Title: Immediate oral, immediate topical or delayed oral antibiotics for acute otitis media with discharge (the Runny Ear STudy: REST)
Funder: Department of Health and Social Care

Abstract: Design: Pragmatic, multicentre, three arm, individually randomised (stratified <2 vs. >/=2 years), non-inferiority, open trial with internal pilot, and economic and qualitative evaluations. Setting: Primary care. Target population: Children with acute otitis media (AOM) with discharge (AOMd). Included: 12 months to 16 years; unilateral otorrhoea as presenting symptom of recent (</=7 days) onset AOM; parent able to give ear drops and complete Symptom and Recovery Questionnaire (SRQ). Excluded: needs hospitalisation or immediate oral antibiotics; bilateral AOM/AOMd; grommet in otorrhoea ear; known allergy to trial meds; immunocompromised. Health technologies: (i) ciprofloxacin 0.3% solution, four drops for 7 days or (ii) delayed BNFC recommended ‘dose-by-age’ amoxicillin suspension tds (clarithromycin bd if penicillin allergy) for 7 days with structured delay advice. One comparator: immediate ‘dose-by-age’ amoxicillin (clarithromycin) for 7 days. All groups to receive standardised symptom advice (paracetamol /ibuprofen/ fluids). Measurement of costs and outcomes: • Primary: Time to resolution all of pain, fever, being unwell, sleep disturbance, otorrhoea, and episodes of distress/crying being rated by parents ‘no’ or ‘very slight’ problem (SRQ). • Secondary: duration of ‘moderately bad or worse’ symptoms (SRQ); antibiotic and analgesic use (SRQ); adverse events (diarrhoea, rash, vomiting and serious complications, SRQ); treatment crossover and adherence (SRQ); parent satisfaction with treatment (research nurse 7 and 14 day telephone calls); NHS resources at 14 days (SRQ); repeat AOM and AOMd episodes, and OMQ-14 hearing assessment at 3 months (questionnaire); qualitative assessment of trial recruitment, medication adherence and follow up. Economic evaluation: simple comparison of cost to the NHS and outcomes at 14 days. Sample size (non-inferiority): Our previous AOM trial compared immediate with delayed antibiotics, and the 73 participating children with AOMd took a median of 3 days (IQR 2,4) to achieve the REST primary outcome. Our PPI has advised a 1.25 day non-inferiority margin. A two group non-inferiority trial normally assumes 2.5% one-sided Type I error. Using 1.25% Type I error to detect non-inferiority for two comparison with 90% power, complete outcome data needed on 106 per arm: 399 children in total with 20% attrition. Difference between current and planned care pathways: Usual care is immediate ‘dose-by-age’ oral amoxicillin (clarithromycin). Intervention groups: (i) immediate topical ciprofloxacin (0.3%) drops; or (ii) delayed oral ‘dose-by-age’ oral amoxicillin (clarithromycin) with structured delay advice. All groups receive standardised symptom advice (paracetamol /ibuprofen/ fluids). Project timetable and recruitment: • Jan-Jun 18: protocol, ethics, set up of REST elements of electronic health record integrated trial platform, site set up; • Jul 18-Feb 19: internal pilot and qualitative study; • Mar 19-Jun 20: main recruitment and follow up; Jul 20-Oct 20 follow up and data cleaning; • Sep 20-Dec 20: data analysis, report writing and results dissemination. Team expertise: With CTU and strong PPI, we are an experienced team of primary care and ENT trialists, senior statistician, health economist and qualitative researchers.

Lay abstract: Middle ear infections (medical term: 'acute otitis media' or 'AOM') are common painful infections in children. There were 2.8M treatment episodes for AOM in 2011 in England and Wales. Germs multiply in the confined middle ear resulting in a build-up of pressure that stretches the ear drum. In around 1 in 7 children, the ear drum bursts, releasing a liquid (medical term: 'discharge' or 'otorrhoea') that can be seen coming out of the ear. It is commonly believed that the pain of AOM improves when the ear drum bursts, but our research shows the pain is similar, with or without the ear drum bursting. At the moment nearly all UK children with AOM and discharge (AOMd) seen by their GP/nurse are treated with antibiotics by mouth. These can cause side effect like rashes, diarrhoea and vomiting and more rarely, severe allergic reactions. They can also make the germs in a child’s body resistant to antibiotics. It may be possible to use alternative treatments for ear discharge. One possibility is to use antibiotic eardrops; our research has shown these are better than antibiotics by mouth for children with runny ears and grommets, probably because the antibiotics are given directly to the place they are most needed. Another potential treatment is a ‘delayed’ antibiotic prescription (where parents are advised to wait to see if the child’s infection improves without antibiotics). Our studies in other infections suggest this can be just as effective and safe, but with fewer side effects. Since AOMd is painful and distressing for children and their families it is important to show that any new treatments work at least as well as the current standard treatment (immediate antibiotics by mouth). The Runny Ear STudy (REST) will test if giving an antibiotic ear drop or a delayed antibiotic by mouth is as good as immediately giving antibiotics by mouth for children (without grommets) who have developed AOMd. REST will be a randomised controlled trial - the most reliable method for testing medicines. We asked parents what concerns them most and what the most parent-child friendly study design would be. Parents told us a wide range of symptoms should be used to assess treatment effectiveness, because they can all cause distress and disrupt family routines. Parents also told us they would not want to leave their child untreated. As a result, REST will use the duration of AOMd symptoms (pain, fever, being unwell, sleep disturbance, discharge, and episodes of distress) as the main test of how good the treatments are, and all children in the study will receive some treatment, either by mouth or as ear drops. We are a highly experienced group of ‘primary care’ and ‘ear nose and throat’ researchers, and we have conducted numerous medicine trials (including the only trial of ear drops for discharge in children with grommets). We think the main challenges to successfully completing this trial will be time and GPs and nurses remembering to recruit. To address these we will promote the trial (through advertisements, social media and conferences) to larger GP practices and we will use a state-of-the-art electronic trial platform (called ‘TRANSFoRm’) to make recruitment and follow up as simple as possible. At the end of the trial we will ensure that the people most likely to benefit hear about the new knowledge, including GPs, nurses, parents, the national press and the National Institute for Health and Care Excellence (NICE).

Research activity codes: 6.1 PHARMACEUTICALS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION