{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T07:54:25Z","timestamp":1787730865260,"version":"build-2784847793"},"reference-count":84,"publisher":"National Institute for Health and Care Research","issue":"67","license":[{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.nationalarchives.gov.uk\/doc\/non-commercial-government-licence\/non-commercial-government-licence.htm"}],"funder":[{"DOI":"10.13039\/501100000664","name":"Health Technology Assessment programme","doi-asserted-by":"publisher","award":["16\/85\/01"],"award-info":[{"award-number":["16\/85\/01"]}],"id":[{"id":"10.13039\/501100000664","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journalslibrary.nihr.ac.uk"],"crossmark-restriction":false},"short-container-title":["Health Technol Assess"],"abstract":"\n Background<\/jats:title>\n Acute otitis media is a painful infection of the middle ear that is commonly seen in children. In some children, the eardrum spontaneously bursts, discharging visible pus (otorrhoea) into the outer ear.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To compare the clinical effectiveness of immediate topical antibiotics or delayed oral antibiotics with the clinical effectiveness of immediate oral antibiotics in reducing symptom duration in children presenting to primary care with acute otitis media with discharge and the economic impact of the alternative strategies.<\/jats:p>\n <\/jats:sec>\n \n Design<\/jats:title>\n This was a pragmatic, three-arm, individually randomised (stratified by age <\u20092 vs. \u2265\u20092 years), non-inferiority, open-label trial, with economic and qualitative evaluations, supported by a health-record-integrated electronic trial platform [TRANSFoRm (Translational Research and Patient Safety in Europe)] with an internal pilot.<\/jats:p>\n <\/jats:sec>\n \n Setting<\/jats:title>\n A total of 44 English general practices.<\/jats:p>\n <\/jats:sec>\n \n Participants<\/jats:title>\n Children aged \u2265\u200912 months and <\u200916 years whose parents (or carers) were seeking medical care for unilateral otorrhoea (ear discharge) following recent-onset (\u2264\u20097 days) acute otitis media.<\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n (1) Immediate ciprofloxacin (0.3%) solution, four drops given three times daily for 7 days, or (2) delayed \u2018dose-by-age\u2019 amoxicillin suspension given three times daily (clarithromycin twice daily if the child was penicillin allergic) for 7 days, with structured delaying advice. All parents were given standardised information regarding symptom management (paracetamol\/ibuprofen\/fluids) and advice to complete the course.<\/jats:p>\n <\/jats:sec>\n \n Comparator<\/jats:title>\n Immediate \u2018dose-by-age\u2019 oral amoxicillin given three times daily (or clarithromycin given twice daily) for 7 days. Parents received standardised symptom management advice along with advice to complete the course.<\/jats:p>\n <\/jats:sec>\n \n Main outcome measure<\/jats:title>\n Time from randomisation to the first day on which all symptoms (pain, fever, being unwell, sleep disturbance, otorrhoea and episodes of distress\/crying) were rated \u2018no\u2019 or \u2018very slight\u2019 problem (without need for analgesia).<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n Participants were recruited from routine primary care appointments. The planned sample size was 399 children. Follow-up used parent-completed validated symptom diaries.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Delays in software deployment and configuration led to small recruitment numbers and trial closure at the end of the internal pilot. Twenty-two children (median age 5 years; 62% boys) were randomised: five, seven and 10 to immediate oral, delayed oral and immediate topical antibiotics, respectively. All children received prescriptions as randomised. Seven (32%) children fully adhered to the treatment as allocated. Symptom duration data were available for 17 (77%) children. The median (interquartile range) number of days until symptom resolution in the immediate oral, delayed oral and immediate topical antibiotic arms was 6 (4\u20139), 4 (3\u20137) and 4 (3\u20136), respectively. Comparative analyses were not conducted because of small numbers. There were no serious adverse events and six reports of new or worsening symptoms. Qualitative clinician interviews showed that the trial question was important. When the platform functioned as intended, it was liked. However, staff reported malfunctioning software for long periods, resulting in missed recruitment opportunities. Troubleshooting the software placed significant burdens on staff.<\/jats:p>\n <\/jats:sec>\n \n Limitations<\/jats:title>\n The over-riding weakness was the failure to recruit enough children.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n We were unable to answer the main research question because of a failure to reach the required sample size. Our experience of running an electronic platform-supported trial in primary care has highlighted challenges from which we have drawn recommendations for the National Institute for Health Research (NIHR) and the research community. These should be considered before such a platform is used again.<\/jats:p>\n <\/jats:sec>\n \n Trial registration<\/jats:title>\n Current Controlled Trials ISRCTN12873692 and EudraCT 2017-003635-10.<\/jats:p>\n <\/jats:sec>\n \n Funding<\/jats:title>\n This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment<\/jats:italic>; Vol. 25, No. 67. See the NIHR Journals Library website for further project information.<\/jats:p>\n <\/jats:sec>","DOI":"10.3310\/hta25670","type":"journal-article","created":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T11:06:32Z","timestamp":1637751992000},"page":"1-76","update-policy":"https:\/\/doi.org\/10.3310\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Immediate oral versus immediate topical versus delayed oral antibiotics for children with acute otitis media with discharge: the REST three-arm non-inferiority electronic platform-supported RCT"],"prefix":"10.3310","volume":"25","clinical-trial-number":[{"clinical-trial-number":"isrctn12873692","registry":"10.18810\/isrctn","type":"results"},{"clinical-trial-number":"2017-003635-10","registry":"10.18810\/euctr","type":"results"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3012-375X","authenticated-orcid":true,"given":"Alastair D","family":"Hay","sequence":"first","affiliation":[{"name":"Centre for Academic Primary Care, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5127-4509","authenticated-orcid":true,"given":"Michael V","family":"Moore","sequence":"additional","affiliation":[{"name":"Primary Care and Population Sciences, University of Southampton, Southampton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7171-8923","authenticated-orcid":true,"given":"Jodi","family":"Taylor","sequence":"additional","affiliation":[{"name":"Bristol Randomised Trials Collaboration, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1591-6997","authenticated-orcid":true,"given":"Nicholas","family":"Turner","sequence":"additional","affiliation":[{"name":"Bristol Randomised Trials Collaboration, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8011-0722","authenticated-orcid":true,"given":"Sian","family":"Noble","sequence":"additional","affiliation":[{"name":"Bristol Randomised Trials Collaboration, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9884-0555","authenticated-orcid":true,"given":"Christie","family":"Cabral","sequence":"additional","affiliation":[{"name":"Centre for Academic Primary Care, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7092-4960","authenticated-orcid":true,"given":"Jeremy","family":"Horwood","sequence":"additional","affiliation":[{"name":"Centre for Academic Primary Care, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5470-276X","authenticated-orcid":true,"given":"Vibhore","family":"Prasad","sequence":"additional","affiliation":[{"name":"School of Population Health and Environmental Sciences, Faculty of Life Sciences and Medicine, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5367-9182","authenticated-orcid":true,"given":"Kathryn","family":"Curtis","sequence":"additional","affiliation":[{"name":"Bristol Randomised Trials Collaboration, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3518-0131","authenticated-orcid":true,"given":"Brendan","family":"Delaney","sequence":"additional","affiliation":[{"name":"Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8052-0302","authenticated-orcid":true,"given":"Roger","family":"Damoiseaux","sequence":"additional","affiliation":[{"name":"Julius Center for Health Sciences and Primary Care & Department of Otorhinolaryngology, UMC Utrecht, Utrecht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7372-315X","authenticated-orcid":true,"given":"Jes\u00fas","family":"Dom\u00ednguez","sequence":"additional","affiliation":[{"name":"School of Population Health and Environmental Sciences, Faculty of Life Sciences and Medicine, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3074-9832","authenticated-orcid":true,"given":"Archana","family":"Tapuria","sequence":"additional","affiliation":[{"name":"School of Population Health and Environmental Sciences, Faculty of Life Sciences and Medicine, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9177-7987","authenticated-orcid":true,"given":"Sue","family":"Harris","sequence":"additional","affiliation":[{"name":"Bristol