Title: Prophylactic antibiotics to prevent chest infections in children with neurological impairment (Parrot) trial
Funder: Department of Health and Social Care

Abstract: Background_x000D_ There are large numbers of children with neurological impairment (NI) caused by conditions such as cerebral palsy. Many are prone to chest infections which can lead to long stays in hospital, additional impairment and even premature death. Despite the suffering caused to children and their families by these severe infections and the high cost to health services, there is very little information on how best to prevent them. Some doctors prescribe long-term antibiotics but we don't really know whether this treatment makes any difference to the numbers of chest infections children suffer from, or whether these antibiotics can cause long term harm._x000D_ _x000D_ Aims_x000D_ This study aims to find out whether 12-month's treatment with an antibiotic called azithromycin reduces how often children with NI have to stay in hospital with chest infections._x000D_ We also want to find out whether this treatment affects:_x000D_ • Number and severity of chest infections_x000D_ • Number of GP visits and A&E attendances with chest infections_x000D_ • Number of courses of extra antibiotics prescribed_x000D_ • Quality of life of child and parent; quality/amount of parent sleep; time off school_x000D_ • Whether we are still able to treat the bugs grown from the children with standard antibiotics_x000D_ _x000D_ Study Design_x000D_ This trial will compare 12-months treatment with azithromycin to placebo (a sham treatment) in children with NI in UK and Australia at high risk of chest infections._x000D_ _x000D_ Methods_x000D_ Children and young people aged 3-17 yrs, with NI, at risk of chest infections, along with their parents, will be approached for the study. For families who agree to participate in the trial, their child will be allocated by chance to receive either 12-months azithromycin or 12-months placebo. Families, researchers and health staff won’t know which one their child is receiving. This is the best way to avoid bias in a trial._x000D_ _x000D_ We will contact parents in person, and by phone, text message or email to monitor hospital admissions, contacts with the GP and chest infections in the children and young people. This is important to see if the antibiotics work to reduce chest infections and if there are cost savings to the health service, or parents._x000D_ _x000D_ We will also collect secretions from the noses of young people using cotton buds to check if the antibiotics are causing the growth of bugs that are resistant to usual antibiotics._x000D_ Parents we talked to before this application suggested that we also collect information to see if the antibiotics improved sleep both for themselves and their children. We will use sleep monitors and questionnaires to do this._x000D_ _x000D_ Family Involvement_x000D_ Parents' views have been influential in the design of this trial. Parents in UK and Australia will help produce plain language information. They will also help design a ‘Parrot’ website that contains information that’s relevant to parents, including videos about the study to encourage recruitment._x000D_ _x000D_ Dissemination_x000D_ Families, healthcare professionals and commissioners will need to know the results of this trial. We will present our findings at conferences, via plain language summaries using social media and through charity websites and stakeholder organisations such as ‘Together for Short Lives’ and ‘Cerebra’. We will also publish the results of this trial in medical journals._x000D_ _x000D_ At the end of the study, we will be able to recommend whether this treatment is effective and represents ‘value for money’ for healthcare providers like the NHS.

Lay abstract: Design_x000D_ Joint UK/Australian multicentre, randomised, double blind, placebo controlled trial comparing 12-month azithromycin to placebo in children with NI at risk of LRTI_x000D_ _x000D_ Setting_x000D_ 37 secondary and tertiary paediatric centres in UK and 3 large centres in Australia with associated networks_x000D_ _x000D_ Target Population_x000D_ Children and young persons with non-progressive NI with persistent respiratory symptoms at risk of hospitalisation for LRTI_x000D_ _x000D_ Exclusion criteria_x000D_ Children with progressive causes of NI, neuromuscular disorders or with pre-existing non-neurological conditions such as CF, immunodeficiency, hypersensitivity or contra-indications to taking macrolides etc._x000D_ _x000D_ Health technologies being assessed_x000D_ Liquid formulation of Azithromycin vs matched placebo_x000D_ _x000D_ Measurements of costs and outcomes_x000D_ Primary outcome is the proportion of children hospitalised for LRTI. Other outcomes will include:_x000D_ • Need for healthcare utilization (GP visits/A&E attendances), rescue antibiotics, changes in concomitant medications, etc._x000D_ • Nasal swab microbiology and bacteria AMR profiling; bacterial & viral microbiology during hospitalisations for presumed LRTI_x000D_ • HR-QoL of both child and parent/carer_x000D_ • Respiratory symptom questionnaire responses_x000D_ • Actigraphy/sleep questionnaire assessment of parent and child sleep quality/amount[28]_x000D_ • School attendance_x000D_ • Resource use by questionnaire and linked routine data from NHS Digital to for HES and GP attendance_x000D_ • CHU9D utility measure for estimation of QALYs_x000D_ _x000D_ Data management/analysis_x000D_ Data will be centrally managed on a GCP compliant database (Infermed MACRO). A complete statistical analysis plan will be written before any comparative analysis is done. The primary analysis will use principle of intention to treat on all randomized participants. Binary outcomes will be reported as relative risk and 95% CIs. Continuous outcomes will be reported as change from baseline and analysed using analysis of covariance. Time to event outcomes will be summarised by Kaplan-Meier curves and compared overall using logrank tests and survival regression methods. Missing data will be monitored and strategies developed to minimise its occurrence._x000D_ _x000D_ Sample size_x000D_ To detect a 30% reduction in hospitalisation rate in children with NI and respiratory symptoms at risk of LRTI, with 90% power (alpha 0.05), we would require 225 patients per group, increasing to 250 allowing for 10% loss to follow-up/attrition, i.e. 500 children in total._x000D_ _x000D_ Difference between current and planned pathways_x000D_ There is no current standard care pathway for these children, hence the need for this study. Currently, there is little evidence to guide practice or the development of guidelines and prophylactic antibiotics are prescribed on an ad hoc basis. _x000D_ _x000D_ Project timetable_x000D_ -6–0 mths: REC/HRA_x000D_ 0–6 mths: Set-up_x000D_ 6–12 mths: Internal pilot_x000D_ 13–54 mths: Trial recruitment proper_x000D_ 6-54 mths: HES/GP & school attendance data collection and analysis in select centres_x000D_ 54-60 mths: Data analysis & monograph preparation_x000D_ _x000D_ Expertise in team_x000D_ PMc/JG/JP/RL/AC/LT/PG/DR/KW/CS-clinical expertise; MP-leverage of CRN resources; HJS-PPI rep.; CM-PPI expertise; PMc/JG/AC/MP-expertise in leading multicenter RCTs; JP/RL/CM/DR/KW-expertise in running definitive RCTs in children with NI; RL/DR-experience in use of GP/HES data for research; HH/PRW/AJ-biostat/trial methodology expertise; PG-sleep/NI expertise; DE-microbiological/genomic expertise; MW-drug/formulations expertise; DH-HEA expertise.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION;NEUROLOGICAL