Clinical trial NCT04077580: The Effect of Methenamine Hippurate to Reduce Antibiotic Prescribing in Elderly Women With Recurrent UTI
Official title: The Effect of Methenamine Hippurate to Reduce Antibiotic Prescribing Due to New Episodes of Urinary Tract Infections (UTI) in Elderly Women With Recurrent UTI - a Triple- Blinded, Randomized Placebo-controlled Phase IV Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Recurrent Urinary Tract Infection
Keywords: blinded randomized trial
frail elderly women
prevention
Lead sponsor: University of Oslo
Sponsor class: OTHER
Collaborators: name: Amsterdam UMC, location VUmc
name: UMC Utrecht
name: Göteborg University
name: Medical University of Lodz
First posted: 2019-09-04
Enrollment: 289
Sex: FEMALE
Minimum age (years): 70
Maximum age (years): 99
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: We will perform a randomised trial in the targeted population, women \>70 years in general practice in the 4 countries. Nursing home patients may be included, all shall give informed consent. Approximately 100 patients in each country.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: The primary objective of this study is to investigate if taking methenamine hippurate reduces the need for antibiotic usage due to recurrent UTI (measured as number of antibiotic courses).
timeFrame: 6 months
Secondary outcomes:
measure: Use of methenamine will give prolonged effect on antibiotic usage .
timeFrame: 6 months after stop of trial treatment
measure: Use of methenamine will reduced incidence of UTI.
timeFrame: 6 months
measure: Use of methenamine reduce severity of UTI symptoms.
timeFrame: 6 months
measure: Use of methenamine hippurate reduce duration of UTI episodes.
timeFrame: 6 months
measure: Use of methenamine will reduce complications such as pyelonephritis and hospital admission for UTI
timeFrame: 6 months
Other outcomes:
Locations:
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Oslo
country: Norway
facility: University of Oslo
city: Łódź
country: Poland
facility: Medical University of Lodz,
city: Borås
country: Sweden
facility: Research and Development Primary Health Care, Region Västra Götaland,
Study officials:
affiliation: Amsterdam UMC, location VUmc
name: Cees Hertogh, prof.MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UMC Utrecht
name: Theo Verheij, prof. MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of Lodz
name: Maciek Godycki.Cwirko, prof MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vastra Gotaland Region
name: Per-Daniel Sundvall, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Sundvall PD, Stuart B, Davis M, Roderick P, Moore M. Antibiotic use in the care home setting: a retrospective cohort study analysing routine data. BMC Geriatr. 2015 Jun 25;15:71. doi: 10.1186/s12877-015-0073-5.
citation: Cronberg S, Welin CO, Henriksson L, Hellsten S, Persson KM, Stenberg P. Prevention of recurrent acute cystitis by methenamine hippurate: double blind controlled crossover long term study. Br Med J (Clin Res Ed). 1987 Jun 13;294(6586):1507-8. doi: 10.1136/bmj.294.6586.1507.
citation: Brumfitt W, Hamilton-Miller JM, Gargan RA, Cooper J, Smith GW. Long-term prophylaxis of urinary infections in women: comparative trial of trimethoprim, methenamine hippurate and topical povidone-iodine. J Urol. 1983 Dec;130(6):1110-4. doi: 10.1016/s0022-5347(17)51709-7.
citation: Alberg T, Holen O, Blix HS, Lindbaek M, Bentele H, Eriksen HM. Antibiotic use and infections in nursing homes. Tidsskr Nor Laegeforen. 2017 Mar 7;137(5):357-361. doi: 10.4045/tidsskr.16.0621. eCollection 2017 Mar. English, Norwegian.
citation: Heltveit-Olsen SR, Sundvall PD, Gunnarsson R, Snaebjornsson Arnljots E, Kowalczyk A, Godycki-Cwirko M, Platteel TN, Koning HAM, Groen WG, Ahren C, Grude N, Verheij TJM, Hertogh CMPM, Lindbaek M, Hoye S. Methenamine hippurate to prevent recurrent urinary tract infections in older women: protocol for a randomised, placebo-controlled trial (ImpresU). BMJ Open. 2022 Nov 1;12(11):e065217. doi: 10.1136/bmjopen-2022-065217.