Preventing Recurrent UTI With Vaginal Estrogen (PRUVE)

Mechanisms of Successful Vaginal Estrogen Prophylaxis for Postmenopausal Women With Recurrent Urinary Tract Infections: Urogenital Microbiota and Host Immune Responses

Among postmenopausal women who suffer from recurrent urinary tract infections (UTI), vaginal estrogen therapy prevents UTI recurrences for 50% of sufferers. This research will investigate why some women benefit but others do not, focusing on (a) the effects of vaginal estrogen therapy on the bacteria that inhabit the vagina and bladder, (b) its influence on immune responses in both compartments, and (c) the extent to which those changes are critical to successful UTI prevention. The findings will be a first step in the development of more effective strategies to prevent UTI, one of the most common and costly benign urologic conditions.

Study Overview

• Status: Enrolling by invitation
• Conditions: Urinary Tract Infections; Recurrent Urinary Tract Infection; Cystitis Recurrent
• Intervention / Treatment: Drug: Vaginal estradiol tablets

Detailed Description

Recurrent urinary tract infections (rUTI) are a significant problem among older women: 13% of female Medicare beneficiaries experience at least one UTI annually and >40% of these develop chronic recurrent UTI. Although UTIs are significantly reduced by vaginal estrogen therapy (VET), 50% of those using VET continue to experience UTI recurrences. It is unknown why some women benefit from VET while others do not. This application focuses on interrogating two mechanisms likely to be central to the effectiveness of VET. The first is the urogenital microbiota: an increase in vaginal lactobacilli is the purported mechanism by which VET reduces rUTI. Important and unanswered questions include how VET influences specific Lactobacillus spp., whether changes to specific Lactobacillus spp are the key to successful prophylaxis, and how VET affects the urinary microbiota. A second mechanism addressed by this application is the host vaginal and urinary immune response. Estrogen appears to influence localized urogenital immune responses, including Th17 and Th1 versus Th2 pathway signaling. Animal studies suggest that these compartmentalized immune responses play a critical role in UTI susceptibility, but human data are lacking. This application will address these unanswered questions. Postmenopausal women with rUTI will be treated with VET. Samples collected before and after VET will characterize vaginal and urinary microbiota, soluble mediators of inflammation in both compartments, and vaginal D-lactic acid. Aims 1 and 2 of this proposal will investigate the impact of VET on the urogenital microbiota and urogenital immune responses, respectively. Aim 3 will characterize the urogenital environments of participants who continue to experience rUTI during VET versus those who remain UTI-free. The accomplishment of these aims will provide pilot data for a larger and more definitive clinical trial. These proposed studies are a key step toward the investigators' goals of identifying biomarkers that reliably predict a successful response to rUTI prophylaxis and ascertaining the biological conditions required for successful UTI prevention. Ultimately, an understanding of the mechanisms of rUTI prevention will allow the development of novel and effective prevention strategies for postmenopausal women suffering from rUTI.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins Bayview Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Participants in this study will be

• Postmenopausal women (menopausal for at least 1 year)
• Minimum age of 55 years

• Participants will have documentation of recurrent UTI, defined as follows:

  • History of treatment for at least 3 UTIs in the past year or 2 episodes within 6 months AND
  • At least one positive urine culture during an acute symptomatic episode.

Exclusion Criteria:

• Women receiving antibiotic prophylaxis to prevent UTI recurrence;
• Women with contraindications to vaginal estrogen (as indicated on the FDA-mandated package insert) and those who have used vaginal or systemic estrogen within the past 6 months;
• Women with an active UTI and those who have received antibiotics within the prior 2 weeks;
• Women with complicated rUTI, defined by immune compromise, anatomic or functional abnormalities of the urinary tract, indwelling catheterization, those performing self-catheterization, and those with neurological disease or illness relevant to the lower urinary tract;
• Women with only asymptomatic bacteriuria (rather than recurrent symptomatic UTI)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Vaginal estrogen therapy; Participants receive Vaginal estrogen therapy.	Drug: Vaginal estradiol tablets; Vaginal estradiol tablets (10mcg).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Vaginal microbiota	Changes to relative vaginal abundance of key Lactobacillus spp. before and after treatment.	Baseline and 12 weeks
Change in Vaginal Interleukin-6 level	Changes to vaginal Interleukin-6 before and after treatment.	Baseline and 12 weeks
Change in Urinary microbiota	Changes to relative urinary abundance of key Lactobacillus spp. before and after treatment.	Baseline and 12 weeks
Change in Urinary Interleukin-6 level	Changes to urinary Interleukin-6 before and after treatment.	Baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urinary tract infection recurrence	Occurrence of symptomatic UTI after at least 12 weeks of therapy.	Weeks 12 to 24

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Maryland
• Investigators: Principal Investigator: Victoria Handa, MD MHS, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2023
• Primary Completion (Estimated): August 31, 2025
• Study Completion (Estimated): August 31, 2025

Study Registration Dates

• First Submitted: September 20, 2022
• First Submitted That Met QC Criteria: September 20, 2022
• First Posted (Actual): September 23, 2022

Study Record Updates

• Last Update Posted (Actual): October 19, 2023
• Last Update Submitted That Met QC Criteria: October 17, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: women
• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Urinary Bladder Diseases; Disease Attributes; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Cystitis; Infections; Communicable Diseases; Recurrence; Urinary Tract Infections; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Estradiol
• Other Study ID Numbers: IRB00314740; R01DK130856 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be shared after study completion
• IPD Sharing Time Frame: Data sharing will be provided within one year of study conclusion.
• IPD Sharing Access Criteria: To be determined
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes