Open access Protocol BMJ Open: first published as 10.1136/bmjopen-2020-037128 on 13 January 2021. Downloaded from D- MannosE to prevent Recurrent urinary tract InfecTions (MERIT): protocol for a randomised controlled trial Marloes Franssen ,1 Johanna Cook,2 Jared Robinson,2 Nicola Williams,2 Margaret Glogowska,2 Yaling Yang,2 Julie Allen,2 Christopher C Butler ,2 Nick Thomas,3 Alastair Hay,4 Michael Moore ,5 Gail Hayward 2 To cite: Franssen M, Cook J, ABSTRACT Strengths and limitations of this study Robinson J, et al. D- MannosE Introduction Recurrent urinary tract infections (RUTIs) to prevent Recurrent urinary have a significant negative impact on quality of life and ► Based on current literature, this will be the first large tract InfecTions (MERIT): healthcare costs. To date, daily prophylactic antibiotics protocol for a randomised publicly funded randomised controlled trial of D- are the only treatment which have been shown to help controlled trial. BMJ Open mannose for prophylaxis of recurrent urinary tract prevent RUTIs. D- mannose is a type of sugar which is 2021;11:e037128. doi:10.1136/ infections. believed to inhibit bacterial adherence to uroepithelial bmjopen-2020-037128 ► This study is the first to use a placebo control in cells, and is already being used by some women in an evaluating the benefit of D- mannose. ► Prepublication history and attempt to prevent RUTIs. There is currently insufficient ► Obtaining the primary outcome by medical notes supplemental material for this rigorous evidence on which to base decisions about its paper is available online. To review will ensure data completeness. use. The D-mannose to prevent recurrent urinary tract view these files, please visit ► The trial may not be powered to detect a secondary infections (MERIT) study will evaluate whether D- mannose the journal online (http:// dx. doi. outcome of symptom burden which is also of value is clinically and cost- effective in reducing frequency of org/ 10. 1136/ bmjopen- 2020- to patient decision making. 037128). infection and symptom burden for women presenting to UK ► Although participants report weekly on their study primary care with RUTI. product usage there are no objective measures Received 24 January 2020 Methods and analysis MERIT will be a two-arm, available to confirm accuracy of reporting. Revised 06 November 2020 individually randomised, double blind placebo controlled, Accepted 26 November 2020 pragmatic trial. Participants will be randomised to take D- mannose powder or placebo powder daily for 6 months. The primary outcome will be the number of medical UTIs (RUTIs) have a considerable negative http://bmjopen.bmj.com/ attendances attributable to symptoms of RUTI. With 508 impact on quality of life, which extends beyond participants we will have 90% power to detect a 50% the unpleasant symptoms to distressing and reduction in the chance of a further clinically suspected disrupted sexual relationships, persistent UTI, assuming 20% lost to follow- up. Secondary outcomes 4 will include: number of days of moderately bad symptoms unmanageable pain and systemic illness. of UTI; time to next consultation; number of clinically UTI accounts for an important proportion suspected UTIs; number of microbiologically proven UTIs; of healthcare costs as a result of outpatient © Author(s) (or their visits, diagnostic tests and prescriptions.5 In employer(s)) 2021. Re- use number of antibiotic courses for UTI; quality of life and permitted under CC BY. healthcare utilisation related to UTI. A within trial economic 2007, UTI recurrence accounted for 10.5 on September 23, 2021 by guest. Protected copyright. Published by BMJ. evaluation will be conducted to examine cost-effectiveness million outpatient consultations and 2–3 1Nuffield Department of of D- mannose in comparison with placebo. A nested million emergency department visits in the Orthopaedics, Rheumathology qualitative study will explore participants’ experiences and USA alone. In addition, UTIs are the most and Musculoskeletal Sciences, perceptions of recruitment to, and participation in a study common cause of infection in hospitalised University of Oxford, Oxford, UK requiring a daily treatment. 