Microbiome-Modulating Prophylaxis RCT: Antibiotic vs Gynoflor in Postmenopausal Women With Recurrent Cystitis

NCT ID: NCT07186465

Last Updated: 2025-09-25

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-09-11
• Study Completion Date: 2026-08-30

Brief Summary

This open-label, parallel-group randomized controlled trial compares two prophylaxis strategies for recurrent urinary tract infection (rUTI) in postmenopausal women: (1) nightly oral nitrofurantoin 100 mg for 6 months versus (2) a vaginal tablet containing Lactobacillus with ultra-low-dose estriol (Gynoflor: nightly for 14 days, then twice weekly to month 6). Participants (≥40 years) are randomized 1:1 in computer-generated blocks and followed for 6 months. The primary endpoint is the proportion with rUTI recurrence within 6 months. Secondary endpoints include time to first recurrence, antibiotic resistance in breakthrough infections, change in lower urinary tract symptoms (Thai RUTISS), and urinary microbiome measures (Lactobacillus dominance and community diversity by qPCR and 16S rRNA). Key assessments occur at baseline and month 6 (urinalysis, culture, urinary microbiome sampling, and kidney function). Adherence and adverse events are captured via twice-weekly phone/Line contacts. Approximately 100 participants (50 per arm) will be enrolled as a feasibility-sized pilot.

Detailed Description

Background and Rationale

Recurrent cystitis is common after menopause and burdens quality of life and healthcare use. Antibiotic prophylaxis is effective but may promote antimicrobial resistance with long-term use. Vaginal Lactobacillus with ultra-low-dose estriol can restore urogenital flora and potentially reduce rUTI and lower urinary tract symptoms. Comparative data versus nightly antibiotic prophylaxis-and effects on the urinary microbiome-remain limited. This trial directly evaluates clinical recurrence and microbiome modulation with nitrofurantoin versus a Lactobacillus/estriol vaginal tablet over 6 months.

Objectives

Primary objective: Compare the 6-month rUTI recurrence proportion between nitrofurantoin and Gynoflor.

Key secondary objectives: (a) time to first recurrence; (b) antimicrobial resistance patterns in breakthrough infections; (c) change in Thai RUTISS score; (d) Lactobacillus dominance and within-sample diversity of the urinary microbiome.

Key Endpoint Definitions

rUTI recurrence (primary): ≥1 symptomatic episode meeting clinical criteria with urine culture growth of a uropathogen during the 6-month follow-up (episodes during temporary treatment holds still count toward the endpoint).

Time to first recurrence: days from randomization to first qualifying rUTI.

Antibiotic resistance: susceptibility profile of cultured uropathogens from breakthrough infections, categorized per local laboratory standards.

Microbiome metrics: quantitative Lactobacillus abundance (qPCR) and alpha diversity indices from 16S rRNA profiling.

Design Overview

Open-label, two-arm, parallel RCT with 1:1 allocation by concealed, computer-generated block randomization. Follow-up is 6 months. Masking is not feasible due to intervention routes; laboratory personnel for microbiome and culture testing are shielded from allocation where practicable.

Interventions (Summary)

Nitrofurantoin arm: 100 mg orally once nightly through month 6.

Gynoflor arm: one vaginal tablet nightly for 14 days, then twice weekly (e.g., Monday/Friday) through month 6.

(Rescue treatment for symptomatic UTI follows standard of care; study prophylaxis resumes afterward to complete 6 months.)

Study Procedures (Selected)

Baseline (Day 0): consent, randomization, Thai RUTISS, urinalysis, urine culture, urinary microbiome sampling, BUN/creatinine.

Follow-up (Months 0-6): twice-weekly phone/Line check-ins to reinforce adherence and capture symptoms/adverse events; prompt clinical evaluation if UTI symptoms arise.

Month 6: repeat Thai RUTISS, urinalysis/culture, urinary microbiome sampling, BUN/creatinine.

Specimen handling: midstream clean-catch urine; UA ~20 mL, culture 5-10 mL, microbiome ~50 mL. Samples processed promptly or refrigerated at 4 °C ≤24 h if needed.

Laboratory Methods (Overview)

Urinary microbiome assays are performed at the Department of Medical Sciences: (1) qPCR estimating Lactobacillus abundance across time points; (2) 16S rRNA gene sequencing for community profiling and alpha diversity.

Sample Size and Analysis Plan (Pilot)

Approximately 100 participants (50/arm) are planned based on local feasibility for an initial pilot. Analyses will follow intention-to-treat with supportive per-protocol summaries. The primary endpoint will be compared between arms using a risk difference with 95% CIs and a chi-square or Fisher's exact test. Time-to-event data will be presented with Kaplan-Meier estimates and log-rank testing. Continuous outcomes (e.g., Thai RUTISS change) will use t-tests or Wilcoxon rank-sum as appropriate; paired pre/post within-arm changes will use paired tests. Missing outcome data will be handled by complete-case analysis with sensitivity analyses (e.g., worst-case imputation for the primary endpoint) if missingness >5-10%.

Safety Monitoring and Adherence

Expected risks include nitrofurantoin intolerance (e.g., GI upset, hypersensitivity), local vaginal irritation, minor phlebotomy discomfort, and time burden. Adverse events are solicited during twice-weekly contacts and at visits; serious adverse events are reported per IRB policy. Given the low-risk profile and pilot scope, a formal DSMB is not planned; the PI and study team review safety at regular intervals. Adherence is promoted by structured reminders and documented via participant report during check-ins.

