Objective To test and compare the efficacy of methenamine hippurate for prevention of recurrent urinary tract infections with the current standard prophylaxis of daily low dose antibiotics. Design Multicentre, open label, randomised, non-inferiority trial. Setting Eight centres in the UK, recruiting from June 2016 to June 2018. Participants Women aged ≥18 years with recurrent urinary tract infections, requiring prophylactic treatment. Interventions Random assignment (1:1, using permuted blocks of variable length via a web based system) to receive antibiotic prophylaxis or methenamine hippurate for 12 months. Treatment allocation was not masked and crossover between arms was allowed. Main outcome measure Absolute difference in incidence of symptomatic, antibiotic treated, urinary tract infections during treatment. A patient and public involvement group predefined the non-inferiority margin as one episode of urinary tract infection per person year. Analyses performed in a modified intention-to-treat population comprised all participants observed for at least six months. Results Participants were randomly assigned to antibiotic prophylaxis (n=120) or methenamine hippurate (n=120). The modified intention-to-treat analysis comprised 205 (85%) participants (antibiotics, n=102 (85%); methenamine hippurate, n=103 (86%)). Incidence of antibiotic treated urinary tract infections during the 12 month treatment period was 0.89 episodes per person year (95% confidence interval 0.65 to 1.12) in the antibiotics group and 1.38 (1.05 to 1.72) in the methenamine hippurate group, with an absolute difference of 0.49 (90% confidence interval 0.15 to 0.84) confirming non-inferiority. Adverse reactions were reported by 34/142 (24%) in the antibiotic group and 35/127 (28%) in the methenamine group and most reactions were mild. Conclusion Non-antibiotic prophylactic treatment with methenamine hippurate might be appropriate for women with a history of recurrent episodes of urinary tract infections, informed by patient preferences and antibiotic stewardship initiatives, given the demonstration of non-inferiority to daily antibiotic prophylaxis seen in this trial. Trial registration ISRCTN70219762 .

BackgroundCough is a common, disabling symptom of idiopathic pulmonary fibrosis (IPF), which may be exacerbated by acid reflux. Inhibiting gastric acid secretion could potentially reduce cough. This study aimed to determine the feasibility of a larger, multicentre trial of omeprazole for cough in IPF, to assess safety and to quantify cough.MethodsSingle-centre, double-blind, randomised, placebo-controlled pilot trial of the proton pump inhibitor (PPI) omeprazole (20 mg twice daily for 3 months) in patients with IPF. Primary objectives were to assess feasibility and acceptability of trial procedures. The primary clinical outcome was cough frequency.ResultsForty-five participants were randomised (23 to omeprazole, 22 to placebo), with 40 (20 in each group) having cough monitoring before and after treatment. 280 patients were screened to yield these numbers, with barriers to discontinuing antacids the single biggest reason for non-recruitment. Recruitment averaged 1.5 participants per month. Geometric mean cough frequency at the end of treatment, adjusted for baseline, was 39.1% lower (95% CI 66.0% lower to 9.3% higher) in the omeprazole group compared with placebo. Omeprazole was well tolerated and adverse event profiles were similar in both groups, although there was a small excess of lower respiratory tract infection and a small fall in forced expiratory volume and forced vital capacity associated with omeprazole.ConclusionsA large randomised controlled trial of PPIs for cough in IPF appears feasible and justified but should address barriers to randomisation and incorporate safety assessments in relation to respiratory infection and changes in lung function.

This document may differ from the final, published version of the research and has been made available online in accordance with publisher policies. To read and/or cite from the published version of the research, please visit the publisher's website (a subscription may be required.) TitleSurgical treatment for recurrent bulbar urethral stricture: A randomised open label superiority trial of open urethroplasty versus endoscopic urethrotomy (The OPEN Trial).

BackgroundAt least half of all adult women will experience infective cystitis (urinary tract infection: UTI) at least once in their life and many suffer from repeated episodes. Recurrent urinary tract infection (rUTI) in adult women is usually treated with long-term, low-dose antibiotics and current national and international guidelines recommend this as the ‘gold standard’ preventative treatment. Although they are reasonably effective, long-term antibiotics can result in bacteria becoming resistant not only to the prescribed antibiotic but to other antimicrobial agents. The problem of antimicrobial resistance is recognised as a global threat and the recent drive for antibiotic stewardship has emphasised the need for careful consideration prior to prescribing antibiotics. This has led clinicians and patients alike to explore potential non-antibiotic options for recurrent UTI prevention.Design /methodsThis is a multicentre, pragmatic, patient-randomised, non-inferiority trial comparing a non-antibiotic preventative treatment for rUTI in women, methenamine hippurate, against the current standard of daily low-dose antibiotics. Women who require preventative treatment for rUTI are the target population. This group is comprised of those with a diagnosis of rUTI, defined as three episodes in 1 year or two episodes in 6 months, and those with a single severe infection requiring hospitalisation. Participants will be recruited from secondary care urology / urogynaecology departments in the UK following referral with rUTI. Participants will be followed up during a 12-month period of treatment and in the subsequent 6 months following completion of the prophylactic medication. Outcomes will be assessed from patient recorded symptoms, quality of life questionnaires and microbiological examination of urine and perineal swabs. The primary outcome is the incidence of symptomatic antibiotic-treated UTI self-reported by participants during the 12-month period of preventative treatment. Health economic outcomes will also be assessed to define the cost-effectiveness of both treatments. A qualitative study will be conducted in the first 8 months of the trial to explore with participants/non-participants’ and recruiting clinicians’ views on trial processes and identify potential barriers to recruitment, reasons for participating and non-participation and for dropping out of the study.DiscussionThe study was commissioned and funded by the National Institute for Health Research (NIHR) and approved under the Medicines and Healthcare products Regulatory Agency (MHRA) notification scheme as a ‘Type A’ study.Trial registrationInternational Standard Randomised Controlled Trial Number (ISRCTN), registry number: ISRCTN70219762. Registered on 31 May 2016.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2998-4) contains supplementary material, which is available to authorized users.

Background Daily, low-dose antibiotic prophylaxis is the current standard care for women with recurrent urinary tract infection. Emerging antimicrobial resistance is a global health concern, prompting research interest in non-antibiotic agents such as methenamine hippurate, but comparative data on their efficacy and safety are lacking. Objective To assess the clinical effectiveness and cost-effectiveness of methenamine hippurate (Hiprex®; Mylan NV, Canonsburg, PA, USA) compared with current standard care (antibiotic prophylaxis) for recurrent urinary tract infection prevention in adult women. Design Multicentre, pragmatic, open-label, randomised, non-inferiority trial of 12 months’ treatment with the allocated intervention, including an early, embedded qualitative study and a 6-month post-treatment observation phase. The predefined non-inferiority margin was one urinary tract infection per person-year. Setting Eight UK NHS secondary care sites. Participants A total of 240 adult women with recurrent urinary tract infection requiring preventative treatment participated in the trial. Interventions A central randomisation system allocated participants 1 : 1 to the experimental (methenamine hippurate: 1 g twice daily) or control (once-daily low-dose antibiotics: 50/100 mg of nitrofurantoin, 100 mg of trimethoprim or 250 mg of cefalexin) arm. Crossover between treatment arms was permitted. Main outcome measures The primary clinical outcome was incidence of symptomatic antibiotic-treated urinary tract infection during the 12-month treatment period. Cost-effectiveness was assessed by incremental cost per quality-adjusted life-year gained, extrapolated over the patient’s expected lifetime using a Markov cohort model. Secondary outcomes included post-treatment urinary tract infections, total antibiotic use, microbiologically proven urinary tract infections, antimicrobial resistance, bacteriuria, hospitalisations and treatment satisfaction. Results Primary modified intention-to-treat analysis comprised 205 (85%) randomised participants [102/120 (85%) participants in the antibiotics arm and 103/120 (86%) participants in the methenamine hippurate arm] with at least 6 months’ data available. During treatment, the incidence rate of symptomatic, antibiotic-treated urinary tract infections decreased substantially in both arms to 1.38 episodes per person-year (95% confidence interval 1.05 to 1.72 episodes per person-year) for methenamine hippurate and 0.89 episodes per person year (95% confidence interval 0.65 to 1.12 episodes per person-year) for antibiotics (absolute difference 0.49; 90% confidence interval 0.15 to 0.84). This absolute difference did not exceed the predefined, strict, non-inferiority limit of one urinary tract infection per person-year. On average, methenamine hippurate was less costly and more effective than antibiotics in terms of quality-adjusted life-years gained; however, this finding was not consistent over the longer term. The urinary tract infection incidence rate 6 months after treatment completion was 1.72 episodes per year in the methenamine hippurate arm and 1.19 in the antibiotics arm. During treatment, 52% of urine samples taken during symptomatic urinary tract infections were microbiologically confirmed and higher proportions of participants taking daily antibiotics (46/64; 72%) demonstrated antibiotic resistance in Escherichia coli cultured from perineal swabs than participants in the methenamine hippurate arm (39/70; 56%) (p-value = 0.05). Urine cultures revealed that during treatment higher proportions of participants and samples from the antibiotic arm grew E. coli resistant to trimethoprim/co-trimoxazole and cephalosporins, respectively. Conversely, post treatment, higher proportions of participants in the methenamine hippurate arm (9/45; 20%) demonstrated multidrug resistance in E. coli isolated from perineal swabs than participants in the antibiotic arm (2/39; 5%) (p = 0.06). All other secondary outcomes and adverse events were similar in both arms. Limitations This trial could not define whether or not one particular antibiotic was more beneficial, and progressive data loss hampered economic evaluation. Conclusions This large, randomised, pragmatic trial in a routine NHS setting has clearly shown that methenamine hippurate is not inferior to current standard care (daily low-dose antibiotics) in preventing recurrent urinary tract infections in women. The results suggest that antimicrobial resistance is proportionally higher in women taking prophylactic antibiotics. Recommendations for research Future research should include evaluation of other non-antibiotic preventative treatments in well-defined homogeneous patient groups, preferably with the comparator of daily antibiotics. Trial registration This trial is registered as ISRCTN70219762 and EudraCT 2015-003487-36. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 23. See the NIHR Journals Library website for further project information.