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

Sponsor

University of Oslo (Other)

Overall Status

Enrolling by invitation

CT.gov ID

NCT04077580

Collaborator

Amsterdam UMC, location VUmc (Other), UMC Utrecht (Other), Göteborg University (Other), Medical University of Lodz (Other)

400

Enrollment

Locations

Arms

Anticipated Duration (Months)

100

Patients Per Site

2.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Urinary Tract Infection	Drug: Methenamine Hippurate 1000 MG	Phase 4

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 Design

Study Type:

Interventional

Anticipated Enrollment :

400 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

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.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.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

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.

Primary Purpose:

Treatment

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

Actual Study Start Date :

Nov 1, 2019

Anticipated Primary Completion Date :

Nov 30, 2022

Anticipated Study Completion Date :

Nov 30, 2022

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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). [6 months]
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.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

70 Years to 99 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Universitair Medisch Centrum Utrecht	Utrecht	Netherlands	3584CX,
2	University of Oslo	Oslo	Norway	NO 0317
3	Medical University of Lodz,	Łódź	Poland	90-153
4	Research and Development Primary Health Care, Region Västra Götaland,	Borås	Sweden	SE-503 38

Sponsors and Collaborators

University of Oslo
Amsterdam UMC, location VUmc
UMC Utrecht
Göteborg University
Medical University of Lodz

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