 Concusions 83 Recommendations for research 83 Acknowedgements 85 References 91 Appendix 1 Resuts suppementary information 97 Appendix 2 Quaitative suppementary information 101 Queen s Printer and Controer of HMSO This work was produced by Pickard et a. under the terms of a commissioning contract issued by the Secretary of State for Heath and Socia Care. 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

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15 DOI: /hta22240 HEALTH TECHNOLOGY ASSESSMENT 2018 VOL. 22 NO. 24 List of tabes TABLE 1 Recruitment sites and PICs with number of participants enroed at site or identified at PICs: hubs and additiona sites 6 TABLE 2 Schedue of tria interventions and outcome data coection from participants 13 TABLE 3 Changes to the protoco requiring reguatory approva 20 TABLE 4 Reasons for ineigibiity 26 TABLE 5 Reasons for withdrawa 26 TABLE 6 Baseine participant characteristics 27 TABLE 7 Eigibiity for incusion in primary anaysis 29 TABLE 8 Resuts of performing Poisson regression on number of symptomatic UTI and frequency of symptomatic UTI 30 TABLE 9 Resuts of performing Poisson regression on number of microbioogicay confirmed UTI and frequency of microbioogicay confirmed UTI 34 TABLE 10 Resuts of performing Poisson regression on rate of asymptomatic bacteriuria and frequency of asymptomatic bacteriuria 35 TABLE 11 Isoates from urine specimens submitted every 3 months (asymptomatic) and at time of UTI 35 TABLE 12 Adverse events reating to prophyaxis and treatment antibiotics from heath-care record, participant review CRF and participant-competed UTI record 36 TABLE 13 Test of trend for resistance of pathogens isoated from surveiance urine sampes submitted during asymptomatic state 46 TABLE 14 Chi-squared test of resistance between groups during asymptomatic state at 9 12 months and periana swabs at 6 12 months 46 TABLE 15 Treatment Satisfaction Questionnaire for Medication scores, with comparisons by group (maximum rating = 100 for each domain) 47 TABLE 16 Numbers of participants with SF-36v2 data avaiabe for each stage of the study 47 TABLE 17 Short Form questionnaire-36 items version 2 MCS and PCS score measurements, by study group at each time point 48 TABLE 18 Short Form questionnaire-36 items version 2 PCS and MCS mean adjusted and unadjusted score comparison at 6 months and 12 months between study groups 49 Queen s Printer and Controer of HMSO This work was produced by Pickard et a. under the terms of a commissioning contract issued by the Secretary of State for Heath and Socia Care. 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

16 LIST OF TABLES TABLE 19 Response rates for economic data 57 TABLE 20 Resourceuseover12months foow-up for those with fu economic data 58 TABLE 21 Tota costs over 12 months foow-up incuding a participants with fu economic data 59 TABLE 22 Tota prescriptions and antibiotic cost per group over 12 months foow-up 60 TABLE 23 Tota costs per group over 12 months foow-up for those with fu economic data 60 TABLE 24 Comparisons of outcome: baseine and 6 and 12 months 61 TABLE 25 Maximum WTP to avoid one UTI episode over a 12-month period 61 TABLE 26 Deterministic and probabiistic cost-effectiveness resuts 62 TABLE 27 Deterministic and probabiistic cost utiity resuts 64 TABLE 28 Deterministic and probabiistic cost benefit resuts 66 TABLE 29 Characteristics of interviewees 70 TABLE 30 Reported SUSAR 97 TABLE 31 Reported SAR 97 TABLE 32 Reported SAEs resuting in death (assessed as unreated to the intervention) 97 TABLE 33 Reported SAEs (assessed as unreated to the intervention) 97 TABLE 34 Change in egfr and serum ALT measuring kidney and iver function respectivey at baseine and 12 months, with comparison between groups 99 xiv NIHR Journas Library

17 DOI: /hta22240 HEALTH TECHNOLOGY ASSESSMENT 2018 VOL. 22 NO. 24 List of figures FIGURE 1 Diagram showing the panned fow of participants through the tria 19 FIGURE 2 Recruitment by month 24 FIGURE 3 Tria Consoidated Standards of Reporting Trias (CONSORT) diagram 25 FIGURE 4 Bar charts showing frequency distribution (a d) and mean (SEM) frequency (e h) of primary outcome and secondary outcomes over the 12-month observation period 31 FIGURE 5 Resistance rates (%) potted over the 12-month tria duration for pathogens isoated from urine specimens taken during symptomatic UTI, by antibiotic and group 37 FIGURE 6 Resistance rates (%) potted over time for bacteria isoated from urine specimens taken during asymptomatic state, by antibiotic and group 40 FIGURE 7 Resistance rates potted over time for E. coi strains isoated from periana swabs, by antibiotic and group 43 FIGURE 8 Cost-effectiveness pane for prophyaxis vs. no prophyaxis: adjusted bootstrapped repications for CEA 63 FIGURE 9 Cost-effectiveness acceptabiity curves for prophyaxis vs. no prophyaxis: adjusted bootstrapped repications for CEA 63 FIGURE 10 Cost-effectiveness pane for prophyaxis vs. no prophyaxis: adjusted bootstrapped repications for primary CUA 65 FIGURE 11 Cost benefit pane for prophyaxis vs. no prophyaxis: adjusted bootstrapped repications for CBA 67 Queen s Printer and Controer of HMSO This work was produced by Pickard et a. under the terms of a commissioning contract issued by the Secretary of State for Heath and Socia Care. 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

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19 DOI: /hta22240 HEALTH TECHNOLOGY ASSESSMENT 2018 VOL. 22 NO. 24 List of boxes BOX 1 Interview guide summary 101 Queen s Printer and Controer of HMSO This work was produced by Pickard et a. under the terms of a commissioning contract issued by the Secretary of State for Heath and Socia Care. 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

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21 DOI: /hta22240 HEALTH TECHNOLOGY ASSESSMENT 2018 VOL. 22 NO. 24 List of abbreviations AE adverse event MS Society Mutipe Scerosis Society ALT aanine transaminase NCTU Newcaste Cinica Trias Unit ANCOVA AnTIC BIA CBA CDC anaysis of covariance Antibiotic Treatment for Intermittent Catheterisation British Infection Association cost benefit anaysis Centers for Disease Contro and Prevention NICE NIHR PCS PI PIC Nationa Institute for Heath and Care Exceence Nationa Institute for Heath Research physica component summary principa investigator participant identification centre CEA cost-effectiveness anaysis PSS Persona Socia Services CEAC CFU CI CISC CRF CRN CUA DMC e-crf egfr EUCAST GBP GCP GP cost-effectiveness acceptabiity curve coony-forming unit confidence interva cean intermittent sef-catheterisation case report form Cinica Research Network cost utiity anaysis Data Monitoring Committee eectronic case report form estimated gomeruar fitration rate European Committee on Antimicrobia Susceptibiity Testing Great British pound Good Cinica Practice genera practitioner QALY QoL RCT REC RSI SAE SAP SAR SD SF-36v2 SF-6D SmPC SOP SUSAR quaity-adjusted ife-year quaity of ife randomised controed tria Research Ethics Committee Reference Safety Information serious adverse event statistica anaysis pan serious adverse reaction standard deviation Short Form questionnaire-36 items version 2 Short Form questionnaire-6 Dimensions Summary of Product Characteristics standard operating procedure suspected unexpected serious adverse reaction HCP heath-care professiona TMG Tria Management Group ID identification TSC Tria Steering Committee IQR IRR ITT MCS interquartie range incidence rate ratio intention to treat menta component summary TSQM UTI WTP Treatment Satisfaction Questionnaire for Medication urinary tract infection wiingness to pay MHRA Medicines and Heathcare products Reguatory Agency Queen s Printer and Controer of HMSO This work was produced by Pickard et a. under the terms of a commissioning contract issued by the Secretary of State for Heath and Socia Care. 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

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23 DOI: /hta22240 HEALTH TECHNOLOGY ASSESSMENT 2018 VOL. 22 NO. 24 Pain Engish summary Peope who have troube emptying their badders naturay often use a fine tube (catheter) inserted through the urine channe (urethra) into the badder to drain urine 3 5 times a day. This is caed cean intermittent sef-catheterisation (CISC). About one-third of peope who use CISC suffer frequent urinary tract infections (UTIs) that require antibiotic treatment. The repeated use of antibiotics may cause side effects and resut in bacteria becoming resistant to antibiotics. This tria was conducted to find out whether or not taking a daiy ow dose of antibiotic (prophyaxis) over 12 months was better than not taking prophyaxis in reducing the rate of infection for peope carrying out CISC who suffer from repeated UTIs. A tota of 404 peope took part in the tria. They were divided into two groups: 203 peope took prophyaxis and 201 peope did not. To make a fair comparison, peope were put into the two groups at random using a computer program. We foowed those who took part for 12 months and counted how many UTIs they suffered. We found that peope taking prophyaxis had haf as many UTIs as those who did not use prophyaxis. The use of prophyaxis seemed worthwhie to patients and the NHS, with few side effects and ony a sma additiona cost. Taking prophyaxis did not seem to improve overa we-being. This appeared to be because participants fet that UTI, athough unpeasant, was not as bad as other heath probems that they had to dea with. The main drawback was that infecting bacteria were more ikey to deveop resistance to antibiotics in peope taking prophyaxis, making it more difficut to treat infection in those individuas and threatening pubic heath. These resuts wi hep patients using CISC who suffer from repeated UTIs to decide whether or not taking prophyaxis is right for them. Queen s Printer and Controer of HMSO This work was produced by Pickard et a. under the terms of a commissioning contract issued by the Secretary of State for Heath and Socia Care. 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

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25 DOI: /hta22240 HEALTH TECHNOLOGY ASSESSMENT 2018 VOL. 22 NO. 24 Scientific summary Background Cean intermittent sef-catheterisation (CISC) is an important management option for peope who cannot empty their badder naturay due to badder outet obstruction or the faiure of badder musce contraction, often associated with neuroogica disease. Recurrent urinary tract infection (UTI) is common among CISC users, affecting 12 88% of patients. This tria was motivated by the need to determine whether or not the possibe benefit of continuous, once-daiy ow-dose antibiotic (prophyaxis) for recurrent UTI seen in sma trias in specific groups coud be appied to the wider popuation of adut CISC users. Any benefit must be worthwhie to patients and society in terms of financia costs and harms, incuding the emergence of antimicrobia resistance. Objectives The hypothesis addressed is that an experimenta strategy of once-daiy ow-dose antibiotic prophyaxis wi reduce the rate of symptomatic antibiotic-treated UTI by 20% compared with a contro strategy of no prophyaxis over a 12-month tria period. To investigate this hypothesis, the foowing objectives were set. Primary objectives Determine the impact of prophyaxis on incidence of symptomatic antibiotic-treated UTI. Determine the incrementa cost per symptomatic UTI avoided. Secondary objectives Determine the effect of prophyaxis on incidence of microbioogicay confirmed UTI. Determine the rates of fever and hospitaisation because of UTI. Determine the rates of asymptomatic bacteriuria. Record adverse events (AEs) reated to use of prophyactic and treatment antibiotics. Assess change in resistance of pathogens isoated from urine and from periana swabs. Measure overa satisfaction with prophyactic antibiotic treatment. Determine the reative effect on heath status. Measure the incrementa cost per quaity-adjusted ife-year (QALY) gained. Assess participants wiingness to pay (WTP) to avoid a UTI. Quaitativey assess the experience and impact of using CISC and suffering recurrent UTI, exporing heath beiefs concerning tria interventions, antibiotic use and antimicrobia resistance. Methods Design An open-abe, patient-randomised, parae-group superiority tria comparing an experimenta strategy of once-daiy ow-dose antibiotic prophyaxis using 50 mg of nitrofurantoin, 100 mg of trimethoprim (Kent Pharmaceuticas, Ashford, UK) or 250 mg of cefaexin (Sandoz Ltd, Hozkirchen, Germany) with a contro strategy of no prophyaxis in aduts using CISC who suffer recurrent UTI over 12 months. A centraised randomisation system using random bock aocation set by an independent statistician aocated Queen s Printer and Controer of HMSO This work was produced by Pickard et a. under the terms of a commissioning contract issued by the Secretary of State for Heath and Socia Care. 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