2 patients, accounting for 17.2% of all noso- Nuffield Department of Primary Ethics and dissemination Ethical approval has been comial infections in England. Furthermore, Care Health Sciences, Oxford obtained from South West- Central Bristol Research Ethics University, Oxford, UK UTIs result in considerable patient morbidity 3 Committee. Publication of the MERIT study is anticipated Windrush Medical Practice, to occur in 2021. and time off work; hence, the management Witney, UK 4 ISRCTN 13283516. of this condition incurs large financial costs, Centre for Academic Primary Trial registration number estimated at US$3.5 billion in the USA per Care, University of Bristol, 6 Bristol, UK year. 5Primary Care Medical Group, BACKGROUND A systematic review of randomised University of Southampton, Urinary tract infection (UTI) is the most controlled trials identified antibiotic Southampton, UK common bacterial infection that women prophylaxis as the only treatment, which has 1 2 Correspondence to consult for in UK primary care. Approxi- been demonstrated to help prevent RUTIs. Dr Gail Hayward; mately 40%–50% of women experience one Antibiotics taken daily for 6–12 months were gail. hayward@ phc. ox. ac. uk UTI episode during their lives.3 Recurrent more effective than placebo at preventing Franssen M, et al. BMJ Open 2021;11:e037128. doi:10.1136/bmjopen-2020-037128 1 Open access BMJ Open: first published as 10.1136/bmjopen-2020-037128 on 13 January 2021. Downloaded from recurrent infection,7 and national guidelines advocate practitioners (GPs) should advise their patients to use their use for this indication.8 However, antibiotics also D- mannose for this indication. resulted in more severe and unpleasant side effects The D- mannose to prevent recurrent urinary tract (eg, vomiting, urticaria, candidiasis). Furthermore, infections (MERIT) double blind placebo- controlled once antibiotic prophylaxis is discontinued, even after randomised controlled trial aims to evaluate the effec- extended periods, approximately 50%–60% of women tiveness of D- mannose in women suffering with RUTI will experience a further UTI within 3 months.9 10 Thus, presenting to UK primary care and its cost effectiveness. antibiotic prophylaxis does not exert benefit once stopped, and is directly linked to antibiotic resistance 11 in uropathogens. Antibiotic resistance has been asso- METHODS AND DESIGN ciated with an increased duration of severe symptoms Study aims, research questions and outcomes of UTIs, irrespective of the use of an appropriate anti- 2 11 The primary aim of MERIT is to assess the effectiveness biotic. of daily use of D- mannose compared with placebo in D- mannose is a type of sugar (a monosaccharide isomer preventing symptomatic UTI in women. of glucose), which is thought to inhibit bacterial adher- The primary outcome of the trial will be the proportion ence to uroepithelial cells by binding to a site on the tip of women experiencing at least one further episode of of the fimbria12 and has shown benefit in animal models 13 clinically suspected UTI for which they contact ambula- in preventing UTIs. tory care (out of hours primary care, in hours primary Currently D- mannose is available commercially to the care, ambulance or the emergency department) within 6 public as a food supplement, and is favoured by many months of study entry. women who have RUTIs, but until recently, there has Secondary outcomes will include (within 6 months of been little empirical evidence to support its use. An open- study entry): label randomised three arm trial including 308 women 14 ► Number of days of moderately bad (or worse) symp- with RUTI seen in outpatient settings found that daily toms of UTI. use of D-mannose for 6 months resulted in an absolute ► Time to next consultation with a clinically suspected reduction in incidence of further UTI of 45% from a UTI. proportion of 60% in the usual care arm, with no adverse ► Number of clinically suspected UTIs. events. The proportion of women experiencing an RUTI ► Number of microbiologically proven UTIs. over 6 months was reduced by 11% compared with daily ► Number of antibiotic courses for UTI. antibiotic use. This finding is supported by recent smaller 15–18 ► Report of consumption of antibiotics using diary studies. during periods of infection. Although there are indicators of efficacy from small ► Proportion of women with a resistant uropathogen underpowered trials, the only adequately powered http://bmjopen.bmj.com/ 15 culture during an episode of acute infection. study to date was not placebo controlled and found an ► Hospital admissions related to UTI. unexpectedly high RUTI incidence in the control arm. ► Quality of life and healthcare utilisation related to Furthermore, a microbiologically confirmed UTI was a UTI. requirement for entry to the study, and participants were ► Healthcare utilisation recorded in the participant withdrawn once they developed a UTI on treatment. diary and during a notes review. Therefore, true incidence of UTI could not be estab- ► Acceptability and process evaluation conducted via lished, a measure for women who experience frequent telephone interviews (after 6 months). RUTIs, who are also the most likely candidates for prophy- on September 23, 2021 by guest. Protected copyright. laxis. Finally, all women on hormonal contraception were