Award Title: Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection (The BATCH Trial)
Funder: Department of Health and Social Care

Abstract: WHAT IS THE PROBLEM?_x000D_
Sepsis is defined as the body’s response to infection, which can often be indistinguishable from the response to other insults like burns or surgery. On one hand, giving antibiotics promptly saves lives, but on the other hand, giving antibiotics to people who don’t need them, leads to overuse of antibiotics and antimicrobial resistance. The Department of Health recommends that antibiotics should be given for as short a course as is safe, to prevent antimicrobial resistance._x000D_
Most hospitals in the NHS use a blood test called C-Reactive Protein (CRP) to monitor response to infection, but it is not specific for bacterial infection and shows a delayed response to infection. Procalcitonin is a blood test which is specific for bacterial infection and responds more quickly than CRP, but is not routinely used in the NHS. Studies done mainly in adults shows that using procalcitonin to guide clinicians may reduce the amount of antibiotics used, reduce hospital stay, and is not associated with adverse effects such as hospital re-admission, incomplete treatment of infections, relapse or death. A recent guideline from the National Institute for Health and Care Excellence (NICE) recommends further research on procalcitonin testing to guide antibiotic use in children._x000D_
AIM OF THE RESEARCH_x000D_
In this study, we will conduct a randomised control trial which will compare current management of bacterial sepsis in children (doctors use clinical judgement and may also use CRP to decide on duration of intravenous antibiotics) with procalcitonin-guided management, where the management is identical to current practice, except that doctors have an additional procalcitonin test with advice on how to interpret the result._x000D_
WHAT WILL BE DONE AND WHO WILL BE INVOLVED?_x000D_
Around 12-15 hospitals treating children will participate in the study. Parents will be given information about the study and invited to take part. Children admitted to hospital with bacterial infection and receiving intravenous antibiotics for more than 48 hours will be randomly assigned to one of the two treatment arms. Doctors and patients will know which treatment arm they are in._x000D_
PATIENT AND PUBLIC INVOLVEMENT_x000D_
We have utilised the input of the Patient and Public Involvement (PPI) Manager for the NIHR Alder Hey Clinical Research Facility and Patient and Public Involvement and Engagement Lead for the NIHR Clinical Research Network. In developing the design of this research study we actively sought the input of Liverpool GenerationR Young Person’s Advisory Group (YPAG) coordinated by the PPI Manager. The group consists of nineteen young people aged between twelve and nineteen years old. The group has worked with several researchers exploring the topic of diagnosing and treating sepsis, and expressed a preference for a shorter course of intravenous antibiotics, if it was safe to do so. The group has discussed at length the issues associated with antimicrobial resistance and the need to educate young people and families about the misuse of antibiotics, and felt that findings from this study could be developed into educational materials for patients, families and clinicians._x000D_
HOW WILL THE RESEARCH BENEFIT PATIENTS?_x000D_
If the study shows that procalcitonin-guided management is superior to current practice, it will lead to improved safety and quality of patient care, reductions in the spread of antimicrobial resistance, and reduced time in hospital.

Lay Abstract: DESIGN: Prospective, individually randomised, two-arm RCT with internal pilot study across 12-15 centres._x000D_
PHASE 1: An internal pilot study to assess the recruitment rates, adherence to intervention, feasibility of individual randomisation, attrition rates, and the proportion of patients in whom we are able to measure both co-primary outcomes. Qualitative process evaluation which aims to improve the trial conduct in Phase 2. Defined stop-go criteria._x000D_
PHASE 2: Two-arm RCT; PCT-guided best practice AMS management versus best practice AMS management alone._x000D_
SETTING: Paediatric wards or PICUs._x000D_
TARGET POPULATION: Hospitalised children <18 years being treated with IV antibiotics for suspected or confirmed bacterial infection._x000D_
HEALTH TECHNOLOGIES BEING ASSESSED: The BATCH trial will assess the use of an additional PCT test  in children hospitalised with suspected or confirmed bacterial infection, to guide antimicrobial prescribing decisions[1]. In children randomised to the intervention arm, a PCT test will be performed in the hospital laboratory at baseline and every 1-3 days whilst on on IV antibiotics. Children in the control arm will not have the PCT test performed. _x000D_
OUTCOMES AND SAMPLE SIZE: Co-primary outcomes: IV antibiotics duration (days) and a composite safety outcome comprising: unscheduled admissions/readmissions, re-instating IV antibiotic therapy and mortality.  Secondary outcomes include total duration of antibiotics, time to discharge from hospital, health utility and other safety outcomes. A positive conclusion will be both a decrease in IV antibiotic duration AND non-inferiority in safety. Our observational study data showed an admission/re-admission rate of 8.8%. In critically ill patients,  3% re-instated IV antibiotic therapy, and 4% mortality was reported [2],[3]. With some overlaps considered, we estimate around 15% overall rate of our composite safety outcome. Assuming a conservative non-inferiority margin of 5%, a one-sided significance level of 0.05 and 90% power we would need 1748 participants. This will give 99% power to detect antibiotic duration decrease and 90% power to test non-inferiority in safety separately. _x000D_
STATISTICAL ANALYSIS: Our primary analysis of co-primary outcomes will a) compare the duration of days of IV antibiotics to assess the superiority of the intervention; b) compare the rate of the composite safety outcome to assess its non-inferiority in safety. Differences in total duration of antibiotics, time to discharge from hospital, health utility and other safety outcomes will also be compared as secondary outcomes._x000D_
ECONOMIC EVALUATION: A cost-effectiveness analysis will be used to assess possible efficiency gains, and results presented in terms of costs per antibiotic treatment duration and per treatment of unmet primary safety endpoints. Using a NHS perspective, relevant direct medical costs and resource use (in-hospital and community) up to Day 28 will be collected. Health-related quality of life will be measured in children 5 years and older using CHU9D. Descriptive and regression analysis will be used to identify key elements of service use and cost and to explore the potential impact of baseline participant characteristics on the costs and outcomes measures. Differences in each arm will be used for the computation of an incremental cost-effectiveness ratio (ICER), and one way sensitivity analysis performed on key model parameters.

Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: INFECTION