Recurrent urinary tract infection (UTI) in elderly women is a major driver of antibiotic prescription. Hence, the question of feasible and appropriate preventive measures are important issues in this field. Methenamine hippurate is frequently prescribed in Norway and Sweden as prophylaxis for recurrent UTI. Methenamine hippurate acts via the production of formaldehyde from hexamine, which in turn acts as a bacteriostatic agent, therefore methenamine hippurate is not defined as an antibiotic. According to a Cochrane review 2012 the rates of adverse events for preventing UTI was low. Although this review showed methenamine hippurate might be effective in preventing UTI in the short term, there is a need for large well-conducted randomised controlled trial (RCT) to clarify both the safety and effectivity of preventive methenamine hippurate for longer term use. This is particularly important for longer term use for people without neuropathic bladder disorders. A Norwegian longitudinal observational study including women aged 50-80 years with recurrent UTI indicated a significant and large reduction of more than 50% in antibiotic prescriptions for UTI after start of prophylactic methenamine hippurate. This further strengthens the need for an RCT of methenamine hippurate as prophylaxis for recurrent UTI.

Rationale for conducting this study:

Existing knowledge suggests that methenamine hippurate is a safe drug with few and mild side effects and with the potential to significantly reduce antibiotic usage for women with recurrent UTIs. Methenamine hippurate has been on the market for a long time but has never been tested to prevent recurrent UTIs in larger RCTs with long time follow-up. Hence, this must be proven in a large randomised trial before recommending large scale use of this drug.

The primary objective of this study is to investigate if taking methenamine hippurate reduce the need for antibiotic usage due to recurrent UTI (measured as number of antibiotic courses). Pyelonephritis, hospitalization and death will be registered as safety endpoints in the study.

Study design: Triple- blinded randomised controlled phase IV trial where patients are randomised to active intervention (methenamine hippurate) or controls (placebo). We will include women aged ≥ 70 years with recurrent UTIs, defined as ≥ 3 episodes of antibiotic treated acute cystitis (acute symptoms specific/related to the urinary tract) during the last twelve months or ≥ 2 episodes during the last six months.

Setting and study population:

Women aged ≥ 70 years with recurrent UTIs in primary care. A total of 400 patients will be randomized in this trial, with approximately 100 patients in each of the participating countries; Norway, Sweden, Poland and the Netherlands. The patients will be treated for 6 months.

Patients will be enrolled August-December 2019, including screening for eligibility and getting informed consent.

Start of study with drugs is from October 1st 2019.

Primary outcome: Number of UTI antibiotic treatments during the six months of treatment. If the participant receives >1 antibiotic courses for UTI without symptom relief it is regarded as one episode and counted as one antibiotic treatment. If there has been an asymptomatic period of at least 14 days in-between two UTI antibiotic courses, this is regarded as a new antibiotic treatment. Outcomes will be assessed after 6 and 12 months

In the analysis standard linear regression will be used where number of UTI antibiotic treatments will be the dependent variable. Group allocation together with the confounding variables above will be independent variables. The dependent variable will be transformed using a rank transformation in case it is not normally distributed. A p-value will be delivered but no useful effect size if a rank transformation is used.

Inclusion Criteria:

• woman
• age ≥ 70 years
• recurrent UTIs defined as ≥ 3 episodes of antibiotic treated acute cystitis (acute symptoms specific/related to the urinary tract) during the last twelve months or ≥ 2 episodes during the last 6 months
• able and willing to comply with all trial requirements
• able and willing to give informed consent

Exclusion Criteria:

• the patient has taken methenamine hippurate within the last 12 months
• the patient is allergic to methenamine hippurate
• the patient is having current antibiotic prophylaxis for UTI
• the patient has a urinary catheter (chronic indwelling catheters as well as intermittent urinary catheterisation)
• the patient has known severe chronic renal failure or estimated creatinine glomerular filtration rate ≤ 30 ml/min (known = registered in general practice clinical records)
• the patient has a known condition or treatment associated with significant impaired immunity (e.g. long-term oral steroids, chemotherapy, or immune disorder) (known = registered in general practice (GP) clinical records)
• the patient has a known severe hepatic impairment (known = registered in GP clinical records)
• the patient is suffering from severe dehydration
• the patient has shown signs of gout
• the patient has a need for long term use of antacids such as magnesium hydroxide, magnesium carbonate, aluminium hydroxide
• the patient has a life expectancy estimated by a clinician to be less than six months
• the patient has been involved in, including completion of, follow-up procedures, in another clinical trial of an investigational medicinal product in the last 90 days
• the patient suffers from incontinence too severe to be able to provide a voided urine specimen
• the patient is participating in ImpresU Work Package 2
• the patient is suffering from significant known abnormal renal tract anatomy/physiology or neuropathic bladder disorders.
• The patient has intolerance versus lactose

The randomisation list will be generated by computer with individual randomisation. Kragerø Tablettproduksjon AS will pack and label IMP with active substance and placebo according to the randomisation list. Participants will be dispensed Investigational Medical Product (IMP) in consecutive order at each study site, through a designated pharmacy, one site in each country. Kragerø Tablettproduksjon AS will have the list available at all times with the possibility to break the code. In addition there will be one envelope for each medication identification (ID) available in each country, at the coordinating centres, containing information of active substance or placebo regarding IMP delivered to that specific country. These envelopes will be stored together with the IMP in a locker. In acute situations, the PI in each country will be able to break the code and disrupt the unblinding process without the consent of the sponsor in order not to hamper necessary medical treatment.