Title: Cefalexin for UTIs – Right treatment Length in Young children (the CURLY trial). A multi-centre, randomised trial to determine the optimal duration of cefalexin therapy for the treatment of febrile urinary tract infections in children
Funder: Department of Health and Social Care

Abstract: Written by the PPI co-applicants_x000D_ _x000D_ Why this research?_x000D_ Urine infections (water infections) are very common in children. Around 1 in 10 girls and 1 in 30 boys will have had a urine infection by the age of 16 years. They can cause high temperatures, tummy pains and vomiting and can be distressing for children and parents. Urine infections are often treated with a course of antibiotic medicine for 7 - 10 days. This would usually be with an antibiotic called cefalexin. Doctors are not sure of how many days are needed for the medicine to work. In adults, just a few days of antibiotics is usually enough to treat the infection, but we are not sure if this is the same for children._x000D_ _x000D_ Shorter courses of antibiotics may have several benefits over longer courses:_x000D_ 1. Fewer side-effects, like diarrhoea and vomiting. _x000D_ 2. A lower risk of developing ‘bad bacteria’, which don’t respond to normal antibiotics._x000D_ 3. Children might start to feel better sooner._x000D_ _x000D_ What is the question being asked?_x000D_ When young children have a urine infection and a high temperature, how many days of antibiotic do they need to take to get better?_x000D_ _x000D_ What sort of study is it?_x000D_ The study is going to compare different treatment lengths of the antibiotic, called “cefalexin”. Families and children won’t be able to choose how many days of antibiotic they get. To make things fair, this will be decided through a process called randomisation._x000D_ _x000D_ How many children will be involved?_x000D_ It is hoped that 705 children will take part over a 2-year period from at least 8 UK hospitals. This number is calculated based on previous scientific research to ensure that the study is large enough to reach a firm conclusion. _x000D_ _x000D_ What will families be asked?_x000D_ We want to recruit children aged between 3 months and 11 years with urine infections to take part in our trial. Families who agree to join the study will be split into 5 even groups. Depending on what group the child is in, they will take the antibiotics for 3, 5, 6, 8, or 10 days. _x000D_ _x000D_ Parents will report the child’s symptoms using email or smartphones. We will check the symptoms carefully to make sure that the treatment is working well. We will also see the child for a follow-up appointment 3 weeks after the start of treatment and collect a third urine sample to test for bacteria at 5 weeks. Doctors will prescribe more antibiotics during the trial if the treatment is not working well._x000D_ _x000D_ How will this research make a difference?_x000D_ At the end of the study, we will know how many days of antibiotic children with urine infections should take to get better. To make sure people learn about this new information we will talk to other doctors and people in the NHS who write national guidelines. Parents who have helped design this study will help deliver the study and the final message to parents and children._x000D_ _x000D_ Has there been involvement from families when planning this research?_x000D_ Two groups of parents and young people were brought together in video meetings. Parents discussed what their main concerns are when their child is unwell and needs antibiotics. The groups helped to decide which outcomes are important, and how and when to follow-up children. Parents felt that their initial fears about not fully treating a urine infection were overcome by the close monitoring that families would receive. The groups also helped to decide how the study information should be presented. A parent from one of the groups is part of the study team.

Lay abstract: Research Question_x000D_ In infants and young children with a clinical diagnosis of febrile urinary tract infection (UTI), what is the optimal duration of oral cefalexin treatment?_x000D_ _x000D_ Background_x000D_ Cefalexin is the NICE-recommended first-line oral antibiotic for children and young people with a febrile UTI, but there is limited evidence for its optimal duration. This is highlighted as a research priority in national guidelines, and is of particular importance given the high incidence of the condition and the increasing emergence of multidrug-resistant organisms._x000D_ _x000D_ Aim_x000D_ To evaluate the efficacy, safety, and effect on bacterial resistance of five cefalexin treatment durations in children with febrile UTIs._x000D_ _x000D_ Primary Objectives_x000D_ To determine the optimal cefalexin duration (the shortest effective treatment duration) for the treatment of febrile UTIs in children determined using both clinical and microbiological cure._x000D_ _x000D_ Secondary Objectives_x000D_ To assess the impact of cefalexin treatment duration on (1) UTI recurrence, (2) antibiotic-associated adverse events, (3) adherence, (4) antimicrobial resistance, (5) quality of life, and (6) cost-effectiveness._x000D_ _x000D_ Design_x000D_ Open label, multi-arm “DURATIONS” design RCT in 8 paediatric emergency departments across the UK, with a 6-month internal pilot. This will produce a “cefalexin duration vs cure rate” curve, to determine the optimal number of treatment days._x000D_ _x000D_ Participants_x000D_ Infants and children with a clinical diagnosis of febrile UTI (defined clinical features and point-of-care urine testing suggesting a likely UTI) in whom the decision has been made to treat with oral cefalexin._x000D_ _x000D_ Interventions_x000D_ Central randomisation in 1:1:1:1:1 ratio to one of 5 cefalexin course durations (3, 5, 6, 8 or 10 days). Cefalexin will be administered as a standard proprietary liquid suspension at a standard recommended dose._x000D_ _x000D_ Outcomes_x000D_ Primary: UTI resolution. Defined, using a composite outcome endorsed by the European Medicines Agency, as patients in whom there is (i) fever resolution and (ii) urine sterilisation and (iii) no additional antibiotic prescription by 16 days post-randomisation. Secondary: UTI recurrence; Antibiotic-associated adverse events; Adherence to trial medication; Antimicrobial resistance (comparison of the antibiotic sensitivities of pre- and post-treatment urine samples along with the identification of ESBL-producing organisms); Quality of life (CHU9D). Follow up to 30 days (+/- 2 days) post-randomisation. Health economic outcomes and consent for future antimicrobial resistance and genomic studies on stored samples and data linkage studies for long term outcomes._x000D_ _x000D_ Sample size_x000D_ A sample size of 500 microbiologically-confirmed participants is required. This is inflated to 705 after allowing for 12% with non-proven UTI culture, 10% with cefalexin-resistant UTI and 10% loss to follow up._x000D_ _x000D_ Timelines_x000D_ 8 months setup,16 months recruitment and follow-up (pilot phase 6 months, main phase 10 months), 6 months for final analysis, write up and data sharing preparation/archiving._x000D_ _x000D_ Impact & Dissemination_x000D_ Findings will have direct and immediate application to clinical practice. Results will be presented at conferences, published in journals, and made available via open-source methods._x000D_ _x000D_ Patient Involvement_x000D_ We have co-produced this application with children and their families. We are committed to work in partnership with families to deliver and disseminate this research to ensure that it has maximum impact.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION