The cystic fibrosis (CF) anti-staphylococcal antibiotic prophylaxis trial (CF START); a randomised registry trial to assess the safety and efficacy of flucloxacillin as a longterm prophylaxis agent for infants with CF

Design; multi-centre randomised open label registry trial (with internal pilot study) Setting; multi-disciplinary care setting (UK Paediatric CF clinics) Literature and background; Systematic review confirms that long-term flucloxacillin treatment results in reduction in Staphylococcus aureus (SA) airway infection but possibly at the expense of earlier Pseudomonas aeruginosa (PsA) airway infection. This limited evidence base has resulted in varied interpretation with diverse practice across the globe. Recent UK registry data suggest an increase prevalence of PsA infection in patients on flucloxacillin, making UK physicians and patient advocacy groups anxious about the validity of this management strategy for infants with CF. Determining that long-term flucloxacillin is safe and effective is a priority research area in the field of Paediatrics, illustrated by the repeated prioritisation of this topic by the NIHR CRN: Children's Respiratory and CF Clinical Studies Group. Target population; Infants with an early diagnosis of CF (mainly through newborn screening) will be observed to 48 months of age. Inclusion/exclusion criteria; Diagnosis of CF before 70 days of age. Infants with an inconclusive diagnosis will be excluded. Intervention; Infants will be randomised to "Prevent and Treat" (flucloxacillin, 125 mg twice a day) or "Detect and Treat" (targeted antibiotic therapy). Outcomes; The primary outcome (time to first growth of PsA) and secondary outcomes (clinical, microbiological and economic) will be collected from the national registry database. At 40-48 months infants will undertake multiple breath washout (MBW) measurement for assessment of airways disease. This will be a voluntary measurement and will be undertaken in a national laboratory. Justification for outcomes; following extensive stakeholder and PPI engagement, we have designed a pragmatic study that will answer a question that is a considerable concern to people with CF and their families, namely does long-term flucloxacillin treatment predispose infants to earlier infection with Pseudomonas. This study will change or confirm current UK practice. Efficacy measures in this age group are challenging; MBW is the only valid measure of early CF airways disease. Sample size; non-inferiority is the optimal study design to answer the research question and change practice. We will enrol 440 infants, with the aim of an intention to treat analysis on 220 in each arm, which provides 80% power (at 0.025 one-sided significance level) to show that the difference between the two interventions is no more than 12 months, an acceptable margin to stakeholders and PPI representatives. Project timetable; The project will be run over six stages; 1) pre-award preparation (database and regulatory issues) and STOP/GO criterion 1 (Registry preparedness), 2) 0-4 months, preparation and site set-up for pilot study, 2) 4-10 months, pilot study (STOP/GO criteria 2 (data quality) and 3 (recruitment), 3) 11-45 months, UK-wide recruitment, 4) 44-80 months, MBW measurement, 5) 90-96 months, data processing, analysis and publication and 6) longterm follow-up of the CF START cohort (not funded by this application). Expertise; CF START will run in partnership with the NIHR Clinical Research Network: Children Clinical Trials Unit (CTU), who have provided methodological and trial management support. The core team are international CF leaders and have expertise in systematic review, study design, trial management and dissemination. The CF START project also reflects a commitment to PPI and partnership working with the UK Cystic Fibrosis Trust, without which this trial design and implementation would not be possible.