Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT03996057 |
| Other study ID # |
201804086 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
June 20, 2018 |
| Est. completion date |
February 11, 2022 |
Study information
| Verified date |
July 2022 |
| Source |
Washington University School of Medicine |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
Description:
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. The Centers for
Disease Control and Prevention estimate that drug resistance contributes to 23,000 deaths,
2,049,442 illnesses, and $20 billion dollars in excess direct healthcare costs in the United
States annually. Thus, 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. One is low-dose vaginal estrogen, which may decrease the rate of
recurrent UTIs by decreasing inflammation, promoting bladder repair, and promoting retention
of lactobacilli. Another is d-mannose, a natural sugar that may decrease bacterial adherence
to the urothelium. Methenamine hippurate has regained interest recently. First, it causes few
side effects. Second, it functions by producing formaldehyde in the urine, which kills
bacteria by denaturing bacterial proteins, RNA, and DNA. Thus far, no methenamine-resistant
bacteria have been reported to develop in vivo. Lastly, several studies have demonstrated
that 2 grams daily of methenamine reduces the incidence of UTI and is likely comparable to
the antibiotic nitrofurantoin for UTI prophylaxis. However, in the investigators' clinical
experience, women often require multiple therapies in order to prevent recurrence. There are
currently few guidelines to help clinicians identify optimal treatment regimens for
prevention of UTI. The clinical challenge is to optimize individual treatment regimens by
maximizing efficacy and minimizing the number of medications, cost, side effects, and
nonadherence for each individual.
The purpose of this pilot study is to 1) examine the feasibility of developing a sequential,
multiple assignment, randomization trial (SMART) and 2) examine the treatment effect of
methenamine hippurate in combination with vaginal estrogen and D-mannose on prevention of
UTI. This adaptive study design allows the investigators to examine the efficacy of
non-antibiotic prophylaxis and initiation of subsequent preventative therapies based on
individual responses. It is a pragmatic, longitudinal approach that mimics patients' clinical
experiences and physicians' decision points during management of UTI prophylaxis. Given the
efficacy and relative safety of methenamine hippurate, the investigators are particularly
interested in its efficacy among those who have had suboptimal response to vaginal estrogen
and D-mannose. The timing of this study is ideal, as the investigators are also currently
conducting a trial of vaginal estrogen plus D-mannose in postmenopausal women. Through this
randomized, controlled pilot study, this proposal would allow the investigators to examine
the feasibility of conducting a larger-scale, adaptive study trial on the use of methenamine
hippurate in combination with vaginal estrogen plus D-mannose, and estimate the treatment
effect of a non-antibiotic regimen augmented with methenamine hippurate in women who continue
to develop recurrence.
This study is a planned extension of a previously proposed clinical trial on d-mannose and
vaginal estrogen (IRB#:201711120); however, any postmenopausal women with a history of
recurrent UTI, who then develop UTI while on a combined prophylaxis regimen of d-mannose and
vaginal estrogen will be eligible for the randomized controlled trial on methenamine
augmentation. The investigators plan to examine the efficacy of the addition of methenamine
hippurate to low dose vaginal estrogen and d-mannose in the UTI prevention through
randomization to methenamine + vaginal estrogen + D-mannose vs continuing vaginal estrogen +
D-mannose alone. Patients will be randomized to either the addition of methenamine hippurate
or continuing with vaginal estrogen + 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 vaginal estrogen, d-mannose, and
methenamine hippurate will be less likely to have recurrent UTI than those with low dose
vaginal estrogen and d-mannose alone. As part of the study, baseline information and vaginal,
urine, and fecal samples may be taken. Additionally, as part of examining feasibility of a
larger study, recruitment, retention, refusal, non-compliance, and adherence rates will be
collected. Patients who decline or drop out of the study will be contacted to answer
questions on reasons for refusal or withdrawal. Subjects who undergo randomization will
either add methenamine to their ongoing vaginal estrogen + D-mannose, or continue on vaginal
estrogen + D-mannose alone. They will receive weekly calls or text reminders to record study
diaries and to take their medications. Patients will follow up at the end of 3 months, at
their usual follow up appointment, for routine examination, questionnaires, and urine and
possible vaginal and fecal samples. Follow up may be extended up to 1 month prior or 6 months
afterward their baseline visit (2-6 months after the baseline visit) for those who do not
make their 3 months appointment. The investigators also plan to describe the uropathogen
profile and antibiotic resistance of UTIs that occur during prophylaxis with vaginal estrogen
+ d-mannose, with or without methenamine hippurate. Lastly, the investigators hope to examine
the impact of a non-antibiotic prophylaxis regimen that includes methenamine hippurate on the
bladder microenvironment as well as the urinary, vaginal, and intestinal microbiomes.
