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

Evaluating Urinary Microbiome Modulation :An RCT of Antibiotic vs Gynoflor Prophylaxis in Postmenopausal Women With Recurrent Cystitis

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.

Study Overview

• Status: Recruiting
• Conditions: Urinary Tract Infections; Cystitis, Recurrent
• Intervention / Treatment: Drug: Nitrofurantoin; Drug: Gynoflor

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.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Lappanawat Santitham; Phone Number: +66944314994; Email: cambellabios@gmail.com

Study Locations

• Thailand
  • Phayatai Ratchathewi
    • Bangkok, Phayatai Ratchathewi, Thailand, 10400
      • Recruiting
      • Faculty of Medicine Ramathibodi Hospital Mahidol University
      • Contact: Lappanawat Santitham; Phone Number: 0944314994; Email: cambellabios@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: 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.; Other Names: Nitrofurantoin macrocrystals/monohydrate
Experimental: 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.	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.; Other Names: Vaginal Lactobacillus with ultra-low-dose estriol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants with recurrent UTI within 6 months	Number of participants who experience ≥1 episode of symptomatic urinary tract infection (UTI) during the 6-month prophylaxis period, confirmed by clinical symptoms and positive urine culture per hospital standard. Event counted once per participant; groups compared between arms.	Baseline to 6 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first recurrent UTI	Days from randomization to first symptomatic, culture-confirmed UTI during the 6-month period; participants without an event are censored at 6 months.	Baseline to 6 months
Antibiotic resistance among breakthrough infections	Proportion of bacterial isolates from breakthrough UTIs that are non-susceptible to commonly tested antibiotics per local microbiology reporting.	During the 6-month prophylaxis period
Lactobacillus abundance by qPCR	Change in Lactobacillus copy number/relative abundance in midstream urine measured by quantitative PCR.	Baseline and month 6
Urinary microbiome diversity by 16S rRNA sequencing	Change in alpha-diversity indices of urine microbiota profiles determined by 16S rRNA gene sequencing.	Baseline and month 6
Incidence of adverse events related to intervention	Number and proportion of participants with any intervention-related adverse event	Up to 6 months
Adherence to assigned prophylaxis	Proportion of scheduled doses taken, assessed by medication logs and twice-weekly contacts	During 6 months
Change in lower urinary tract symptom score (RUTISS, Thai)	Change in Recurrent Urinary Tract Infection Symptom Scale (RUTISS) Section C Severity Score Description: Mean change in the Recurrent Urinary Tract Infection Symptom Scale (RUTISS) Section C total severity score from baseline to Month 6. Section C summarizes four domains (urinary symptoms, urinary presentation, UTI pain/discomfort, bodily sensations). The Overall RUTISS Severity Score is calculated as: sum of Section C responses ÷ 11 × 10, yielding a 0-100 scale. Higher scores = worse symptom/pain severity. Time Frame: Baseline and Month 6. Unit of Measure: Points (0-100). Scale Details: Minimum = 0, Maximum = 100, Higher = worse	Baseline and month 6

Collaborators and Investigators

• Sponsor: Mahidol University

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2025
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): August 30, 2026

Study Registration Dates

• First Submitted: September 15, 2025
• First Submitted That Met QC Criteria: September 15, 2025
• First Posted (Estimated): September 22, 2025

Study Record Updates

• Last Update Posted (Estimated): September 25, 2025
• Last Update Submitted That Met QC Criteria: September 22, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Lower Urinary Tract Symptoms; Thailand; Nitrofurantoin; Lactobacillus; Postmenopausal Women; Antibiotic Prophylaxis; qPCR; Antimicrobial Resistance; Estriol; Adherence Monitoring; Urinary Microbiome; Gynoflor; Vaginal Probiotics; 16S rRNA Sequencing; RUTISS Questionnaire
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Disease Attributes; Urological Manifestations; Infections; Urinary Bladder Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Recurrence; Urinary Tract Infections; Cystitis; Lower Urinary Tract Symptoms; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nitro Compounds; Furans; Nitrofurans; Nitrofurantoin
• Other Study ID Numbers: MURA2024/339; Ref.2024/671 (Other Identifier: HREC, Ramathibodi Hospital, Mahidol Univ.)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) underlying the primary and secondary outcome results will be shared. A data dictionary and coding key will be provided. Direct identifiers will be removed and dates shifted as needed. Data will be shared for research purposes only and not for commercial use.
• IPD Sharing Time Frame: Available beginning 12 months after the primary results are published (or 24 months after database lock, whichever comes first) and for 5 years thereafter.
• IPD Sharing Access Criteria: Qualified researchers may request access by emailing the study PI/central contact with: (1) a brief proposal and analysis plan, (2) documentation of ethics/IRB approval or exemption, and (3) a signed Data Use Agreement. Requests will be reviewed by the study steering team. Approved users will receive data via secure transfer; re-identification attempts and onward sharing are prohibited, and publications must acknowledge the original study.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

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