Title: 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
Funder: Department of Health and Social Care

Abstract: 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.

Lay abstract: The aim of the CF START study is to determine the safest and most effective antibiotic strategy for infants diagnosed with cystic fibrosis. Cystic fibrosis (or CF) is an inherited genetic condition. Infants with CF in the UK are most often diagnosed following a positive newborn screening test. They may appear quite well initially but quickly develop significant chest infections, which if untreated will cause lung damage and early death. For many years, physicians in the UK have prescribed children with CF long-term antibiotics that they take every day. Most often this is an antibiotic called flucloxacillin. The aim of this strategy is to prevent lung infection with Staphylococcus, which is known to be a common bug causing infection for people with CF. Physicians in other countries have been more reticent to use this approach and have tended to only prescribe antibiotics when the infant has a cough or grows a bug from a cough (or throat) swab. The reason they use this more targeted approach is that they are concerned that use of long-term antibiotics may predispose the child to earlier infections with other more resistant bugs, in particular Pseudomonas. The UK newborn screening programme has thrown into perspective the issue of how to best treat these infants who appear well at diagnosis. In addition, results from the national registry suggest that children with CF who are not on flucloxacillin may have less infection with Pseudomonas. It is apparent therefore that this is an opportune time to undertake a study in the UK to determine the safest and most effective approach for these children. For the CF START study, 440 infants with a clear diagnosis of CF will be randomly allocated to receive either flucloxacillin given twice every day (called “Prevent and Treat”) or antibiotics given in a more targeted manner (“Detect and Treat”). We will record the age of the infant when they first grow Pseudomonas from a cough swab, as well as other bugs. We shall also record how many extra courses of antibiotics are required and the number of hospital admissions. These outcomes will be recorded on the national Registry database, as part of routine care, which means the families will not be required to make extra clinic visits. Finally, once the child is over 40 months of age, the family will be invited to a national respiratory laboratory for a test of lung function, the lung clearance index. This part of the study will be voluntary for the families and will provide important information on respiratory condition of children in the study.

Research activity codes: 6.1 PHARMACEUTICALS;7.1 INDIVIDUAL CARE NEEDS
Health categories: CONGENITAL DISORDERS