Randomised Trials Collaboration, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3664-1873","authenticated-orcid":true,"given":"Paul","family":"Little","sequence":"additional","affiliation":[{"name":"Primary Care and Population Sciences, University of Southampton, Southampton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7573-3220","authenticated-orcid":true,"given":"Andrew","family":"Lovering","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, North Bristol NHS Trust, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7240-4563","authenticated-orcid":true,"given":"Richard","family":"Morris","sequence":"additional","affiliation":[{"name":"Bristol Randomised Trials Collaboration, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4388-5569","authenticated-orcid":true,"given":"Kate","family":"Rowley","sequence":"additional","affiliation":[{"name":"Bristol Randomised Trials Collaboration, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5129-4596","authenticated-orcid":true,"given":"Annie","family":"Sadoo","sequence":"additional","affiliation":[{"name":"Bristol Randomised Trials Collaboration, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5496-4580","authenticated-orcid":true,"given":"Anne","family":"Schilder","sequence":"additional","affiliation":[{"name":"Ear Institute, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1446-9614","authenticated-orcid":true,"given":"Roderick","family":"Venekamp","sequence":"additional","affiliation":[{"name":"Julius Center for Health Sciences and Primary Care & Department of Otorhinolaryngology, UMC Utrecht, Utrecht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2949-7711","authenticated-orcid":true,"given":"Scott","family":"Wilkes","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Sunderland, Sunderland, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8308-2886","authenticated-orcid":true,"given":"Vasa","family":"Curcin","sequence":"additional","affiliation":[{"name":"School of Population Health and Environmental Sciences, Faculty of Life Sciences and Medicine, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"6221","published-online":{"date-parts":[[2021,11]]},"reference":[{"key":"key20211124105249048_ref1-bib1","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1136\/bmj.322.7282.336","article-title":"Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media","volume":"322","author":"Little","year":"2001","journal-title":"BMJ"},{"key":"key20211124105249048_ref1-bib2","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.1016\/S0140-6736(06)69606-2","article-title":"Antibiotics for acute otitis media: a meta-analysis with individual patient data","volume":"368","author":"Rovers","year":"2006","journal-title":"Lancet"},{"key":"key20211124105249048_ref1-bib3","doi-asserted-by":"publisher","first-page":"101","DOI":"10.3399\/bjgp10X483148","article-title":"Ear discharge in children presenting with acute otitis media: observational study from UK general practice","volume":"60","author":"Smith","year":"2010","journal-title":"Br J Gen Pract"},{"key":"key20211124105249048_ref1-bib4","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/1471-2296-9-10","article-title":"Measuring the financial burden of acute cough in pre-school children: a cost of illness study","volume":"9","author":"Hollinghurst","year":"2008","journal-title":"BMC Fam Pract"},{"key":"key20211124105249048_ref1-bib5","doi-asserted-by":"publisher","first-page":"a1490","DOI":"10.1136\/bmj.a1490","article-title":"Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): economic evaluation of a randomised controlled trial","volume":"337","author":"Hollinghurst","year":"2008","journal-title":"BMJ"},{"key":"key20211124105249048_ref1-bib6","doi-asserted-by":"publisher","first-page":"G39","DOI":"10.1016\/j.vaccine.2010.06.014","article-title":"The health care burden and societal impact of acute otitis media in seven European countries: results of an internet survey","volume":"28","author":"Wolleswinkel-van den Bosch","year":"2010","journal-title":"Vaccine"},{"key":"key20211124105249048_ref1-bib7","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1093\/fampra\/cmi035","article-title":"The prevalence of symptoms and consultations in pre-school children in the Avon Longitudinal Study of Parents and Children (ALSPAC): a prospective cohort study","volume":"22","author":"Hay","year":"2005","journal-title":"Fam Pract"},{"key":"key20211124105249048_ref1-bib8","first-page":"170","article-title":"Consultations for middle ear disease, antibiotic prescribing and risk factors for reattendance: a case-linked cohort study","volume":"56","author":"Williamson","year":"2006","journal-title":"Br J Gen Pract"},{"key":"key20211124105249048_ref1-bib9","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1001\/archpedi.154.4.395","article-title":"Antimicrobial use in defined populations of infants and young children","volume":"154","author":"Finkelstein","year":"2000","journal-title":"Arch Pediatr Adolesc Med"},{"key":"key20211124105249048_ref1-bib10","first-page":"603","article-title":"Variations in antibiotic prescribing and consultation rates for acute respiratory infection in UK general practices 1995\u20132000","volume":"55","author":"Ashworth","year":"2005","journal-title":"Br J Gen Pract"},{"key":"key20211124105249048_ref1-bib11","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1093\/pubmed\/fdh160","article-title":"Why has antibiotic prescribing for respiratory illness declined in primary care? A longitudinal study using the General Practice Research Database","volume":"26","author":"Ashworth","year":"2004","journal-title":"J Public Health"},{"key":"key20211124105249048_ref1-bib12","volume-title":"Otitis Media (Acute): Antimicrobial Prescribing Guidance","author":"National Institute for Health and Care Excellence (NICE)","year":"2018"},{"key":"key20211124105249048_ref1-bib13","volume-title":"BNF for Children 2020","author":"National Institute for Health and Care Excellence"},{"key":"key20211124105249048_ref1-bib14","doi-asserted-by":"publisher","first-page":"2371","DOI":"10.1001\/jama.2015.6645","article-title":"Noninferiority trials: is a new treatment almost as effective as another?","volume":"313","author":"Kaji","year":"2015","journal-title":"JAMA"},{"key":"key20211124105249048_ref1-bib15","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1136\/bmj.314.7082.722","article-title":"Open randomised trial of prescribing strategies in managing sore throat","volume":"314","author":"Little","year":"1997","journal-title":"BMJ"},{"key":"key20211124105249048_ref1-bib16","volume-title":"UK Five Year Antimicrobial Resistance Strategy 2013 to 2018","author":"Department of Health and Social Care"},{"key":"key20211124105249048_ref1-bib17","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.ijporl.2013.11.030","article-title":"Acute otitis media in young children \u2013 what do parents say?","volume":"78","author":"Barber","year":"2014","journal-title":"Int J Pediatr Otorhinolaryngol"},{"key":"key20211124105249048_ref1-bib18","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1056\/NEJMoa1301630","article-title":"A trial of treatment for acute otorrhea in children with tympanostomy tubes","volume":"370","author":"van Dongen","year":"2014","journal-title":"N Engl J Med"},{"key":"key20211124105249048_ref1-bib19","doi-asserted-by":"publisher","first-page":"e1182","DOI":"10.1542\/peds.2014-3141","article-title":"Cost-effectiveness of treatment of acute otorrhea in children with tympanostomy tubes","volume":"135","author":"van Dongen","year":"2015","journal-title":"Pediatrics"},{"key":"key20211124105249048_ref1-bib20","doi-asserted-by":"publisher","first-page":"i308","DOI":"10.1136\/bmj.i308","article-title":"Are topical antibiotics an alternative to oral antibiotics for children with acute otitis media and ear discharge?","volume":"352","author":"Venekamp","year":"2016","journal-title":"BMJ"},{"key":"key20211124105249048_ref1-bib21","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1186\/s12879-016-1697-6","article-title":"Faecal carriage of antibiotic resistant Escherichia coli in asymptomatic children and associations with primary care antibiotic prescribing: a systematic review and meta-analysis","volume":"16","author":"Bryce","year":"2016","journal-title":"BMC Infect Dis"},{"key":"key20211124105249048_ref1-bib22","doi-asserted-by":"publisher","first-page":"i939","DOI":"10.1136\/bmj.i939","article-title":"Global prevalence of antibiotic resistance in paediatric urinary tract infections caused by Escherichia coli and association with routine use of antibiotics in primary care: systematic review and meta-analysis","volume":"352","author":"Bryce","year":"2016","journal-title":"BMJ"},{"key":"key20211124105249048_ref1-bib23","doi-asserted-by":"publisher","first-page":"3029","DOI":"10.1001\/jama.293.24.3029","article-title":"Information leaflet and antibiotic prescribing strategies for acute lower respiratory tract infection: a randomized controlled trial","volume":"293","author":"Little","year":"2005","journal-title":"JAMA"},{"key":"key20211124105249048_ref1-bib24","unstructured":"Royal College of General Practitioners. Research and Surveillance Centre: Weekly Returns Service Annual Report 2011. London: Royal College of General Practitioners; 2011."