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

NCT04077580 | Completed Phase 4 DMC

• 1 other identifier: Eudract 2018-002235-15
• Study Type: interventional
• Target: 289
• Locations: 4 countries
• Sites: 4

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.

Conditions

Recurrent Urinary Tract Infection

Keywords

blinded randomized trial; frail elderly women; prevention

Outcome Measures

Primary Outcomes (1)

• 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).

  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.

  6 months

Secondary Outcomes (5)

• Use of methenamine will give prolonged effect on antibiotic usage .

  6 months after stop of trial treatment

• Use of methenamine will reduced incidence of UTI.

  6 months

• Use of methenamine reduce severity of UTI symptoms.

  6 months

• Use of methenamine hippurate reduce duration of UTI episodes.

  6 months

• Use of methenamine will reduce complications such as pyelonephritis and hospital admission for UTI

  6 months

Study Arms (2)

Methenamine hippurate

EXPERIMENTAL

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

Drug: Methenamine Hippurate 1000 MG

Placebo

PLACEBO COMPARATOR

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

Drug: Methenamine Hippurate 1000 MG

Interventions

Methenamine Hippurate 1000 MG DRUG

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

Also known as: Placebo tablets with identical size, shape and stamps

Methenamine hippurate; Placebo

Eligibility Criteria

• Age: 70 Years - 99 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Oslo: lead
• Amsterdam UMC, location VUmc: collaborator
• UMC Utrecht: collaborator
• Göteborg University: collaborator
• Medical University of Lodz: collaborator

Study Sites (4)

Universitair Medisch Centrum Utrecht

Utrecht, 3584CX,, Netherlands

Location

University of Oslo

Oslo, NO 0317, Norway

Location

Medical University of Lodz,

Lodz, 90-153, Poland

Location

Research and Development Primary Health Care, Region Västra Götaland,

Borås, SE-503 38, Sweden

Location

Related Publications (11)

• 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.

  PMID: 23076896 RESULT

• 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.

  PMID: 28493770 RESULT

• 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.

  PMID: 29170359 RESULT

• Aydin A, Ahmed K, Zaman I, Khan MS, Dasgupta P. Recurrent urinary tract infections in women. Int Urogynecol J. 2015 Jun;26(6):795-804. doi: 10.1007/s00192-014-2569-5. Epub 2014 Nov 20.

  PMID: 25410372 RESULT

• 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.

  PMID: 22575772 RESULT

• 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.

  PMID: 26108340 RESULT

• 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.

  PMID: 3111615 RESULT

• 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.

  PMID: 6227756 RESULT

• 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.

  PMID: 28272565 RESULT

• 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 Nov;31(11):1873-1879. doi: 10.1016/j.cmi.2025.07.006. Epub 2025 Jul 14.

  PMID: 40669691 DERIVED

• 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.

  PMID: 36319057 DERIVED

MeSH Terms

Conditions

Urinary Tract Infections

Interventions

methenamine hippurate

Condition Hierarchy (Ancestors)

Infections; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Study Officials

• Cees Hertogh, prof.MD

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

• Theo Verheij, prof. MD

  UMC Utrecht

  PRINCIPAL INVESTIGATOR

• Maciek Godycki.Cwirko, prof MD

  Medical University of Lodz

  PRINCIPAL INVESTIGATOR

• Per-Daniel Sundvall, MD PhD

  Vastra Gotaland Region

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: professor

Model Details: 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.

Study Record Dates

• First Submitted: August 12, 2019
• First Posted: September 4, 2019
• Study Start: November 1, 2019
• Primary Completion: June 30, 2023
• Study Completion: June 30, 2023
• Last Updated: September 3, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

PL (1); NL (1); NO (1); SE (1)