The Effect of Methenamine Hippurate to Reduce Antibiotic Prescribing in Elderly Women With Recurrent UTI

NCT ID: NCT04077580

Last Updated: 2024-09-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 289 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-11-01
• Study Completion Date: 2023-06-30

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.

Conditions

Recurrent Urinary Tract Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Methenamine hippurate

Tablets containing 1 g methenamine hippurate, dosage 1 tablet morning and evening.

Group Type: EXPERIMENTAL

Methenamine Hippurate 1000 MG

Intervention Type: DRUG

Methenamine and placebo is taken 1 tablet morning and evening for 180 days

Placebo

Placebo tablets containing 1 g of lactose, with identical size, shape and stamps

Group Type: PLACEBO_COMPARATOR

Methenamine Hippurate 1000 MG

Intervention Type: DRUG

Methenamine and placebo is taken 1 tablet morning and evening for 180 days

Interventions

Methenamine Hippurate 1000 MG

Methenamine and placebo is taken 1 tablet morning and evening for 180 days

Intervention Type: DRUG

Other Intervention Names

Placebo tablets with identical size, shape and stamps

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

• Minimum Eligible Age: 70 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Amsterdam UMC, location VUmc

OTHER

Sponsor Role: collaborator

UMC Utrecht

OTHER

Sponsor Role: collaborator

Göteborg University

OTHER

Sponsor Role: collaborator

Medical University of Lodz

OTHER

Sponsor Role: collaborator

University of Oslo

OTHER

Sponsor Role: lead

Responsible Party

Morten Lindbaek

professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Cees Hertogh, prof.MD

Role: PRINCIPAL_INVESTIGATOR

Amsterdam UMC, location VUmc

Theo Verheij, prof. MD

Role: PRINCIPAL_INVESTIGATOR

UMC Utrecht

Maciek Godycki.Cwirko, prof MD

Role: PRINCIPAL_INVESTIGATOR

Medical University of Lodz

Per-Daniel Sundvall, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Vastra Gotaland Region

Locations

Universitair Medisch Centrum Utrecht

Utrecht, , Netherlands

University of Oslo

Oslo, , Norway

Medical University of Lodz,

Lodz, , Poland

Research and Development Primary Health Care, Region Västra Götaland,

Borås, , Sweden

Countries

Netherlands; Norway; Poland; Sweden

References

Lee BS, Bhuta T, Simpson JM, Craig JC. Methenamine hippurate for preventing urinary tract infections. Cochrane Database Syst Rev. 2012 Oct 17;10(10):CD003265. doi: 10.1002/14651858.CD003265.pub3.

Reference Type: RESULT

PMID: 23076896 (View on PubMed)

Davis C, Rantell A. Lower urinary tract infections in women. Br J Nurs. 2017 May 11;26(9):S12-S19. doi: 10.12968/bjon.2017.26.9.S12.

Reference Type: RESULT

PMID: 28493770 (View on PubMed)

Barclay J, Veeratterapillay R, Harding C. Non-antibiotic options for recurrent urinary tract infections in women. BMJ. 2017 Nov 23;359:j5193. doi: 10.1136/bmj.j5193. No abstract available.

Reference Type: RESULT

PMID: 29170359 (View on PubMed)

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Reference Type: RESULT

PMID: 25410372 (View on PubMed)

van Buul LW, van der Steen JT, Veenhuizen RB, Achterberg WP, Schellevis FG, Essink RT, van Benthem BH, Natsch S, Hertogh CM. Antibiotic use and resistance in long term care facilities. J Am Med Dir Assoc. 2012 Jul;13(6):568.e1-13. doi: 10.1016/j.jamda.2012.04.004. Epub 2012 May 9.

Reference Type: RESULT

PMID: 22575772 (View on PubMed)

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.

Reference Type: RESULT

PMID: 26108340 (View on PubMed)

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.

Reference Type: RESULT

PMID: 3111615 (View on PubMed)

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.

Reference Type: RESULT

PMID: 6227756 (View on PubMed)

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.

Reference Type: RESULT

PMID: 28272565 (View on PubMed)

Heltveit-Olsen SR, Arnljots ES, Sundvall PD, Gunnarsson R, Kowalczyk A, Godycki-Cwirko M, Platteel TN, Groen WG, Lithen SS, Sundvall S, Ahren C, Grude N, Verheij TJM, Hertogh CMPM, Lindbaek M, Hoye S. Methenamine hippurate as prophylaxis for recurrent urinary tract infections in older women-a triple-blind, randomised, placebo-controlled, phase IV trial (ImpresU). Clin Microbiol Infect. 2025 Jul 14:S1198-743X(25)00344-1. doi: 10.1016/j.cmi.2025.07.006. Online ahead of print.

Reference Type: DERIVED

PMID: 40669691 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36319057 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

Eudract 2018-002235-15

Identifier Type: -

Identifier Source: org_study_id