The Effect of Methenamine Hippurate to Reduce Antibiotic Prescribing in Elderly Women With Recurrent UTI (ImpresUWP3)

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

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Recurrent Urinary Tract Infection
• Intervention / Treatment: Drug: Methenamine Hippurate 1000 MG

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.

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Utrecht, Netherlands, 3584CX,
    • Universitair Medisch Centrum Utrecht
• Norway
  • Oslo, Norway, NO 0317
    • University of Oslo
• Poland
  • Łódź, Poland, 90-153
    • Medical University of Lodz,
• Sweden
  • Borås, Sweden, SE-503 38
    • Research and Development Primary Health Care, Region Västra Götaland,

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years to 99 years (Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methenamine hippurate; Tablets containing 1 g methenamine hippurate, dosage 1 tablet morning and evening.	Drug: Methenamine Hippurate 1000 MG; Methenamine and placebo is taken 1 tablet morning and evening for 180 days; Other Names: Placebo tablets with identical size, shape and stamps
Placebo Comparator: Placebo; Placebo tablets containing 1 g of lactose, with identical size, shape and stamps	Drug: Methenamine Hippurate 1000 MG; Methenamine and placebo is taken 1 tablet morning and evening for 180 days; Other Names: Placebo tablets with identical size, shape and stamps

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Use of methenamine will give prolonged effect on antibiotic usage .	Number of UTI antibiotic treatments during the six months following completion of treatment.	6 months after stop of trial treatment
Use of methenamine will reduced incidence of UTI.	Number of UTIs (acute symptoms specific/related to the urinary tract) during the six months of treatment.	6 months
Use of methenamine reduce severity of UTI symptoms.	Registration of symptom severity when initiating treatment for UTI	6 months
Use of methenamine hippurate reduce duration of UTI episodes.	Registration of number of days of symptoms during UTI episodes.	6 months
Use of methenamine will reduce complications such as pyelonephritis and hospital admission for UTI	register complications such as pyelonephritis and hospital admission for UTI	6 months

Collaborators and Investigators

• Sponsor: University of Oslo
• Collaborators: Göteborg University; UMC Utrecht; Medical University of Lodz; Amsterdam UMC, location VUmc
• Investigators: Principal Investigator: 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

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2019
• Primary Completion (Estimated): November 30, 2023
• Study Completion (Estimated): November 30, 2023

Study Registration Dates

• First Submitted: August 12, 2019
• First Submitted That Met QC Criteria: September 2, 2019
• First Posted (Actual): September 4, 2019

Study Record Updates

• Last Update Posted (Actual): June 29, 2023
• Last Update Submitted That Met QC Criteria: June 27, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: prevention; blinded randomized trial; frail elderly women
• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Disease Attributes; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Infections; Recurrence; Urinary Tract Infections; Anti-Infective Agents; Anti-Bacterial Agents; Anti-Infective Agents, Urinary; Methenamine; Methenamine hippurate; Methenamine mandelate
• Other Study ID Numbers: Eudract 2018-002235-15

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No