Methenamine in a Non-antibiotic, Multimodal Approach to UTI Prevention

NCT03996057 | Withdrawn Phase 4 DMC FDA Drug

• 1 other identifier: 201804086
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

Urinary tract infections (UTIs) are the most common bacterial infection and are especially common in postmenopausal women, who often experience recurrent UTIs. Women with recurrent UTIs are commonly treated with antibiotics, but side effects, collateral damage to commensal bacteria, and antimicrobial resistance result from frequent antibiotic use. It is paramount that researchers develop non-antibiotic treatment strategies for UTIs. Several non-antibiotic strategies may be successful in preventing recurrent UTIs in postmenopausal women, including low-dose vaginal estrogen, d-mannose, and methenamine hippurate. Methenamine hippurate (MH) is interesting as it causes few side effects, kills bacteria by denaturing bacterial proteins, RNA, and DNA, and does not develop resistance. Several studies have demonstrated the efficacy of daily methenamine on the incidence of UTI. However, women often require multiple therapies in order to prevent recurrence. There are currently few guidelines to help clinicians identify optimal treatment regimens for non-antibiotic prevention of UTI. The purpose of this pilot study is to examine the feasibility of developing a sequential, multiple assignment, randomization trial (SMART); and examine the treatment effect of MH in combination with vaginal estrogen (VET) and D-mannose on prevention of UTI. The investigators plan to examine the efficacy of the addition of MH to low dose VET and d-mannose in the UTI prevention through randomization to MH + VET + D-mannose vs continuing VET + D-mannose alone. The primary outcome will be the proportion of patients who have symptomatic, culture-proven UTI during a 3 month treatment period. The investigators hypothesize that women on low dose VET, d-mannose, and MH will be less likely to have recurrent UTI than those with VET and d-mannose alone. This study uses a pragmatic, longitudinal approach that mimics patients' clinical experiences and physicians' decision points during management of UTI prophylaxis. Through this randomized, controlled pilot study, this proposal would allow the investigators to examine the feasibility of conducting a larger-scale, adaptive study trial, and estimate the treatment effect of a non-antibiotic regimen augmented with MH in women who continue to develop recurrence.

Conditions

UTI; Female Urogenital Diseases; UTI - Lower Urinary Tract Infection

Keywords

Urinary tract infection; UTI; Women; Postmenopausal women; Prevention; Non-antibiotic

Outcome Measures

Primary Outcomes (4)

• Culture proven, symptomatic urinary tract infection (UTI)

  Proportion of patients who have symptomatic, culture-proven UTI during a 3 month treatment period.

  3 months

• Recruitment rate

  Proportion of patients approached who are eligible for the study and consent to participate vs those who do not agree to participate.

  Through study recruitment, an average of 1 year

• Retention rate

  Proportion of patients who finish the 3 months study versus those who are recruited, randomized, but do not complete the study.

  3 months

• Adherence

  Average adherence to recommended dosage/frequency of vaginal estrogen, d-mannose, and methenamine hippurate use, as well as achievement of at least 75% adherence to medications.

  3 months

Secondary Outcomes (3)

• Frequency of culture proven, symptomatic urinary tract infection (UTI)

  3 months

• Treatment for urinary tract infection (UTI)

  3 months

• Side effects or adverse events

  3 months

Study Arms (2)

Methenamine augmentation

EXPERIMENTAL

2g methenamine hippurate twice daily for 90 days added to a baseline regimen of low dose vaginal estrogen (two to three times per week) and d-mannose (1000 mg twice daily)

Drug: Methenamine Hippurate 1000 MG; Drug: Vaginal estrogen; Dietary Supplement: D-mannose

No methenamine augmentation

ACTIVE COMPARATOR

Baseline regimen of low dose vaginal estrogen (two to three times per week) and d-mannose (1000 mg twice daily)

Drug: Vaginal estrogen; Dietary Supplement: D-mannose

Interventions

Methenamine Hippurate 1000 MG DRUG

Discussed in arm/group description

Methenamine augmentation

Vaginal estrogen DRUG

Any form of low dose vaginal estrogen, whether ring, cream, tablet, or capsule. Depends on what patient is already using.

Methenamine augmentation; No methenamine augmentation

D-mannose DIETARY_SUPPLEMENT

Powder or tablet, depending on what patient is already using.

Methenamine augmentation; No methenamine augmentation

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Postmenopausal women
• History of recurrent UTI (\>=3 culture proven UTIs in one year or \>=2 in 6 months)
• Recurrent, culture proven UTI while on vaginal estrogen for at least 4 weeks + d-mannose prophylaxis
• English speaker

You may not qualify if:

• Not postmenopausal
• Complicated UTIs
• Known renal tract anomaly
• Liver dysfunction
• Neurogenic bladder
• Incomplete bladder emptying (PVR \> 150 cc when voided volume \>150 cc)
• Self-catheterization or use of indwelling catheter
• Contraindication to vaginal estrogen, methenamine hippurate, or d-mannose, including allergic reactions
• History of or current endometrial cancer
• History of estrogen sensitive breast cancer without approval of patient, patient's oncologist, oncologic surgeon, or primary care physician to use vaginal estrogen after counseling
• History of interstitial cystitis/painful bladder syndrome
• Urothelial cancer
• Enrolled in other clinical trials for UTIs other than Washington University study IRB# 201711120
• Currently on daily antibiotic prophylaxis and unwilling to stop this intervention

Sponsors & Collaborators

• Washington University School of Medicine: lead

Related Publications (1)

• Cooper TE, Teng C, Howell M, Teixeira-Pinto A, Jaure A, Wong G. D-mannose for preventing and treating urinary tract infections. Cochrane Database Syst Rev. 2022 Aug 30;8(8):CD013608. doi: 10.1002/14651858.CD013608.pub2.

  PMID: 36041061 DERIVED

MeSH Terms

Conditions

Female Urogenital Diseases; Urinary Tract Infections

Interventions

methenamine hippurate; Mannose

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Hexoses; Monosaccharides; Sugars; Carbohydrates

Study Officials

• Christine Chu, MD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Attempt will be made to mask the current arm during assessment of outcomes (symptomatic UTI) when the participant calls in with symptoms, as the participant will be asked not to reveal their current prophylaxis regimen unless deemed medically or clinically necessary at the time.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized control pilot trial

Study Record Dates

• First Submitted: June 17, 2019
• First Posted: June 24, 2019
• Study Start: June 20, 2018
• Primary Completion: February 11, 2022
• Study Completion: February 11, 2022
• Last Updated: July 8, 2022

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will not share