},{"key":"key20211124105249048_ref1-bib25","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1097\/INF.0b013e318258f100","article-title":"Good agreement between parents and physician in the assessment of ear discharge in children","volume":"31","author":"van Dongen","year":"2012","journal-title":"Pediatr Infect Dis J"},{"key":"key20211124105249048_ref1-bib26","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1093\/fampra\/18.5.553","article-title":"Validation study of a diary for use in acute lower respiratory tract infection","volume":"18","author":"Watson","year":"2001","journal-title":"Fam Pract"},{"key":"key20211124105249048_ref1-bib27","doi-asserted-by":"publisher","first-page":"a1302","DOI":"10.1136\/bmj.a1302","article-title":"Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomised controlled trial","volume":"337","author":"Hay","year":"2008","journal-title":"BMJ"},{"key":"key20211124105249048_ref1-bib28","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1093\/fampra\/cmg613","article-title":"The duration of acute cough in pre-school children presenting to primary care: a prospective cohort study","volume":"20","author":"Hay","year":"2003","journal-title":"Fam Pract"},{"key":"key20211124105249048_ref1-bib29","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1370\/afm.1954","article-title":"Improving the diagnosis and treatment of urinary tract infection in young children in primary care: results from the DUTY prospective diagnostic cohort study","volume":"14","author":"Hay","year":"2016","journal-title":"Ann Fam Med"},{"key":"key20211124105249048_ref1-bib30","doi-asserted-by":"publisher","first-page":"f7027","DOI":"10.1136\/bmj.f7027","article-title":"Duration of symptoms of respiratory tract infections in children: systematic review","volume":"347","author":"Thompson","year":"2013","journal-title":"BMJ"},{"key":"key20211124105249048_ref1-bib31","doi-asserted-by":"publisher","first-page":"961526","DOI":"10.1155\/2015\/961526","article-title":"Translational medicine and patient safety in Europe: TRANSFoRm \u2013 architecture for the learning health system in Europe","volume":"2015","author":"Delaney","year":"2015","journal-title":"Biomed Res Int"},{"key":"key20211124105249048_ref1-bib32","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1007\/s11136-009-9558-z","article-title":"Mapping analyses to estimate health utilities based on responses to the OM8-30 Otitis Media Questionnaire","volume":"19","author":"Dakin","year":"2010","journal-title":"Qual Life Res"},{"key":"key20211124105249048_ref1-bib33","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1503\/cmaj.141608","article-title":"Effect of nasal balloon autoinflation in children with otitis media with effusion in primary care: an open randomized controlled trial","volume":"187","author":"Williamson","year":"2015","journal-title":"CMAJ"},{"issue":"72","key":"key20211124105249048_ref1-bib34","doi-asserted-by":"publisher","DOI":"10.3310\/hta19720","article-title":"An open randomised study of autoinflation in 4- to 11-year-old school children with otitis media with effusion in primary care","volume":"19","author":"Williamson","year":"2015","journal-title":"Health Technol Assess"},{"key":"key20211124105249048_ref1-bib35","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.ijmedinf.2017.06.006","article-title":"eSource for clinical trials: implementation and evaluation of a standards-based approach in a real world trial","volume":"106","author":"Ethier","year":"2017","journal-title":"Int J Med Inform"},{"key":"key20211124105249048_ref1-bib36","author":"Integrating the Healthcare Enterprise"},{"key":"key20211124105249048_ref1-bib37","volume-title":"CDISC Journal: Healthcare Link and eSource","author":"Bain","year":"2011"},{"key":"key20211124105249048_ref1-bib38","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1136\/amiajnl-2012-001312","article-title":"A unified structural\/terminological interoperability framework based on LexEVS: application to TRANSFoRm","volume":"20","author":"Ethier","year":"2013","journal-title":"J Am Med Inform Assoc"},{"key":"key20211124105249048_ref1-bib39","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1197\/jamia.M2157","article-title":"Implementing single source: the STARBRITE proof-of-concept study","volume":"14","author":"Kush","year":"2007","journal-title":"J Am Med Inform Assoc"},{"key":"key20211124105249048_ref1-bib40","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1177\/1740774510395635","article-title":"A point-of-care clinical trial comparing insulin administered using a sliding scale versus a weight-based regimen","volume":"8","author":"Fiore","year":"2011","journal-title":"Clin Trials"},{"key":"key20211124105249048_ref1-bib41","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1016\/j.ejso.2008.11.005","article-title":"Preoperative imatinib mesylate for unresectable or locally advanced primary gastrointestinal stromal tumors (GIST)","volume":"35","author":"Fiore","year":"2009","journal-title":"Eur J Surg Oncol"},{"key":"key20211124105249048_ref1-bib42","doi-asserted-by":"publisher","first-page":"1624","DOI":"10.1001\/jama.290.12.1624","article-title":"Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy","volume":"290","author":"Tunis","year":"2003","journal-title":"JAMA"},{"key":"key20211124105249048_ref1-bib43","doi-asserted-by":"publisher","first-page":"e55","DOI":"10.1136\/bmj.e55","article-title":"Pragmatic randomised trials using routine electronic health records: putting them to the test","volume":"344","author":"Staa","year":"2012","journal-title":"BMJ"},{"key":"key20211124105249048_ref1-bib44","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1056\/NEJMoa1608033","article-title":"Effectiveness of fluticasone furoate-vilanterol for COPD in clinical practice","volume":"375","author":"Vestbo","year":"2016","journal-title":"N Engl J Med"},{"key":"key20211124105249048_ref1-bib45","volume-title":"Digital Infrastructure for the Learning Health System: The Foundation for Continuous Improvement in Health and Health Care: Workshop Series Summary","author":"Institute of Medicine","year":"2011"},{"key":"key20211124105249048_ref1-bib46","unstructured":"Food and Drug Administration. Guidance for Industry: Electronic Source Data in Clinical Investigations. Silver Spring, MD: Food and Drug Administration; 2013."},{"key":"key20211124105249048_ref1-bib47","volume-title":"Digital Infrastructure for the Learning Health System: The Foundations for Continuous Improvement in Health and Health Care","author":"Grossman","year":"2011"},{"key":"key20211124105249048_ref1-bib48","doi-asserted-by":"publisher","first-page":"2411","DOI":"10.1056\/NEJMp1605348","article-title":"A global, neutral platform for sharing trial data","volume":"374","author":"Bierer","year":"2016","journal-title":"N Engl J Med"},{"key":"key20211124105249048_ref1-bib49","first-page":"115","article-title":"Effective recruitment strategies in primary care research: a systematic review","volume":"20","author":"Ngune","year":"2012","journal-title":"Qual Prim Care"},{"key":"key20211124105249048_ref1-bib50","doi-asserted-by":"publisher","first-page":"486.e1","DOI":"10.1016\/j.cmi.2017.01.010","article-title":"Prospective evaluation of the aetiology of actute otitis media with spontaneous tympanic membrance perforation","volume":"23","author":"Marchisio","year":"2017","journal-title":"Clin Microbiol Infect"},{"key":"key20211124105249048_ref1-bib51","volume-title":"BNF for Children 2017\u201318","author":"Paediatric Formulary Committee","year":"2017"},{"key":"key20211124105249048_ref1-bib52","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1001\/archotol.125.3.337","article-title":"Ofloxacin otic solution in patients with otitis media: an analysis of drug concentrations","volume":"125","author":"Ohyama","year":"1999","journal-title":"Arch Otolaryngol Head Neck Surg"},{"key":"key20211124105249048_ref1-bib53","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/eye.1999.17","article-title":"Reliability of drop size from multi-dose eye drop bottles: is it cause for concern?","volume":"13","author":"German","year":"1999","journal-title":"Eye"},{"key":"key20211124105249048_ref1-bib54","doi-asserted-by":"publisher","first-page":"S89","DOI":"10.1016\/j.otohns.2003.12.009","article-title":"The development of antibiotic resistant organisms with the use of ototopical medications","volume":"130","author":"Weber","year":"2004","journal-title":"Otolaryngol Head Neck Surg"},{"key":"key20211124105249048_ref1-bib55","doi-asserted-by":"publisher","first-page":"S57","DOI":"10.1016\/j.otohns.2003.12.008","article-title":"Animal ototoxicity of topical antibiotics and the relevance to clinical treatment of human subjects","volume":"130","author":"Roland","year":"2004","journal-title":"Otolaryngol Head Neck Surg"},{"key":"key20211124105249048_ref1-bib56","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1097\/00005537-200204000-00018","article-title":"Intentional ablation of vestibular function using commercially available topical gentamicin-betamethasone eardrops in patients with Meniere\u2019s disease: further evidence for topical eardrop ototoxicity","volume":"112","author":"Kaplan","year":"2002","journal-title":"Laryngoscope"},{"key":"key20211124105249048_ref1-bib57","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1016\/j.bbrc.2008.09.134","article-title":"Mitochondrial 12S rRNA susceptibility mutations in aminoglycoside-associated and idiopathic bilateral vestibulopathy","volume":"377","author":"Elstner","year":"2008","journal-title":"Biochem Biophys Res Commun"},{"key":"key20211124105249048_ref1-bib58","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1111\/j.1749-4486.2007.01532.x","article-title":"Evidence review and ENT-UK consensus report for the use of aminoglycoside-containing ear drops in the presence of an open middle ear","volume":"32","author":"Phillips","year":"2007","journal-title":"Clin Otolaryngol"},{"key":"key20211124105249048_ref1-bib59","unstructured":"Joint Formulary Committee. British National Formulary. 74 ed. London: BMJ Group and Pharmaceutical Press; 2017\u201318."},{"key":"key20211124105249048_ref1-bib60","doi-asserted-by":"publisher","first-page":"2116","DOI":"10.1097\/00005537-200312000-00011","article-title":"Topical ciprofloxacin\/dexamethasone is superior to ciprofloxacin alone in pediatric patients with acute otitis media and otorrhea through tympanostomy tubes","volume":"113","author":"Roland","year":"2003","journal-title":"Laryngoscope"},{"key":"key20211124105249048_ref1-bib61","doi-asserted-by":"publisher","first-page":"e40","DOI":"10.1542\/peds.113.1.e40","article-title":"Topical ciprofloxacin\/dexamethasone otic suspension is superior to ofloxacin otic solution in the treatment of children with acute otitis media with otorrhea through tympanostomy tubes","volume":"113","author":"Roland","year":"2004","journal-title":"Pediatrics"},{"key":"key20211124105249048_ref1-bib62","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1001\/jamaoto.2016.3537","article-title":"Efficacy and safety of ciprofloxacin plus fluocinolone in otitis media with tympanostomy tubes in pediatric patients: a randomized clinical trial","volume":"143","author":"Spektor","year":"2017","journal-title":"JAMA Otolaryngol Head Neck Surg"},{"key":"key20211124105249048_ref1-bib63","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/j.ijporl.2008.10.021","article-title":"Effect of ototopical ciprofloxacin-dexamethasone on myringotomy in a rat model","volume":"73","author":"Yazici","year":"2009","journal-title":"Int J Pediatr Otorhinolaryngol"},{"key":"key20211124105249048_ref1-bib64","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1097\/MLG.0b013e31802f3c86","article-title":"Effects of ciprofloxacin-dexamethasone on myringotomy wound healing","volume":"117","author":"Hebda","year":"2007","journal-title":"Laryngoscope"},{"key":"key20211124105249048_ref1-bib65","volume-title":"Quinolone- and Fluoroquinolone-containing Medicinal Products","author":"European Medicines Agency"},{"key":"key20211124105249048_ref1-bib66","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1016\/S2213-2600(16)30223-5","article-title":"Development and internal validation of a clinical rule to improve antibiotic use in children presenting to primary care with acute respiratory tract infection and cough: a prognostic cohort study","volume":"4","author":"Hay","year":"2016","journal-title":"Lancet Respir Med"},{"key":"key20211124105249048_ref1-bib67","doi-asserted-by":"publisher","first-page":"3028","DOI":"10.1161\/CIRCULATIONAHA.108.768986","article-title":"Medication adherence: its importance in cardiovascular outcomes","volume":"119","author":"Ho","year":"2009","journal-title":"Circulation"},{"key":"key20211124105249048_ref1-bib68","volume-title":"Trial NL6535 (NTR6723): Is Treatment with Eardrops as Good as Oral Treatment for Children with Acute Otitis Media Presenting with Ear Discharge?","author":"Netherlands Trial Register"},{"key":"key20211124105249048_ref1-bib69","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1186\/s13063-020-04419-7","article-title":"A multi-centre, pragmatic, three-arm, individually randomised, non-inferiority, open trial to compare immediate orally administered, immediate topically administered or delayed orally administered antibiotics for acute otitis media with discharge in children: the Runny Ear STudy (REST): study protocol","volume":"21","author":"Curtis","year":"2020","journal-title":"Trials"},{"key":"key20211124105249048_ref1-bib70","volume-title":"Numbers of Patients Registered at a GP Practice \u2013 July 2015","author":"NHS Digital","year":"2015"},{"key":"key20211124105249048_ref1-bib71","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1177\/009286150203600312","article-title":"On the use of the accelerated failure time model as an alternative to the proportional hazards model in the treatment of time to event data: a case study in influenza","volume":"36","author":"Kay","year":"2002","journal-title":"Therapeutic Innovation and Regulatory Science"},{"key":"key20211124105249048_ref1-bib72","volume-title":"Status Updates: Tube, Overground, TfL Rail, DLR & Tram","author":"Transport for London"},{"key":"key20211124105249048_ref1-bib73","volume-title":"Unit Costs of Health and Social Care 2019","author":"Curtis","year":"2019"},{"key":"key20211124105249048_ref1-bib74","volume-title":"National Cost Collection for the NHS 2020","author":"NHS England"},{"key":"key20211124105249048_ref1-bib75","doi-asserted-by":"publisher","first-page":"1753","DOI":"10.1177\/1049732315617444","article-title":"Sample size in qualitative interview studies: guided by information power","volume":"26","author":"Malterud","year":"2016","journal-title":"Qual Health Res"},{"key":"key20211124105249048_ref1-bib76","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1136\/bmj.311.6999.251","article-title":"Qualitative interviews in medical research","volume":"311","author":"Britten","year":"1995","journal-title":"BMJ"},{"key":"key20211124105249048_ref1-bib77","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1191\/1478088706qp063oa","article-title":"Using thematic analysis in psychology","volume":"3","author":"Braun","year":"2006","journal-title":"Qual Res Psychol"},{"key":"key20211124105249048_ref1-bib78","doi-asserted-by":"publisher","first-page":"g1606","DOI":"10.1136\/bmj.g1606","article-title":"Delayed antibiotic prescribing strategies for respiratory tract infections in primary care: pragmatic, factorial, randomised controlled trial","volume":"348","author":"Little","year":"2014","journal-title":"BMJ"},{"key":"key20211124105249048_ref1-bib79","doi-asserted-by":"publisher","first-page":"e014506","DOI":"10.1136\/bmjopen-2016-014506","article-title":"Feasibility cluster randomised controlled trial of a within-consultation intervention to reduce antibiotic prescribing for children presenting to primary care with acute respiratory tract infection and cough","volume":"7","author":"Blair","year":"2017","journal-title":"BMJ Open"},{"key":"key20211124105249048_ref1-bib80","volume-title":"GP IT Futures systems and services","author":"NHS Digital"},{"key":"key20211124105249048_ref1-bib81","unstructured":"European Parliament. Regulation (EU) 2016\/679 of the European Parliament and of the Council of 27 April 2016 on the Protection of Natural Persons with Regard to the Processing of Personal Data and on the Free Movement of Such Data, and Repealing Directive 95\/46\/EC (General Data Protection Regulation), OJ 2016 L 119\/1. Luxembourg: Publications Office of the European Union; 2016."},{"key":"key20211124105249048_ref1-bib82","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1001\/archpedi.159.7.679","article-title":"Delayed prescription may reduce the use of antibiotics for acute otitis media: a prospective observational study in primary care","volume":"159","author":"Marchetti","year":"2005","journal-title":"Arch Pediatr Adolesc Med"},{"key":"key20211124105249048_ref1-bib83","volume-title":"RSC Communicable and Respiratory Disease Report for England.","author":"Royal College of General Practitioners","year":"2020"},{"key":"key20211124105249048_ref1-bib84","volume-title":"Defining the Role of Authors and Contributors","author":"ICMJE"}],"container-title":["Health Technology Assessment"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/njl-admin.nihr.ac.uk\/document\/download\/2038124","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.journalslibrary.nihr.ac.uk\/publications\/hta25670\/hta25670.xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/njl-admin.nihr.ac.uk\/document\/download\/2038124","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,15]],"date-time":"2023-08-15T15:38:43Z","timestamp":1692113923000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.journalslibrary.nihr.ac.uk\/hta\/hta25670"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11]]},"references-count":84,"journal-issue":{"issue":"67","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["10.3310\/hta25670"],"URL":"https:\/\/doi.org\/10.3310\/hta25670","relation":{},"ISSN":["1366-5278","2046-4924"],"issn-type":[{"value":"1366-5278","type":"print"},{"value":"2046-4924","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11]]},"assertion":[{"value":"This content has been made freely available to all.","name":"free","label":"Free to read"},{"value":"1-2018","name":"contractual_start_date","label":"Contractual start date","group":{"name":"article_history","label":"Article History"}},{"value":"9-2020","name":"editorial_review_begun","label":"Editorial review begun","group":{"name":"article_history","label":"Article History"}},{"value":"6-2021","name":"accepted_for_publication","label":"Accepted for publication","group":{"name":"article_history","label":"Article History"}}]}}