Title: Antibiotics for lower Respiratory Tract Infection in Children presenting to Primary Care (ARTIC PC)
Funder: Department of Health and Social Care

Abstract: Design: RCT nested in an observational study Setting: Primary care. Prior Literature. Cochrane/Medline searches identified no placebo-controlled trials of antibiotics for children with uncomplicated Lower Respiratory Tract Infection (LRTI) Target population: Children 6 months to 12 years adults) Health technologies: Amoxicillin 50mg/kg/24 hours (in divided doses for 7 days) or placebo Inclusion Criteria. Acute uncomplicated LRTI (acute cough as the most prominent symptom and lower tract symptoms/signs (sputum/’rattly chest’/coarse rhonchi;breathless;pain). Exclusion: Non-infective (e.g.reflux,PE) or croup (viral aetiology very likely). Those with clinically suspected pneumonia or very unwell and/or unwilling to be randomised will be invited to participate in an observational study collecting the same data. Baseline measures: structured history/examination; pulse oximetry;X ray (for clinically undetected consolidation); and optional samples: swabs (for bacteriology) and pinprick (for CRP and Full blood count). Measurement of costs/outcomes: Primary outcome: duration of moderately bad symptoms (from validated symptom diary). Secondary outcomes: symptom severity (days 2-4); the development of new or worsening symptoms; complications. Health related quality of life will be measured by proxy methods in which The Health Utilities Index (HUI-Mark III)and EuroQoL (EQ5D) will be completed by patients or carers (on days 1,3,7,14,21,28). Follow-up (at 1 month): measure lung function (if aged 6+). Sample size: 938 children are required (alpha=0.01;beta=0.1;80% follow-up) to estimate effectiveness in 5 pre-specified subgroups to detect a 3 day difference in duration of symptoms rated moderately bad or worse for a subgroup representing at least 30% of the sample (our data suggests 30-65%). Subgroups: sputum seen and/or heard by parents(’rattly chest’) or clinicians; history of fever; physician rating of being unwell; short of breath; chest signs (non-focal coarse crepitations/rhonchi/wheeze). Analysis. Multiple linear regression models will provide estimates both overall and for subgroups and estimates of interaction with intervention by subgroup. In addition we will explore to what extent results from additional tests (bacteriology,biomarkers, abnormalities on chest-X rays,etc)are potential effect modifiers, and will explore differences between the purely observational data set and the trial data and our other large observational cohorts (TARGET and 3C studies). We will conduct economic evaluation alongside the clinical trial. Costs will take an NHS and personal social service (PSS) perspective (primary analysis) and societal perspective (secondary analysis). Outcomes will be measured as costs per symptomatic day prevented and the incremental cost per QALY gained. Cost-effectiveness acceptability curves will also be produced. In addition, a decision analytic model will be developed to explore the cost-effectiveness implication over the long term and investigate the potential implication of the costs associated with antibiotic resistance. Project timetables. 0-12 months finalise R+D approval, site preparation/training, confirm feasibility/viability of procedures/recruitment rates/qualitative work/internal pilot(one site);13-32 months main recruitment and 1 month follow-up(all sites);32-36 months data cleaning,analysis,write up. Assumptions:20 children per annum will be approached in each practice.

Lay abstract: Although chest infections are one of the commonest infections managed in children seen in primary care there have been no placebo controlled studies to show what effect antibiotics have - in contrast to adults where there is now good evidence to show that for most people antibiotics do not work, and also modest effects in important subgroups of patients. The trouble with prescribing for most children is that we are using antibiotics too much which is causing the bacteria to become resistant, which is likely to lead in the future to serious infections for our children becoming untreatable from ‘superbugs’. Most children who see the doctor with a chest infection currently get antibiotics, and the groups of children that are even more likely to get antibiotic at the moment are those who have one or more particular features - phlegm (sputum), fever, shortness of breath, or rattly noises heard in the chest when the doctor listens with the stethoscope. It is a real priority to show which groups of children that GPs prescribe for currently benefit and which do not, so that antibiotics can be targeted appropriately and the effectiveness of antibiotics can be conserved for future generations. Almost 1000 children with chest infections presenting in primary care will get either amoxicillin (an antibiotic) or not get amoxicillin for 1 week to see whether antibiotics make any difference to symptom severity, or the duration of illness. All children will be given advice about using pain killers and will be followed up carefully during the next month. The study will be large enough to be able to show which, if any, groups of children that GPs currently prescribe for benefit from antibiotics (such as those with fever compared to those with no fever), and which groups do not. Parents and children who are happy to have further tests will have a pinprick blood sample, a swab of the throat and an X ray done. This is to see whether simple markers of inflammation and infection or the presence of bacteria, or any lung involvement seen on the X ray can predict benefit from antibiotics.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION