Vaginal Estradiol vs Oral Beta-3 Agonist for Overactive Bladder Syndrome

Study Overview
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Brief Summary
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A single site, double-blinded, randomized controlled trial for postmenopausal women with urinary frequency, urgency, nocturia with or without urgency urinary incontinence symptoms. Patient's will be randomized between 0.01% vaginal estradiol cream with placebo oral pill or daily 50 milligrams oral Mirabegron with a placebo vaginal cream for 12 weeks.

Detailed Description
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Background/significance: Overactive Bladder Syndrome (OAB) is defined as urinary urgency, with or without urgency incontinence, and usually accompanied by frequency and nocturia. OAB remains an increasingly more prevalent disease, affecting over 45% of postmenopausal women over the age 65 within the United States. Epidemiological research continues to consistently highlight OAB's impact on patience's mental health, sleep quality, physical activity, occupational productivity and overall quality of life. OAB's economic burden cannot be overstated as well as a US cost-of-illness study reported a total cost of $66 billion in 2007 and estimated cost of over $82 billion in 2021. Mainstay first-line forms of management for OAB include behavioral modifications such as bladder training (timed voiding, urge suppression techniques), pelvic floor physical therapy, fluid management and bladder irritant restrictions. Second-line forms of management consistent of pharmacotherapy including oral anticholinergics or beta-3 adrenoreceptor agonists. Multiple studies have shown that vaginal estrogen improves symptoms of urinary urgency and frequency in postmenopausal women. Limited data currently exist comparing beta-3 antagonists to vaginal estrogen use for overactive bladder syndrome as well as the combination of both. Purpose: This study aims to compare the efficacy of vaginal estradiol with that of oral mirabegron in the treatment of overactive bladder in postmenopausal women and characterize outcomes in women undergoing combined therapy. Study design: This is a single site, double-blinded, randomized controlled trial for 152 postmenopausal women with urinary frequency, urgency, nocturia with or without urgency urinary incontinence symptoms. Patient's will be randomized between 0.01% vaginal estradiol cream 1/2 gram once nightly for two weeks then three times per week or 50 milligrams oral Mirabegron once a night. Procedures: Postmenopausal women with bothersome OAB symptoms will be eligible for the study. OAB symptoms will be based on the OAB-q (SF) symptom bother questionnaire with an initial score greater than 20. Other inclusion criteria include ability to speak English. Exclusion criteria include: Post void residual >200mL or >1/3 patient's total bladder volume, currently on or previously taking anticholinergic or beta- 3 antagonists within the past 1 month, untreated, symptomatic pelvic organ prolapse greater than Stage 2, contraindication to vaginal estrogen therapy, contraindication to Mirabegron, undiagnosed postmenopausal vaginal bleeding within the past 12 months, current diagnosis of a condition which explains their overactive bladder or incontinence symptoms. Participants who elect to enroll will have a post-void residual determined, a demographic sheet, the OAB-q (SF) health-related quality of life (HRQL) questionnaire, a 24-hour voiding diary and Patient Global Impression of Severity (PGI-S). Participants will be randomized via random allocation rule fixed blocking in a 1:1 ratio to either vaginal estrogen or oral Mirabegron. After 12 weeks of single therapy, the patients will be contacted for follow up to complete all previous questionnaires, a 24-hour voiding diary as well as the PGI-I questionnaire. After the initial 12-weeks, single therapy follow up appointment, participants will be offered dual treatment (both vaginal estrogen and Mirabegron same doses/frequencies.) If the patient agrees she will receive dual treatment for 12 weeks and follow up with the same questionnaires.

Official Title
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Vaginal Estradiol vs Oral Beta-3 Agonist for Treatment of Overactive Bladder Syndrome: A Single-Therapy, Double-Blind, Randomized Controlled Trial

Conditions
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Overactive Bladder Syndrome

Intervention / Treatment
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* Drug: Vaginal estrogen
* Drug: Mirabegron 50 MG [Myrbetriq]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Raw score of 14 or more on OAB-q SF (adjusted score of 20) Postmenopausal defined by not having a period for 12 months or bilateral oophorectomy a least 12 months status post procedure, or women with prior hysterectomy and preserved ovaries over age 55 years old or having a documented follicle stimulating hormone level greater than 40mIU/mL. Ability to speak and read English Exclusion Criteria: Contraindications to Vaginal Estrogen or Mirabegron Post void residual >200mL or >1/3 patient's total bladder volume Currently on or previously taking anticholinergic or beta- 3 agonists within the past 1 month Symptomatic pelvic organ prolapse greater than Stage 2, contraindication to vaginal estrogen therapy Undiagnosed postmenopausal vaginal bleeding within the past 12 months Current diagnosis of Multiple sclerosis, Parkinson's Disease, prior spinal cord injury, Spina Bifida, prior pelvic irradiation, Interstitial Cystitis, recurrent urinary tract infection.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single site, double blinded, randomized controlled trial of Mirabegron vs Vaginal Estradiol for overactive bladder syndrome
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Vaginal Estradiol with placebo oral pill<br>Patient will receive 0.01% estradiol cream 1/2 gram applied vaginally once nightly for two weeks then three times per week with once daily placebo oral pill | Drug: Vaginal estrogen<br>* 0.01% estradiol cream 1/2 gram applied vaginally once nightly for two weeks then three times per week with once daily placebo oral pill<br>* Other names: Micronized Estrogen;|
| Active Comparator: Oral Mirabegron with placebo vaginal cream<br>Patient will receive 50 milligrams oral Mirabegron once daily and placebo vaginal cream (Medisca's VersaPro Cream Base) once nightly for two weeks then three times per week | Drug: Mirabegron 50 MG [Myrbetriq]<br>* 50mg oral Mirabegron once daily<br>* Other names: Myrbetriq;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OAB-q short form (SF) symptom bother scores | Primary Aim: Compare changes in the six-item OAB-q short form (SF) symptom bother scores from baseline to 12 weeks post treatment in postmenopausal women who receive either vaginal estradiol or Mirabegron. We will also compare 12-weeks post treatment OAB-q SF symptom bother scores after single therapy trials with patients who desire combined therapy for another 12 weeks. The OAB-q SF symptom bother questionnaire is based on six individual questions a 6-point scale ranging from 1 or not at all to 6 or a very great deal. Per the guidance of the scoring manual, the raw scores are converted into scores ranging from 0 to 100 (0 being the minimum score and 100 being the maximum score.) The higher the score signifies that the patient has worse bothersome overactive bladder symptoms. The conversion to a 100 point scale is based on the equation as follows: ((Raw score - 6) / 36) x 100. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| health-related quality of life (HRQL) of the OAB-q SF scores | Compare health-related quality of life (HRQL) of the OAB-q SF from baseline to 12 weeks post treatment. We will also compare 12-weeks post treatment HRQL scores after single therapy trials with patients who desire combined therapy for another 12 weeks. The health-related quality of life (HRQL) portion of the OAB-q SF is based on 13 individual questions a 6-point scale ranging from 1 or none of the time to 6 or all of the time with the lowest score being 13 to the highest score being 78. The higher the score signifies that the patient has worse overactive bladder symptoms that affect their quality of life. | 12 weeks | 
| Patient Global Impression of Severity (PGI-S) scores | Compare Patient Global Impression Severity (PGI-S) scores at baseline versus 12 weeks post treatment. We will also compare 12-weeks post treatment Patient Global Impression of Severity (PGI-S) scores after single therapy trials with patients who desire combined therapy for another 12 weeks. The Patient Global Impression Severity (PGI-S) is a single question which describes the severity of their urinary tract condition. It is a single question on a scale ranging from 1 not present to 7 extremely severe. The higher the score signifies that the patient has worse severity of their symptoms. | 12 weeks | 
| Patient Global Impression of Improvement (PGI-I) scores | Evaluate Patient Global Impression of Improvement (PGI-I) scores at 12 weeks post treatment. We will also compare 12-weeks post treatment Patient Global Symptom Improvement (PGI-I) scores after single therapy trials with patients who desire combined therapy for another 12 weeks. The Patient Global Impression of Improvement (PGI-I) is a single question which describes how their urinary tract condition is compared to how it was before treatment. It is a single question on a scale ranging from 1 very much improved to 7 very much worse. The higher the score signifies that the patient has worse symptoms compared to prior treatment, the lower the score signifies that the patient has improved symptoms compared how it was before treatment. A score of 4 signifies not change in their described symptoms compared with how it was before treatment. | 12 weeks | 
| Number of voids | Compare number of times the patient voids via 24-hour bladder diary at baseline and 12 weeks post treatment. We will also compare 12-weeks post treatment number of voids after single therapy trials with patients who desire combined therapy for another 12 weeks. This is an objective measurement of how many times the patient voids over a 24 hour time frame post treatment. Though unlikely the lowest quantity would be 0 throughout the day. The more the patient documents voiding throughout the day the signifies worse the patient's described overactive bladder symptoms. | 12 weeks | 
| Number of urge incontinence episodes | Compare number of urge incontinence episodes via 24-hour bladder diary at baseline and 12 weeks post treatment. We will also compare 12-weeks post treatment number of urge incontinence episodes after single therapy trials with patients who desire combined therapy for another 12 weeks. This is an objective measurement of how many times the patient has urge incontinence episodes over a 24 hour time frame post treatment. Though unlikely the lowest quantity would be 0 throughout the day. The more the patient documents voiding throughout the day the signifies worse the patient's described overactive bladder symptoms. | 12 weeks |