26 SCIENTIFIC SUMMARY participants to each group. Centra trias office and aboratory staff assessed outcomes without knowedge of participants aocated group. Setting and participants The tria was set in the UK, recruiting participants from primary, community and secondary care NHS organisations. Incusion criteria Adut aged 18 years. Estabished user of CISC who was predicted to continue using it for 12 months. Abe to give informed consent for participation in the tria. Abe and wiing to adhere to a 12-month foow-up period. Had suffered either at east two episodes of UTI reated to CISC in the previous 12 months or at east one episode of UTI requiring hospitaisation. Or, for those aready using prophyaxis, the competion of a 3-month washout period without prophyaxis. Abe to take a once-daiy ora dose of at east one of 50 mg of nitrofurantoin, 100 mg of trimethoprim or 250 mg of cefaexin. Patients were excuded if they were taking prophyactic antibiotic against UTI and decining the 3-month washout period. Women who were pregnant or breastfeeding, or who intended to become pregnant during the tria period, and peope unabe to give informed consent were excuded. Measurement of cinica outcomes Primary Occurrence of cinica UTI was defined as the presence of symptoms together with taking a treatment course of antibiotic for UTI. This was measured by participant return of a UTI record for each event, as we as a 3-monthy participant questionnaire and a 3-monthy tria visit case report form (CRF) competed by the oca research team. At the end of the tria, these records were reviewed by two members of the centra tria team and the primary outcome adjudicated in accordance with a written protoco to avoid doube-counting of episodes. Any disagreement or uncertainty was arbitrated by a third member of the centra tria team, who aso checked 10% of episodes. A outcome assessors were unaware of aocated group. Secondary Microbioogicay proven UTI was defined as the confirmed report of symptomatic antibiotic-treated UTI (primary outcome) together with a positive urine cuture. In addition, a fever of > 38 C and hospitaisation for UTI were recorded. We defined a positive cuture as the presence of one or two isoates at coony-forming units/m. Asymptomatic bacteriuria was defined as a positive cuture from urine specimens submitted at baseine and 3, 6, 9 and 12 months in the absence of cinica UTI. Adverse reactions reated to prophyaxis and the treatment antibiotic were recorded by a participantcompeted UTI record and a 3-monthy participant questionnaire, in addition to a 3-monthy visit CRF and heath record review competed by oca research staff. AEs were coected by 3-monthy heath record review and those deemed serious (serious adverse events) were sent urgenty to the centra tria office by fax transmission. Bacteria ecoogica change was assessed by comparing resistance patterns of pathogens isoated from urine specimens sent to the centra aboratory by participants at the time of UTI with pathogens isoated during asymptomatic periods at the time of 3-monthy review visits. Changes to Escherichia coi coonising the faeca microbiome were assessed by cuture of periana swabs taken at baseine and 6- and 12-month tria visits. xxiv NIHR Journas Library

27 DOI: /hta22240 HEALTH TECHNOLOGY ASSESSMENT 2018 VOL. 22 NO. 24 Satisfaction with prophyactic antibiotic treatment was measured by participant competion of the Treatment Satisfaction Questionnaire for Medication (TSQM) at 12 months encompassing domains for effectiveness, side effects and convenience. Heath status over 12 months was assessed by participant competion of the Short Form questionnaire-36 items version 2 (SF-36v2) at baseine and 6 and 12 months. The anaysis focused on the menta component summary (MCS) score and the physica component summary (PCS) score. Participants were aso asked to compete and return the SF-36v2 at the time of symptomatic UTI as part of the UTI questionnaire. Data from compete SF-36v2 were aso used to generate utiity vaues and QALYs for the cost utiity anaysis. Participant attitudes towards use of antibiotic prophyaxis were assessed by an exporatory case-based study with thematic anaysis of semistructured interviews. Measurement of heath economic outcomes Primary Incrementa cost per symptomatic UTI avoided was cacuated from coected costs associated with prophyaxis and no prophyaxis strategies. Heath-care costs were assessed by a participant-competed heath resource utiisation questionnaire at 6 and 12 months and 3-monthy record review. Monetary costs of these events were derived from standard UK sources. For patient costs, participants competed a time and trave questionnaire at 12 months. Secondary Cost utiity anaysis was based on estimated QALYs from responses to the SF-36v2, incuding at the time of symptomatic UTI. Participants WTP to avoid a UTI was assessed by a competion of a bespoke contingent vauation questionnaire after the 12-month tria period. Statistica anaysis It was assumed that an overa 20% reduction in symptomatic UTI rate from an average of three episodes to 2.4 episodes over 12 months was the minimum cinicay important difference. Using the Poisson rate test, competion of the tria by 158 participants in each group, 316 participants in tota, woud give 90% power to detect this difference at the 5% eve. A tota of 372 participants woud aow for a 15% attrition rate. This gave 92% power to detect a 25% difference in the high-frequency subgroup (from four to three episodes per year) and 99% power for a 50% reduction in the ow-frequency subgroup (from two to one episodes per year). A statistica anayses were carried out on a modified intention-to-treat basis, retaining participants in their aocated groups and incuding a participants in the primary outcome anaysis for whom 6 months of continuous foow-up data had been coected. The reative rate of symptomatic antibiotic-treated UTI was defined as the incident rate ratio (IRR), cacuated by dividing the UTI rate in the prophyaxis group by that found in the no-prophyaxis group, aowing for different durations of foow-up. Anaysis of the primary outcome measure was performed as a univariate approach using the Poisson rate test and a Poisson regression modeing approach aowing for days not at risk whie taking treatment courses of antibiotics. Regression modeing was used to detect effects of covariates incuding stratification factors and other baseine variabes suggested to increase risk of UTI. The univariate anaysis was considered to be the primary anaysis for reporting. For TSQM scores, the two-sampe t-test was used as a simpe univariate anaysis. Chi-squared test and tests for trend were used for anaysis of resistance patterns. For univariate anaysis of the MCS and PCS components of the SF-36v2, the simpe t -test was used. For adjusted anayses of the TSQM scores and the components of the SF-36v2, a inear regression/anaysis of covariance was performed with the same covariates used in the primary outcome anaysis. Queen s Printer and Controer of HMSO This work was produced by Pickard et a. under the terms of a commissioning contract issued by the Secretary of State for Heath and Socia Care. 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. xxv

