A Phase 4 interventional study of Nitrofurantoin and Gynoflor in Cystitis, Recurrent and Urinary Tract Infections, sponsored by Mahidol University. Recruiting at 1 site in Thailand. Open to female participants aged 40 Years and older. Per ClinicalTrials.gov, last updated 2025-09-25.
Sponsored by Mahidol University · Phase 4, Interventional, and Prevention
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.
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.
69 studies on the registry are indexed under Cystitis; 17 are open to participants now.
This study's planned enrollment of 100 is below the median of 112 across 50 interventional studies indexed under Cystitis.
Browse Cystitis studies →Mahidol University is the lead sponsor of 747 studies on the registry; 119 are open to participants now.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Postmenopausal
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Excipients
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Cancer (malignancy)
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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
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
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.
Also known as: Nitrofurantoin macrocrystals/monohydrate
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.
Also known as: Vaginal Lactobacillus with ultra-low-dose estriol
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.
Time frame: Baseline to 6 months after randomization
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.
Time frame: 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.
Time frame: During the 6-month prophylaxis period
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
Time frame: Baseline and month 6
Lactobacillus abundance by qPCR
Change in Lactobacillus copy number/relative abundance in midstream urine measured by quantitative PCR.
Time frame: 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.
Time frame: Baseline and month 6
Incidence of adverse events related to intervention
Number and proportion of participants with any intervention-related adverse event
Time frame: Up to 6 months
Adherence to assigned prophylaxis
Proportion of scheduled doses taken, assessed by medication logs and twice-weekly contacts
Time frame: During 6 months
Plan to share: Yes — 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.
Supporting information: Study protocol, Statistical analysis plan, Informed consent form, Clinical study report, Analytic code
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.
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.
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Studies of the drug tested here: Lactobacillus acidophilus/Estriol Vaginal Tablet