Data Management and Quality

Case report forms are source-verified against electronic medical records and laboratory outputs. Microbiome and culture laboratories follow internal QC procedures; analytical staff are kept unaware of allocation when feasible. Randomization files are access-restricted; analysis is pre-specified prior to database lock.

Conditions

Cystitis, Recurrent; Urinary Tract Infections

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Nitrofurantoin Prophylaxis

Nightly oral nitrofurantoin 100 mg for 6 months as prophylaxis for recurrent UTI in postmenopausal women. If symptomatic UTI occurs, treat per standard care and, once resolved, continue assigned prophylaxis to complete 6 months. Monitoring per protocol: baseline and month-6 visits with urinalysis, urine culture, urinary microbiome, and kidney function; twice-weekly phone/Line check-ins for adherence, symptoms, and adverse events.

Group Type: ACTIVE_COMPARATOR

Nitrofurantoin

Intervention Type: DRUG

Nightly oral nitrofurantoin 100 mg for 6 months as prophylaxis for recurrent UTI in postmenopausal women. If symptomatic UTI occurs, treat per standard care and, once resolved, continue assigned prophylaxis to complete 6 months. Monitoring per protocol: baseline and month-6 visits with urinalysis, urine culture, urinary microbiome, and kidney function; twice-weekly phone/Line check-ins for adherence, symptoms, and adverse events.

Gynoflor Vaginal Tablet

Vaginal tablet containing Lactobacillus with ultra-low-dose estriol (Gynoflor) for 6 months: insert 1 tablet nightly for 14 days, then twice weekly through month 6. Same monitoring and management as comparator: if UTI occurs, treat per standard care and then resume assigned prophylaxis to finish 6 months.

Group Type: EXPERIMENTAL

Gynoflor

Intervention Type: DRUG

Vaginal tablet containing Lactobacillus with ultra-low-dose estriol. Insert 1 tablet nightly for 14 days, then twice weekly through month 6 as prophylaxis against recurrent urinary tract infection. If a symptomatic UTI occurs, treat per standard of care; after resolution, continue assigned prophylaxis to complete 6 months. Monitoring identical to comparator.

Interventions

Nitrofurantoin

Nightly oral nitrofurantoin 100 mg for 6 months as prophylaxis for recurrent UTI in postmenopausal women. If symptomatic UTI occurs, treat per standard care and, once resolved, continue assigned prophylaxis to complete 6 months. Monitoring per protocol: baseline and month-6 visits with urinalysis, urine culture, urinary microbiome, and kidney function; twice-weekly phone/Line check-ins for adherence, symptoms, and adverse events.

Intervention Type: DRUG

Gynoflor

Vaginal tablet containing Lactobacillus with ultra-low-dose estriol. Insert 1 tablet nightly for 14 days, then twice weekly through month 6 as prophylaxis against recurrent urinary tract infection. If a symptomatic UTI occurs, treat per standard of care; after resolution, continue assigned prophylaxis to complete 6 months. Monitoring identical to comparator.

Intervention Type: DRUG

Other Intervention Names

Nitrofurantoin macrocrystals/monohydrate; Vaginal Lactobacillus with ultra-low-dose estriol

Eligibility Criteria

Inclusion Criteria

• Female, postmenopausal, age ≥40 years
• Clinical history of recurrent urinary tract infection (rUTI) as assessed by the investigator
• Able and willing to take assigned prophylaxis for 6 months
• Able to attend baseline and Month 6 study visits and provide urine samples
• Able to provide written informed consent
• Willing and able to complete twice-weekly phone/LINE follow-ups

Exclusion Criteria

• Current symptomatic UTI at enrollment (may be treated and reconsidered after resolution)
• Known hypersensitivity or contraindication to nitrofurantoin or to the Lactobacillus/estriol vaginal tablet (Gynoflor) or their excipients; significant renal impairment or other label-based contraindications to nitrofurantoin per local practice
• Planned urologic surgery or procedure expected during the 6-month study period
• Recent bacterial vaginosis (e.g., within the past month) or active vulvovaginal skin disorders precluding vaginal product use
• History of hormone-dependent malignancy (e.g., breast, uterine, or cervical cancer) or unexplained abnormal vaginal bleeding
• Significant liver disease (e.g., active hepatitis) or other conditions judged by the investigator to make participation unsafe
• Participation in another interventional trial that could interfere with outcomes
• Withdrawal of consent or severe adverse event requiring discontinuation

• Minimum Eligible Age: 40 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Mahidol University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Faculty of Medicine Ramathibodi Hospital Mahidol University

Bangkok, Phayatai Ratchathewi, Thailand

Site Status: RECRUITING

Countries

Thailand

Central Contacts

Lappanawat Santitham

Role: CONTACT

cambellabios@gmail.com

+66944314994

Facility Contacts

Lappanawat Santitham

Role: primary

cambellabios@gmail.com

0944314994

Other Identifiers

Ref.2024/671

Identifier Type: OTHER

Identifier Source: secondary_id

MURA2024/339

Identifier Type: -

Identifier Source: org_study_id