28 SCIENTIFIC SUMMARY Heath economic anaysis Cost-effectiveness was measured by summing treatment and participant costs and taking an average across participants in each tria group. The number of UTIs was derived from primary outcome data. The incrementa cost-effectiveness ratio was then cacuated by dividing the difference in costs by the difference in the number of UTIs for each group. From participant responses to the SF-36v2 competed at 6 and 12 months and at the time of symptomatic UTI, heath state utiities were estimated using an estabished agorithm appied to the Short Form questionnaire-6 Dimensions. QALYs were then derived using an area-under-the-curve approach. The difference in mean QALYs between groups was cacuated. Costs were summed from tria and NHS sources and means cacuated for each group. Cost utiity was expressed as the incrementa cost per QALY gained. Data from the contingent vauation questionnaire were incorporated into the economic evauation using a cost benefit anaysis framework. Quaitative anaysis Those participants who consented to being approached by a quaitative researcher were purposivey samped to ensure that interviews were conducted with both men and women of various ages in each tria group, geographicay spread across seven sites. Semistructured interviews were conducted using a topic guide for consistency, whie aso aowing participants to raise any other reevant issues. The researcher carried out a interviews by teephone from a private room with audio-recording. Interviews were transcribed, checked for accuracy and manuay coded. Data were then subjected to thematic anaysis to generate categories and themes appropriate to the quantitative research questions. Resuts We identified 1743 patients, of whom 404 were randomised. Tria participants were recruited from cinics in secondary care (n = 340; 84%), primary care (n = 50; 12%) and community NHS services (n = 14; 4%) over a 26-month period (25 November 2013 to 29 January 2016). A tota of 332 (82%) participants competed the 12-month tria of aocated intervention and foow-up, with an additiona 29 participants having 6 months of foow-up data, which were required for incusion in the primary anaysis. Thus, 361 (89%) of the randomised participants were incuded in the primary anaysis. Participants aocated to prophyaxis (n = 203) were we matched at baseine to those in the no-prophyaxis group (n = 201) with regard to demographics, cause of badder dysfunction, regimen of CISC use, previous frequency of UTI and presence of risk factors for UTI. The number of participants with asymptomatic bacteriuria in each group at baseine was comparabe [prophyaxis, n = 76 (37%); no prophyaxis, n = 77 (38%)]. In univariate anaysis, the IRR for symptomatic antibiotic-treated UTI over 12 months in the prophyaxis group reative to no prophyaxis was 0.52 [95% confidence interva (CI) 0.44 to 0.61]. Reduction in frequency of microbioogicay proven UTI was simiar (IRR 0.49, 95% CI 0.39 to 0.60). The absoute reduction in UTI episodes over 12 months was 50% from a median (interquartie range) of 2 (1 4) in the no-prophyaxis group to 1 (0 2) in the prophyaxis group. These resuts were unchanged in the Poisson regression mode incuding days at risk of UTI, prior frequency of UTI and other possibe confounders. There was no cinicay significant difference in measured heath status between the two groups over 12 months and no difference in utiity vaue at the time of UTI. Pathogens, predominanty E. coi (58%), isoated from 3-monthy urine specimens submitted by the prophyaxis group were more ikey to have a higher frequency of resistance to trimethoprim (p < 0.001), co-trimoxazoe (p = 0.002) and nitrofurantoin (p = 0.038) at 12 months than isoates from the no-prophyaxis group. We found significant trends over 12 months in increased resistance of pathogens isoated from urine specimens provided by the prophyaxis xxvi NIHR Journas Library