Efficacy, safety and impact on antimicrobial resistance of duration and dose of antibiotic treatment for children with Community-Acquired Pneumonia (CAP): a randomIsed controlled Trial - CAP-IT

DESIGN: Randomised placebo-controlled factorial non-inferiority trial of amoxicillin dose and duration in paediatric CAP. PRIOR LITERATURE: Cochrane/Medline identifies no placebo-controlled randomised trials of amoxicillin dose and duration for childhood CAP and development of antimicrobial resistance in the well-resourced setting. SETTING: Paediatric Emergency Departments (PEDs) and paediatric wards at UK NHS hospitals and one hospital in the Republic of Ireland. TARGET POPULATION: Previously healthy children aged greater than 6 months and weighing less than 24kg with uncomplicated CAP (cough+fever+ signs of breathing difficulty) in whom the decision has been made to treat with antibiotics. Exclusion: Documented penicillin allergy, patient already on antibiotics, bilateral wheezing without focal chest signs, complicated CAP: requirement for invasive ventilation/ non-invasive positive pressure ventilation, accompanying shock (>20ml/kg fluid resuscitation), hypotension, GCS<15, complications involving pleural space, pulmonary abscess. HEALTH TECHNOLOGY: Concurrent randomisation to: (1) 3 days of amoxicillin followed by placebo for 4 days or 7 days of amoxicillin; AND to (2) amoxicillin 35-50mg/kg/d or 70-90mg/kg/d in 2 doses (blinded). Randomisation will be in PEDs for children managed there (PED group) and at the time of switch to oral treatment following no more than 48 hours of oral or intravenous beta-lactam in-hospital treatment (WARD group). BASELINE MEASURES: Structured history/examination including X-ray and blood tests as indicated clinically, nasopharyngeal (NP) swab, stool sample in a subset of children. OUTCOME MEASUREMENTS: Treatment failure rate by day 29 (any clinically indicated systemic antibacterial treatment prescribed for respiratory tract infection (including CAP) other than trial medication up to and at week 4 final follow-up). Main secondary outcome: phenotypic resistance to penicillin at week 4 measured in S. pneumoniae isolates colonising the nasopharynx. Other secondary outcomes: 1)severity and duration of parent/guardian-reported CAP symptoms, 2)specified clinical adverse events, including thrush, skin rashes and diarrhoea, , 3)adherence to trial drug. MICROBIOLOGY: Detection of S. pneumoniae in nasopharyngeal swabs will primarily use culture-based techniques; identification of changes in antibiotic resistance will use traditional techniques. . SAMPLE SIZE: To demonstrate non-inferiority for the primary outcome for both interventions, a minimum of 800 children will be recruited. Assumptions: 1)15% failure rate, 2)non-inferiority margin 8%, 3)1- sided 95% CI, 4)power = 90%, 5)15% loss to follow-up. DATA ANALYSIS: Analyses will be intention to treat and follow CONSORT. PED and WARD strata will be analysed jointly. Estimates of main primary and secondary effects (efficacy, resistance and toxicity) will be undertaken using multivariate logistic analyses. TIMETABLE: Recruitment started in February 2017, and is planned to finish in April 2019. EXPERTISE: The study team is a multidisciplinary research group bringing together expertise in clinical trials and epidemiology of paediatric bacterial infections and with the microbiology of antimicrobial resistance.