Title: ALternative To prophylactic Antibiotics for the treatment of Recurrent urinary tract infections in women (ALTAR study)
Funder: Department of Health and Social Care

Abstract: DESIGN: A multi-site, pragmatic patient-randomised non-inferiority trial comparing two treatments for the prevention of recurrent urinary tract (rUTI) in women during 12-months treatment and 6-months following treatment completion. SETTING: High volume UK urology/ urogynaecology units practices with equivalent care pathways for rUTI. TARGET POPULATION: Women over 18yrs with rUTI requiring preventative treatment. EXCLUSIONS: Women with underlying structural/functional urinary tract abnormalities or who lack capacity to consent/complete essential trial documentation HEALTH TECHNOLOGIES: Low dose prophylactic antibiotic for 12 months is the standard preventative treatment for rUTI. Cochrane meta-analysis showed an 85% reduction in UTI episodes during treatment compared to placebo. The experimental arm is methenamine hippurate an oral urinary antiseptic given for 12 months supported by a Cochrane meta-analysis showing 76% reduction in UTIs during treatment over placebo. OUTCOMES: Data will be collected at baseline, during months 3,6,9 and 12 of treatment and at 3 and 6 month review after treatment completion (months 15 and 18). The primary clinical outcome is occurrences of UTI in the 12 months treatment period and is defined as the presence of >=1 relevant symptom and the taking of a treatment course of antibiotic. Primary health economic outcome is the incremental cost per QALY gained over the 12 months of preventative therapy against UTI. Secondary outcomes include UTI frequency during follow-up, QoL, rate of antimicrobial resistance found in patients urine/faecal reservoir, cost effectiveness of treatments, antibiotic use and qualitative findings regarding patient and clinician preference from the initial feasibility phase. SAMPLE SIZE: We plan to recruit 255 patients to the trial, 120 in each treatment arm and 15 patients who decline trial participation but agree to qualitative interviews. If there is an actual difference of 0.6 episodes (in favour of treatment with antibiotics), then two groups of 87 patients are required to be 90% sure that the lower limit of a one-sided 95% confidence interval (or equivalently a 90% two-sided confidence interval) will be above the non-inferiority limit of 1 UTI episode assuming a standard deviation of 0.9 episodes per year. Total sample size assuming 2 groups and an attrition rate of 25% = 232, rounded up to 240. PROJECT TIMETABLE: Trial duration of 54 months is planned commencing in Feb 2016 and including a 6 month embedded qualitative study paralleling the main study to explore patients and clinicians views and inform changes to trial protocol. The main study is as follows: months 1-3 finalisation of regulatory approvals and documentation; month 4/5 staggered set up of centres; months 4–31 participant recruitment and follow up; month 10 completion of feasibility study; months 15-48 completion of follow up, health economic and interim analysis; months 48–54 data checking, preparation and completion of analysis. All centres receive approx. 20 suitable referrals/month. Using a conservative estimate of 70% eligibility and 30% consenting to inclusion, the recruitment period of 27 months would yield well over 250 patients. EXPERTISE IN TEAM: All clinicians are research-active and experienced in the care of patients with rUTI. The Newcastle CTU brings specific methodological expertise; to ensure correct design, conduct, data management and analysis. Patient representation will come from the Cystitis and Overactive Bladder foundation.

Lay abstract: Most women experience cystitis (otherwise known as urinary tract infection; UTI) at least once in their life and some get repeated episodes which are uncomfortable and stressful – this is known as recurrent urinary tract infection (rUTI) and affects around 300,000 women each year in the UK. Giving long term low dose antibiotics is the most frequently used prevention for rUTI and although reasonably effective at supressing the infecting bacteria, they have side effects and causes bacteria to become resistant to antibiotics. There are some alternative preventative options for rUTI that don’t involve antibiotics but doctors are unsure how well they work and so tend to mostly advise antibiotics. The ALTAR trial aims to compare one such alternative non-antibiotic prevention for rUTI, a drug called methanamine hippurate, against the current standard of daily low dose antibiotic to see if the methanamine is at least as good at preventing UTI and has less side effects, particularly a lower chance of resistant bacteria developing. The preventative treatments to be compared are: 1. Once-daily low dose antibiotic for 12-months (standard) 2. Methanamine hippurate, a urinary antiseptic given as a tablet twice daily for 12-months For the trial, women seeking help for rUTI who are seen in a hospital urology clinic at one of our study centres will be given information about the study and asked if they would like to take part. For women that do decide to take part, their preventative therapy (methanamine or antibiotic) will be decided at random by a computer programme, similar to a toss of a coin. The reason for this is that it is the only way to guarantee a fair comparison between two options. We will follow each woman during the 12- months that they take the UTI prevention and then for 6 months afterwards to record the benefits, side effects and costs of each treatment. The main outcome that we will use to decide the result will be the number of episodes of UTI women in each group suffer during the 12-months of preventative treatment. We will also record the types of bacteria found and their resistance to antibiotics. Throughout the study women will be able to have the usual short course of treatment antibiotics for any episodes of UTI that they suffer. To carry out the study successfully we will need 255 women to take part and we have planned the study to be completed in 54 months. The main problem that we think women may find during the study is if they don’t get any benefit from the prevention treatment that they are allocated. We have designed the study so we can quickly find this out mainly by planned regular contact with participants. We have taken into account the need for some women to have to switch to another prevention treatment during the first 12 months. This study is trying to help solve an important problem with our current overuse of antibiotics which is causing more and more resistant bacteria and so difficult to treat infections. We have assembled a team of clinical trial experts and enthusiastic doctors from large NHS centres. The funding requested is needed to pay the staff to do the study and provide the resources required to collect and process the outcome information. If the study does show that methanamine is as good as antibiotic at preventing UTI it will result in substantial NHS savings related to lower bacterial resistance levels and less hard to treat infections.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION