Posterior Tibial Nerve Stimulation (PTNS) Plus Mirabegron to Treat Refractory OAB Symptoms (PTNS-M Study)

Study Overview
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Brief Summary
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Abstract Introduction: Urgency Urinary Incontinence (UUI) is a common condition with a prevalence of 9-31% in women in the United States. Despite current treatments, a high number of women have symptoms refractory to first- and second-line treatment approaches. Aims: The primary aim of this randomized controlled trial is to compare the efficacy of percutaneous tibial nerve stimulation (PTNS) and mirabegron treatment versus PTNS with placebo on change in the number of UUI episodes over a 12-week treatment course. Secondary aims include comparing the efficacy of combined treatment of PTNS and mirabegron versus PTNS with placebo on improvement in urinary incontinence symptom specific distress and quality of life related to UUI over a 12-week course of PTNS. Methods: A total of 54 consented participants will be recruited and randomized with 27 patients in the PTNS with mirabegron (daily 50 mg dose for the 12-week course) group and 27 patients in the PTNS with placebo group. Demographics and baseline data will be analyzed by student's t-test and chi-squared test or Fischer's Exact test as appropriate. Hypothesis: We anticipate that combination therapy will prove superior to monotherapy for reducing the number of UUI episodes over a 12-week treatment course.

Detailed Description
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Specific Aims: Introduction/Background: Urgency Urinary Incontinence (UUI) remains a challenging clinical problem for urogynecologists as they treat women and seek to find better therapies. There is a wealth of literature addressing individual therapies for first, second, and third line treatments for UUI. There are three main third line treatment options for UUI including percutaneous tibial nerve stimulation (PTNS), sacral neuromodulation, and intradetrusor botox. At the current time, there are limited studies that have looked at a combination of second and third-line therapy therapies for UUI. While some anticholinergic medications have been studied in combination with percutaneous tibial nerve stimulation (PTNS) such as solifenacin, tolterodine, and trospium, there is limited data on the combination of mirabegron, a beta-3 agonist, and PTNS for treatment of refractory UUI. The studies that looked at anticholinergic medications in combination with PTNS revealed improvement in UUI compared to PTNS plus placebo. However, there are patients who do not tolerate anticholinergic medications well because of side effects. A relatively new finding as reported by the American Urogynecologic Society (AUGS) about avoiding anticholinergic medications in women greater than age 70 secondary to increased risk for cognitive impairment, dementia, and Alzheimer's disease is further impetus to conduct this trial [1]. The rationale for studying mirabegron in combination with PTNS versus PTNS plus placebo is important as mirabegron does not have the significant side effect profile that anticholinergic medications have and better tolerated in the older population. Therefore, more research should be performed to evaluate the effect of the combination of mirabegron and PTNS for refractory UUI. The purpose of this study is to evaluate the combination of PTNS and mirabegron and compare that to PTNS plus placebo in the treatment of refractory UUI. Hypothesis: Combination therapy of PTNS and mirabegron, a beta-3 agonist, will contribute to greater improvement in the number of urgency urinary incontinence episodes as measured by a 3-day bladder diary compared to PTNS plus placebo in women. Method: This is a randomized clinical trial comparing the efficacy of combination therapy with PTNS plus mirabegron to PTNS plus placebo in women with refractory urgency urinary incontinence. Primary Aim: The primary aim of this study is to compare the efficacy of combined treatment of PTNS and mirabegron versus PTNS plus placebo on change in the number of UUI episodes at 12 weeks. Secondary Aims: Comparing urinary symptom specific distress and quality of life over a 12-week course of PTNS. Comparing the side effect/adverse event profile of combined treatment of PTNS and mirabegron versus PTNS plus placebo over a 12-week course of PTNS Comparing the treatment efficacy and adverse events of combined treatment of PTNS and mirabegron versus PTNS plus placebo in women > 70 years of age as a sub analysis within the study

Official Title
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Title: A Randomized Clinical Trial Comparing Percutaneous Tibial Nerve Stimulation in Combination With Mirabegron to Percutaneous Tibial Nerve Stimulation Plus Placebo in Women With Refractory OAB Symptoms

Conditions
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Overactive Bladder

Intervention / Treatment
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* Drug: Mirabegron 50 MG
* Device: Posterior Tibial Nerve Stimulation (PTNS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients > 18 years old at UAB facilities with refractory urgency urinary incontinence that have failed first line and second line treatments Ability to consent Ability to complete all study related items and interviews Exclusion Criteria: Patients with a history of any known or determined urinary retention or urinary tract obstruction PVR > 150 ml in clinic prior to the start of PTNS History of bladder augmentation surgery Patients who are pregnant or who have the suspicion of pregnancy Uncontrolled hypertension Hypersensitivity to mirabegron Superficial and/or deep skin infection where PTNS intervention is required Spinal cord injury or clinically significant neurological disorders known to affect urgency urinary incontinence Bleeding diathesis Failure of previous third line treatment options such as sacral neuromodulation, PTNS, or Botox Pacemaker, implantable defibrillator Current use of Interstim sacral nerve stimulator or TENS in the pelvic region, back, or legs Coagulopathy Chronic swollen, infected, inflamed skin or skin eruptions (e.g., phlebitis, thrombophlebitis, varicose veins) in the region where the PTNS needles or surface electrodes would be placed Metal implant in foot/toes near TENS electrode location Marked sensory deficit (numbness) of feet or ankles in the region where the PTNS needles or surface electrodes would be placed Currently pregnant or planning to become pregnant during the course of the study Unwilling to use acceptable form of contraceptive if the participant is of childbearing potential Unable or unwilling to complete the 3-day bladder diary Visual impairment prohibiting reading the paper diary Inability to provide informed consent, complete questionnaires independently, or to attend intervention sessions Unable to speak, read, or write in English

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Posterior Tibial Nerve Stimulation with Mirabegron<br>One arm of the study will receive PTNS combined with mirabegron. In the PTNS with mirabegron arm, the patient will take a 50 mg dose daily for 12 weeks of the trial. This arm of the study will have 27 patients randomized to this arm of the study. The percutaneous approach entails insertion of a 36-gauge needle electrode at a 60 degree angle approximately 5 cm or 3 finger breadths cephalad to the medial malleolus and posterior to the tibia. A portable electrical stimulator delivers an adjustable current in the range of 0.5-9 mA. The generators commonly are set for a pulse frequency of 20 Hz with a goal of creating a motor and/or sensory response in the foot. The stimulation sessions last for 30 min once per week for 12 continuous weeks. | Drug: Mirabegron 50 MG<br>* Posterior Tibial Nerve Stimulation with Mirabegron vs. Posterior Tibial Nerve Stimulation Plus Placebo<br>* Other names: Posterior Tibial Nerve Stimulation (PTNS);Device: Posterior Tibial Nerve Stimulation (PTNS)<br>* Posterior Tibial Nerve Stimulation with Mirabegron vs. Posterior Tibial Nerve Stimulation Plus Placebo<br>|
| Placebo Comparator: Posterior Tibial Nerve Stimulation Plus Placebo<br>The other arm of the study will receive PTNS with placebo. In the PTNS with placebo arm, the patient will receive a placebo daily during the 12-week trial. PTNS will be performed as described: The percutaneous approach entails insertion of a 36-gauge needle electrode at a 60 degree angle approximately 5 cm or 3 finger breadths cephalad to the medial malleolus and posterior to the tibia. A portable electrical stimulator delivers an adjustable current in the range of 0.5-9 mA. The generators commonly are set for a pulse frequency of 20 Hz with a goal of creating a motor and/or sensory response in the foot. The stimulation sessions last for 30 min once per week for 12 continuous weeks. | Device: Posterior Tibial Nerve Stimulation (PTNS)<br>* Posterior Tibial Nerve Stimulation with Mirabegron vs. Posterior Tibial Nerve Stimulation Plus Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Number of UUI Episodes Over a 3-day Voiding Diary Pre- vs. Post-treatment. This Includes a Baseline Measure Pre-trial and a Pos-trial Measure in 12 Weeks | change in the number of urgency urinary incontinence episodes as measures by a 3-day voiding diary pre- vs. post-treatment. This includes a baseline measure pre-trial and then a post-trial measure in 12 weeks and then you calculate the difference. The difference between the two measures (baseline vs. post-trial) was then compared with a sample t test. | 3 day voiding diary will be filled out prior to the 12 week PTNS trial and voiding diary will be filled out immediately after the 12 week PTNS trial | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Symptom Distress as Measured by the Urinary Distress Index (UDI-6) Questionnaire Pre- (Baseline Measure) vs. Post-treatment (Post-trial Measure) | This is a quality of life measure using a validated questionnaire called the Urinary Distress Index Scale with a range from 0-100 with higher scores meaning worse urinary distress such as urinary incontinence and leakage and bother with the life stresses related to urinary incontinence. Will include a baseline measure pre-trial and then a post-trial measure (post-trial). This includes a pre-trial measure (baseline) and a post-trial measure and then a calculation of the difference. The difference between the two measures (baseline vs. post-trial) was then compared with a sample t test. | 12 weeks | 
| Change in UUI (Urge Urinary Incontinence)/OAB (Overactive Bladder) Quality of Life as Measured by the Incontinence Impact Questionnaire Short Form (IIQ-7) Questionnaire Pre- (Baseline Measure) vs. Post-treatment (Post-trial Measure in 12 Weeks) | The IIQ-7 (Incontinence Impact Questionnaire) is a measure of distress caused by urge urinary incontinence and overactive bladder in the patient. This scale is a scale of 0-100 with 0 being minimal impact and 100 being worse impact and distress. This includes a baseline pre-trial measure and a post-trial measure at 12 weeks. This includes a pre-trial measure (baseline) and then a post-trial measure and then a calculation of the difference. The difference between the two measures (baseline vs. post-trial) was then compared with a sample t test. | pre-trial 0-100 scale measurement and then 12 weeks later post-trial measurement 0-100 with higher scores meaning worse impact. | 
| Change in UUI (Urge Urinary Incontinence)/OAB (Overactive Bladder) Quality of Life as Measured by the Overactive Bladder Questionnaire-Short Form (OAB-q SF) Questionnaire Pre- (Baseline Measure) vs. Post-treatment (Post-trial Measure) | This is the change in Quality of life measure for urge urinary incontinence for the OABq SF scale and it is a 0-100 scale where 0 equals minimum symptoms and 100 equals maximal symptoms. Lower scores indicate better quality of life and higher scores indicate worse quality of life. This includes a pre-trial measure and a post-trial measure at 12 weeks and then a calculation of the difference. The difference between the two measures (baseline vs. post-trial) was then compared with a sample t test. | pre trial measurements as described and then 12 weeks later post-trial measurements as described. |