Red Clover Isoflavones in Postmenopausal Women With Urge Urinary Incontinence and Overactive Bladder

The Effect of Red Clover Isoflavones on Urinary Microbiota Composition and Interaction With the Urothelium in Postmenopausal Women

The purpose of this study is to investigate the effect of red clover isoflavones in postmenopausal women with and without urge urinary incontinence and overactive bladder

Study Overview

• Status: Completed
• Conditions: Overactive Bladder; Urge Incontinence
• Intervention / Treatment: Dietary supplement: Red Clover Extract (RCE); Other: Placebo (PL)

• Study Type: Interventional
• Enrollment (Actual): 108
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Hjørring, Denmark, 9800
    • North Denmark Regional Hospital (Vendsyssel Hospital)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Postmenopausal (more than 5 years since last menstruation)
• Read and understand Danish

Exclusion Criteria:

• Participants receive treatment with estrogen both oral, transdermal, and topical within three months prior to inclusion in the study
• Participants take estrogen-like compounds (isoflavones) three months prior to inclusion in the study
• Participants take prebiotic and/or probiotic supplements within three months prior to study inclusion
• Receive antibiotics (any) within three months prior to inclusion in the study
• Recurrent urinary tract infections (defined as ≥ 2 infections in the last six months or ≥ 3 infections during the last year)
• Acute urinary tract infection defined as positive urine culture and symptoms of acute cystitis
• Previous or current diseases of the digestive and/or urinary systems evaluated by PI (including, but not limited to inflammatory bowel disease (IBD) and cancer)
• Current or prior suffering from breast, ovary, and/or endometrial cancer
• Use hormone spiral within the last 5 years if they are under 60 years
• Hysterectomy before cessation of menstrual periods if the women are below the age of 60

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Symptomatic RCE; Bladder symptomatic group receiving red clover extract containing the two isoflavones formononetin and biochanin A. Isoflavone amount is 57.45 mg isoflavones daily (55.84 mg aglycones daily), in 70 ml red clover extract (35 ml twice daily, morning and evening with a meal)	Dietary supplement: Red Clover Extract (RCE); Red clover extract containing isoflavones Formononetin and biochanin A together with a heterogenous culture of probiotic lactic acid bacteria, and a natural sugar free raspberry/orange flavor. Isoflavone amount is 57.45 mg isoflavones daily (55.84 mg aglycones daily), in 70 ml red clover extract (35 ml twice daily, morning and evening together with a meal)
Experimental: Healthy RCE; Healthy group without bladder symptoms receiving red clover extract containing the two isoflavones formononetin and biochanin A. Isoflavone amount is 57.45 mg isoflavones daily (55.84 mg aglycones daily), in 70 ml red clover extract (35 ml twice daily, morning and evening with a meal)	Dietary supplement: Red Clover Extract (RCE); Red clover extract containing isoflavones Formononetin and biochanin A together with a heterogenous culture of probiotic lactic acid bacteria, and a natural sugar free raspberry/orange flavor. Isoflavone amount is 57.45 mg isoflavones daily (55.84 mg aglycones daily), in 70 ml red clover extract (35 ml twice daily, morning and evening together with a meal)
Placebo Comparator: Symptomatic PL; Bladder symptomatic group receiving placebo	Other: Placebo (PL); Placebo containing water, brown coloring, and natural sugar free raspberry/orange flavor.
Placebo Comparator: Healthy PL; Healthy group without bladder symptoms receiving placebo	Other: Placebo (PL); Placebo containing water, brown coloring, and natural sugar free raspberry/orange flavor.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline microbiota composition in women suffering from UUI and OAB at three months follow-up	The microbiota composition is analyzed using sequencing of bacterial DNA. We are investigating the urinary, vaginal and gut microbiota. In women with urge urinary incontinence (UUI) and overactive bladder (OAB) receiving RCE (symptomatic RCE), a possible change in the urinary, vaginal and fecal microbiota composition from baseline to three month follow-up, compared to controls receiving placebo (symptomatic PL) are investigated. Symptomatic RCE from baseline to follow-up vs. Symptomatic PL from baseline to follow-up	From baseline to three months follow-up
Change in baseline microbiota composition at three months follow-up	The microbiota composition is analyzed using sequencing of bacterial DNA. Comparison of healthy women without bladder symptoms receiving RCE (healthy RCE) at baseline to three months follow-up compared to controls (healthy PL) from baseline to follow-up. Healthy RCE from baseline to follow-up vs. Healthy PL from baseline to follow-up	From baseline to three months follow-up
Difference in baseline microbiota composition between women with and without UUI and OAB	The microbiota composition is analyzed using sequencing of bacterial DNA. Is there a difference in the urinary, vaginal and gut microbiota in women with and without urge urinary incontinence (UUI) and overactive bladder (OAB) at baseline? Symptomatic PL baseline vs. Healthy PL baseline	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of the urinary, vaginal, and fecal microbiota	The microbiota composition is analyzed using sequencing of bacterial DNA. This composition is evaluated using alpha-diversity (measured based on number of unique bacteria as well as Shannon diversity and phylogenic diversity) and beta-diversity, as indicated by unifrac distance and bray-Curtis dissimilarity. Comparison of the urinary, vaginal, and fecal microbiota composition at baseline. All the different compartments are measured using the same Units of Measure. Healthy PL baseline urinary vs. Healthy PL baseline vaginal vs. Healthy PL baseline gut	Baseline
Change in overactive bladder symptoms from baseline in women suffering from UUI and OAB at three months follow-up	Overactive bladder symptoms are measured using the questionnaire International Consultation on Incontinence Questionnaire (ICIQ) Overactive Bladder (ICIQ-OAB). Comparison of symptom scores in women with UUI and OAB before and after treatment with RCE compared to placebo. Symptomatic RCE from baseline to follow-up vs. Symptomatic PL from baseline to follow-up	From baseline to three months follow-up
Change in urinary incontinence symptoms from baseline in women suffering from UUI and OAB at three months follow-up	Urinary incontinence symptoms are measured using the questionnaire International Consultation on Incontinence Questionnaire (ICIQ) Urinary Incontinence Short Form (ICIQ-UI-SF). Comparison of symptom scores in women with UUI and OAB before and after treatment with RCE compared to placebo. Symptomatic RCE from baseline to follow-up vs. Symptomatic PL from baseline to follow-up	From baseline to three months follow-up
Change in blood estrogen levels from baseline to three months follow-up	Blood estrogen levels are measured from serum blood samples. Blood samples are taken at baseline before RCE and PL intake and after three months treatment.	From baseline to three months follow-up
Change in blood isoflavone levels from baseline to three months follow-up	Blood isoflavone levels are measured in ng/mL from plasma blood samples. Blood samples are taken at baseline before RCE and PL intake and after three months treatment.	From baseline to three months follow-up
Change in blood equol levels from baseline to three months follow-up	Blood equol levels are measured in nmol/L from plasma blood samples. Blood samples are taken at baseline before RCE and PL intake and after three months treatment.	From baseline to three months follow-up
Change in gastrointestinal symptoms from baseline to three months follow-up	Gastrointestinal symptoms are measured using Rom IV criteria before and after RCE and PL intake.	From baseline to three months follow-up
Change in Irritable Bowel Syndrome Severity Score Scale from baseline to three months follow-up	Gastrointestinal symptoms are measured using the Irritable Bowel Syndrome Severity Score Scale before and after RCE and PL intake.	From baseline to three months follow-up
Change in Gastrointestinal Symptom Rating Scale from baseline to three months follow-up	Gastrointestinal symptoms are measured using the Gastrointestinal Symptom Rating Scale before and after RCE and PL intake.	From baseline to three months follow-up

Collaborators and Investigators

• Sponsor: Vendsyssel Hospital
• Collaborators: University of Aarhus
• Investigators: Principal Investigator: Annemarie B Villadsen, Vendsyssel Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2019
• Primary Completion (Actual): October 20, 2021
• Study Completion (Actual): October 20, 2021

Study Registration Dates

• First Submitted: August 3, 2021
• First Submitted That Met QC Criteria: August 11, 2021
• First Posted (Actual): August 19, 2021

Study Record Updates

• Last Update Posted (Actual): April 26, 2023
• Last Update Submitted That Met QC Criteria: April 25, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Microbiome; Microbiota
• Additional Relevant MeSH Terms: Urologic Diseases; Urinary Bladder Diseases; Lower Urinary Tract Symptoms; Urological Manifestations; Urination Disorders; Urinary Incontinence; Urinary Bladder, Overactive; Urinary Incontinence, Urge
• Other Study ID Numbers: N-20190028

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual deidentified participant data will be shared upon article publication. Microbiome data (DNA sequences) will be uploaded to the Sequence Read Archive (SRA) at the National Center for Biotechnology Information (NCBI).
• IPD Sharing Time Frame: Data will become available upon article publication at NCBI.
• IPD Sharing Access Criteria: All will have access to the microbiome data

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No