IntraVESical Preparations for REcurrent Urinary Tract Infection PRevention (The VESPER Study): a multi-arm, multi-site open label randomised superiority trial.

Design: A pragmatic, multi-arm, multi-site, patient-randomised superiority trial with internal pilot, qualitative and economic evaluations. Setting: UK multi-centre trial at 20 secondary care NHS organisations recruiting women who have failed first-line treatments for recurrent uncomplicated urinary tract infection (UTI) prevention. Research Question: In women who fail first-line preventative treatment for rUTI does the use of intravesical treatments result in a greater reduction in the rate of symptomatic UTIs compared to the current guideline-recommended second-line prophylactic antibiotic therapy and is this cost-effective for the UK NHS? Background: UTI is a common condition but despite effective first line preventative treatments 1 in 5 women will require second line treatment. Current clinical guidelines are unable to make strong recommendations for these refractory cases. Our preliminary survey data suggests around 80% of clinicians are already using intravesical treatments in routine practice without robust evidence to support this. VESPER will address this evidence gap and provide accurate data regarding the efficacy of intravesical treatments compared to second-line oral antibiotics. Intravesical treatments do not affect the gut microbiota and may reduce antimicrobial resistance as a result. Research Objectives: The primary objective is to determine the relative clinical effectiveness and cost-effectiveness of 3 second-line preventative treatments for women with refractory recurrent uncomplicated UTI in NHS setting. The treatments under investigation are: • Intravesical antibiotics (Gentamicin) • Intravesical Glycosaminoglycan (GAG) replacement compounds • Second-line prophylactic oral antibiotics Outcomes: Primary Clinical Outcome Symptomatic, antibiotic-treated UTI rate during a 6-month treatment period Primary Economic Outcome Incremental cost per quality-adjusted life year (QALY) gained at 12 months. Secondary Outcomes will include occurrence of UTI in the follow-up period, change in rUTI Impact Questionnaire [17], antibiotic use, microbiologically-proven UTI, antimicrobial resistance development, prevalence of asymptomatic bacteriuria, compliance with allocated treatment, UTI severity, costs to the NHS, personal social services and women, quality-adjusted life years (QALYs), incremental cost per QALY gained at 6 months, incremental net benefit at 12 months, incremental cost per QALY gained over a lifetime horizon, women’s marginal willingness-to-pay for the interventions and to avoid a UTI, participant satisfaction with treatment and adverse events. Outcomes will be collected for each participant over a 6-month treatment period following randomisation and after a further follow-up period of 6-months (total study period = 12 months) and analysed at trial completion. Sample Size 412 participants in total (62 in the oral comparator arm and 175 in each intravesical experimental arm). We will randomise participants using a 1:3:3 ratio (oral antibiotics: intravesical antibiotics: intravesical GAG). Recruitment target per site is 21 patients over 21 months. Project timeline Timetable: M1-7 set-up, M8-15 internal RCT pilot, M16 stop/go assessment, M8-28 recruitment, M14-41 follow-up completion; M42-48 analysis and write-up. Dissemination - main paper to a general medical journal - lay summary by patient advisory group - highlight results to guideline-writers / policy makers - social media to publicise results