Clinical trial NCT04907032
Conditions: Overactive Bladder
Sponsor: University of Alabama at Birmingham
Start date: 2021-10-01; Completion date: 2023-04-15
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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:
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

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Mirabegron 50 MG intervention 2: Posterior Tibial Nerve Stimulation (PTNS)
Intervention descriptions: intervention 1: Posterior Tibial Nerve Stimulation with Mirabegron vs. Posterior Tibial Nerve Stimulation Plus Placebo intervention 2: Posterior Tibial Nerve Stimulation with Mirabegron vs. Posterior Tibial Nerve Stimulation Plus Placebo

Protocol documents:
Prot_SAP_001.pdf: 
 
 
 
 
 
NCT04907032 Document Date: 6/7/2023  
 
Study Title: Percutaneous Tibial Nerve Stimulation-Mirabegron (PTNS-M) Study: 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 Study 
Protocol and Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
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 
 
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.  
 
Results:  TBD 
 
Anticipated Conclusion:  We anticipate that combination therapy will prove superior to 
monotherapy for reducing the number of UUI episodes over a 12-week treatment course.  
 
 
 
 
 
 


 
 
 
 
 
 
 
 
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   
 
 
Research Strategy: 
Significance:  Urgency Urinary Incontinence (UUI), is the complaint of involuntary loss of urine 
associated with urgency [2], a common condition that affects between 9-31% [3,4] of women 
and is a significant healthcare burden costing up to 19 billion dollars per year including the costs 
of over the counter products such as pads and diapers along with medical evaluation and 
treatment [5].  This condition causes negative impact on sexual and social functioning and can 
be associated with depression.  UUI may be associated with neuromuscular problems and may 
be associated with anatomical problems, such as large uterine fibroids, pelvic masses, severe 
uterovaginal prolapse, bladder outlet obstruction, or even severe obesity [6].  First line therapy 
includes behavioral therapy while second line therapy includes medication with either 
anticholinergic or beta-3 agonist medications.  Anticholinergic medications have long been the 
mainstay of second-line treatment for overactive bladder (OAB)/UUI, but have significant side 
effects including dry mouth and constipation [7] which has led to poor patient compliance and 
high discontinuation rates in clinical practice [8,9].  Likewise, as previously mentioned, the 2021 
update from AUGS for OAB recommends avoiding the use of anticholinergic medication in 
women greater than 70 years old due to negative cognitive effects [1,10,11].  The beta-3 
agonist, mirabegron, is better tolerated by the geriatric population, and thus, provides another 
option that is just as efficacious as anticholinergic medications for combination therapy with 
PTNS, especially in cases of refractory UUI [11,12].   
 
Refractory UUI indicates consideration of third line therapies.  Current third line therapy 
options include Sacral Neuromodulation (SNM), Onabotulinumtoxin A (Botox) injected into the 
detrusor muscle during cystoscopy, and percutaneous tibial nerve stimulation (PTNS).  Recent 
interest has peaked with respect to combination of either second and third line therapies or 
combinations of third line therapies for refractory UUI [13].  Sacral Neuromodulation requires a 
patient to go to the operating room in order to receive treatment for UUI while 
Onabotulinumtoxin A (Botox) requires procedural treatment with injection into the detrusor 
muscle and carries increased risk of urinary retention and urinary tract infection.  A recent 
retrospective observational cohort study of adult female patients with OAB looked at the delay 
between stopping second line therapy and starting the initiation of third line therapy [14].  Their 
conclusion was that women with OAB who undergo third-line therapy do so on average more 
than 3 years after starting medications.  Time to third-line treatment is largely driven by the 
number of antimuscarinic medications tried and timing of diagnostic evaluation by a specialist.  
They found that predictors of shorter time to third-line therapy included younger age, delayed 
gastric emptying, diabetes, bothersome side effects of antimuscarinics, earlier specialist 
evaluation and diagnostic testing, and mirabegron use [14].  
 
 
Some patients would prefer a less invasive treatment such as PTNS to more procedural 
modalities of SNM and Botox.  Scientific professional society guidelines advise PTNS as a third 
line treatment [15].  PTNS has been validated via sham-based trials, as a third line option with 


proven benefit that is less invasive than the other third line options for management of UUI.  
Although researchers have studied PTNS, Botox, and SNM alone and have seen benefit for 
patients, recent interest has peaked into the efficacy of combination therapy.  Further studies 
are needed regarding combination therapies, particularly those including third line modalities 
[13]. 
 
PTNS in combination with anticholinergic medications has been studied and outcomes 
compared [16,17,18,19].  In most of these studies, when PTNS plus placebo is compared to 
PTNS in combination with an anticholinergic medication, the combination therapy was found to 
be more effective than PTNS plus placebo or an anticholinergic medication alone (Table 1).  In 
previous systematic reviews, when PTNS alone was compared to medications (anticholinergics) 
alone, no difference was found and each monotherapy was considered to be equally efficacious 
[20,21].   
 
Table 1:  Summary of studies looking at combination of PTNS with anticholinergic 
medications 
 
Author 
Comparison 
N 
Results 
Vecchioli-
Scaldazza 
et al., 
2018 [16] 
Solifenacin versus 
posterior tibial 
nerve stimulation 
(PTNS) versus 
combination 
therapy 
(PTNS+solifenacin) 
27 OAB-SS (overactive bladder symptom score) 
                    solifenacin     vs.  PTNS                       
p=0.0039 
                    solifenacin     vs.  solifenacin+PTNS    
p=<0.0001 
                    PTNS  vs.  solifenacin+PTNS              
p=0.009 
PGI-I  (patient global impression of improvement 
                    SS      vs.   PTNS         p=0.0017 
                    SS      vs.   SS+PTNS  p=<0.0001 
                    PTNS  vs.  SS+PTNS  p=0.0002 
 
Sancaktar 
et al., 
2010 [17] 
Tolterodine alone 
vs. stroller afferent 
neuro-stimulation 
(SANS)+Tolterodine 
38   UUI episodes (per week)  before therapy    after 
therapy         p 
Tolterodine alone                22.8+2.4              
12.3+0.8            <0.001 
Tolterodine+SANS              22.4+2.8               6.4+0.5   
<0.001 
            P                                 >0.05                 <0.001 
Eftekhar 
et al., 
2014 [18] 
Tolterodine alone 
vs. 
PTNS+Tolterodine 
30 Comparison of UUI symptom specific distress pre vs. 
post treatment 
PTNS+tolterodine            vs.          tolterodine         
(p=0.03) 
Kizilyel et 
al., 2015 
[19] 
PTNS vs. 
Tolterodine 
vs.PTNS + 
Tolterodine 
30 Reduction in # of UUI episodes most significant in 
PTNS+tolterodine 
PTNS plus placebo (p<0.01) 
Tolterodine (P<0.05) 
PTNS+Tolterodine (P<0.001) 
 
 
Because the older population of women is a major focus of this study, it remains 
important to focus on less invasive treatments that are better tolerated by the geriatric 


population as a whole.  Therefore, because PTNS offers a less invasive approach to third line 
therapy and because mirabegron does not have the negative cognitive effects that 
anticholinergic meds cause in the geriatric population, this combination of PTNS + mirabegron 
offers great potential for providing better treatment for UUI/OAB, especially in women 70 years 
of age or greater. 
 
Given the significant burden associated with UUI/OAB expecially in older women, 
combination therapy of less invasive approach and with PTNS and the mirabegron has fewer 
adverse effects and may provide improved efficacy, adherence, and safety. 
 
 
Innovation:  The main innovation for this study will be the combination of PTNS with 
mirabegron.  Further research needs to occur on combination therapy that can be offered on an 
outpatient basis to patients that either do not desire to have an invasive procedure or are not 
optimal surgical candidates.  Based upon the previous studies looking at combination therapy 
with PTNS and anticholinergic medications, one can see that PTNS in combination with 
medication is more efficacious than either medication alone or PTNS plus placebo (Table 1).  
While mirabegron is contraindicated in patients with uncontrolled hypertension, overall, patients 
tolerate it better than anticholinergic medications.  Thus, mirabegron offers hope as a better 
medication combination with PTNS for all age groups of patients.  This study also involves 
looking at the efficacy of combination therapy of PTNS and mirabegron in the geriatric 
population > 70 years of age, as mirabegron has not been associated with the exacerbating 
symptoms of dementia that anticholinergic medications do within the geriatric population 
[1,11,12].  Therefore, studying mirabegron in combination with PTNS offers great hope for the 
treatment of refractory UUI in the geriatric population. 
 
Approach: 
 
Study Design 
 
A randomized controlled clinical trial with female patients consented at the University Alabama 
at Birmingham (UAB) facilities. The study will evaluate female patients with UUI that are 
refractory to second-line treatment or who cannot tolerate anticholinergic medications.  Patients 
will complete a 3-day voiding diary prior to the 12-week treatment of PTNS (at baseline) and at 
the completion of the 12-week treatment with PTNS. 
 
 
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 
 
Intervention 
 
Prior to beginning the treatment intervention, patients who are currently on medical therapy will 
stop medical therapy 2 weeks prior to the start of the trial.  One arm of the study will receive 
PTNS combined with mirabegron and the other arm of the study will receive PTNS with placebo.  
In the PTNS with mirabegron arm, the patient will take a 50 mg dose daily for 12 weeks of the 
trial.  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. 
 
Primary Outcome 
 
Change in the number of UUI episodes over a 3-day voiding diary pre- vs. post-treatment. 
 
 
Secondary Outcomes 
 
 
Number of voids on a 3-day voiding diary pre- vs. post-treatment 


 
Number of stress urinary incontinence (SUI) episodes pre- vs. post-treatment on a 3-
day voiding diary 
 
Change in symptom distress as measured by the Urinary Distress Index (UDI-6) 
questionnaire pre- vs. post-treatment 
 
Change in UUI/OAB quality of life as measured by the Incontinence Impact 
Questionnaire Short Form (IIQ-7) and Overactive Bladder Questionnaire-Short Form 
(OAB-q SF) questionnaires pre- vs. post-treatment 
 
Adverse Events 
Protocol in detail 
Women seen in the Urogynecology and Urology clinics at the University of Alabama at 
Birmingham who are seeking treatment for refractory UUI symptoms will be screened.  Patients 
who have failed a credible behavioral therapy intervention and medical therapy or not tolerating 
medical therapy will be evaluated for this study.  Those patients satisfying the 
inclusion/exclusion criteria will be offered participation.  Informed consent will be reviewed and 
signed with patients wishing to proceed.   
At enrollment, any subjects who are using medical therapy including anticholinergic or 
β3 agonist medications will stop these therapies for 2 weeks prior to treatment.  Baseline clinical 
data including a 3-day bladder diary, OAB-q-SF, IIQ-7, UDI-6, and a pain catastrophizing scale 
after washout as indicated will be collected as well as clinical and demographic information.  
Data from subjects’ urodynamic testing will be abstracted from the clinical chart if performed 
within the prior 12 months of the enrollment date.  If no urodynamic testing is available then this 
data will not be collected for those subjects. Subjects will be randomized the day of the first 
scheduled PTNS appointment.  Subjects will be blinded to which group they are assigned. 
Subjects will be randomized to the PTNS with mirabegron group or to PTNS plus 
placebo group.  The PTNS with mirabegron group will undergo one PTNS treatment per week 
for 30 minutes, will start taking 50 mg daily of mirabegron on the day of the first PTNS 
procedure and will continue the daily 50 mg dose for the duration of the 12 week PTNS trial.  
The PTNS plus placebo group will take the placebo starting the day of the first PTNS treatment 
and will take the placebo daily for the remainder of the 12-week clinical trial.  
Subjects will fill out a 3-day voiding diary immediately post-treatment after the last 
session of PTNS.  The patient will also complete the OAB-q-SF, IIQ-7, and UDI-6.  
Randomization/Allocation 
Patients will be randomized to the PTNS with mirabegron group or PTNS with placebo group in 
a 1:1 fashion using variable size permuted blocks of 2, 4, and 6.  A sequentially numbered 
sealed envelope will be selected to reveal the randomized intervention.  This will be done by a 
member of the research team on the day of the first PTNS treatment.  Subjects will be blinded to 
which group they are assigned.  Allocation concealment will be ensured by using a centralized 
service to provide sequentially numbered, opaque, sealed envelopes. 
Sample Size Calculation 


The main hypothesis is that the women in the PTNS with mirabegron group will have more 
improvement in the number of UUI episodes than women in the PTNS plus placebo group.  
Given this hypothesis, based on existing data,[17] a 2-sided alpha=0.05, the estimate for that 
difference in improvement has been estimated to be 2.5 UUI episodes over a 3-day bladder 
diary pre-vs. post-treatment with a standard deviation of 3 and a power of 0.80. Assuming an 
attrition rate of 10%, the total N per arm is estimated to be 27 subjects (a total of 54 subjects) for 
this study. The sample size estimation results are summarized in Table 2. 
 
 
 
 
 
 
 
 
Table 2:  Power analysis for change in UUI episodes pre-vs. post-treatment  
Detectable  Standard 
Deviation 
Power 
N 
2.5 
2 
0.85 
13 
2.5 
2 
0.90 
15 
*2.5 
3 
0.80 
24 
2.5 
3 
0.85 
27 
 
Data analysis 
For the primary analysis, an intention-to-treat analysis including all eligible patients randomizing 
to treatment will be used.  Baseline clinical and demographic data will be compared between 
groups.  The primary outcome (changes in the number of UUI episodes pre- vs. post-treatment) 
will be compared via general linear models. 
Potential Pitfalls 
The plan is to recruit 54 subjects based on the estimated sample size over a 12-18 month study 
period.  Recruitment will be accomplished through multiple co-investigators in the division of 


Urogynecology and Pelvic Reconstructive Surgery.  An adequate sample size over the study 
period based on our experience from previous studies is feasible.  The average number of 
patients per year between Urology and Urogynecology receiving PTNS is between 50 to 70.  
The Division of Urogynecology has an established clinical research team with clinical nurses 
and nurse coordinators dedicated to clinical trials and will regularly monitor the recruitment 
process to achieve our study enrollment goal.  Our team has a strong interdisciplinary 
relationship between Urogynecology and the Continence Clinic of the Department of Geriatrics 
and we do not anticipate problems with study enrollment.  We have an excellent research track 
record as one of the Pelvic Floor Disorder Network sites, our center has successfully recruited 
women with urgency urinary incontinence symptoms for the Anticholinergic Therapy vs 
OnabotulinumtoxinA for Urgency Urinary Incontinence trial (ABC trial) and the OnabotulinumA 
vs Sacral Neuromodulation on refractory Urgency Urinary Incontinence in Women trial 
(ROSETTA trail) [22,23].  Compared to antimuscarinics, the insurance coverage for mirabegron 
is difficult and presents a major obstacle to patients being able to receive mirabegron.  To 
overcome this issue, the study will provide the medications.  Given the need for further 
treatments for refractory UUI, these study outcomes will be a significant contribution to the 
current literature and have the potential to influence clinical care.   
 
 
 
 
 
 
 
 
Timeline 


I am currently in my first year of fellowship and if I did not remain at the institution following 
fellowship, I would still be principal investigator and direct this study.  We have a strong 
research team including co-investigators in the Urogynecology Division, FPMRS fellows, 
research nurse coordinators, and nurses dedicated to research trials. All are focused on 
maintaining a solid infrastructure for success.  
 
Regular research meetings will take place with the team throughout the trial with review 
of clinics to identify possible patients and to ensure delegation of tasks for completion of 
enrollment and follow-up. We will also advertise the study on a currently existing social media 
research site and in existing UAB internet periodicals and the Birmingham newspaper. I will also 
be actively involved in the statistical analysis with the assistance of the Center for Clinical and 
Translational Sciences (CCTS) and Center for Women’s Reproductive Health (CWRH) at UAB.  
My dedication to this project and the research infrastructure in our division will assist in seeing 
this project through to completion.  
 
Impact for Future Study 
 
Another future innovation in this study draws upon a supplementary study to NOTABLe, a Pelvic 
Floor Disorders Network study evaluating PTNS vs. sham treatment for fecal incontinence. 
Genetic polymorphisms associated with placebo effect in the treatment of fecal incontinence 
were assessed [personal communication, Richter].  This supplementary study to NOTABLe 
assessed the relationship between response to PTNS or sham treatment and genetic single 
nucleotide polymorphisms (SNP) associated with treatment response via the COMT val158met 
genetic polymorphism.  In the future as this current study evolves, we would like to have 
patients from both arms of the study provide blood samples that one can utilize for further 
analysis characterizing the relationship between SNPs and treatment response.  This 
supplemental analysis will add to the growing literature on the placebome and provide critical 
information for planning future pelvic floor studies that account for the variation in an individuals’ 
likelihood of being a placebo responder. 
May/June2021:  
startup and IRB 
approval (obtained)
June 2021 to August 
2022: Recruitment 
and Enrollment
September 2022 to 
November 2022: 
Completion of Study 
December 2022 to 
April 2023: Data 
Analysis, Manuscript 
Preparation and 
Project Presentation


 
 
 
 
References: 
1. Clinical Consensus Statement: Association of Anticholinergic Medication Use and 
Cognition in Women with Overactive Bladder.  Female Pelvic Medicine & Reconstructive 
Surgery. 2021;27(2):69-71. 
2. American College of Obstetricians and Gynecologists, “Urinary Incontinence in Women” 
Practice Bulletin, No 155, Nov 2015. 
3. Hu J, Pierre E F.  Urinary Incontinence in Women:  Evaluation and Management.  Am 
Fam Physician. 2019;100(6):339-348. 
4. Khandelwal C, Kistler C.  Diagnosis of Urinary Incontinence.  Am Fam Physician. 
2013;87(8):543-550. 
5. Coyne KS, Wein A, Nicholson S, Kvasz M, Chen Cl, Milsom I.  Economic Burden of 
Urgency Urinary Incontinence in the United States: A Systematic Review.  J Manag Care 
Pharm. 2014 Feb;20(2):130-40. Doi: 10.18553/jmcp.2014.20.2.130. PMID: 24456314. 
6. Walters, Mark D. and Mickey Karram ed.  Urogynecology and Reconstructive Pelvic 
Surgery, 4th ed. Elsevier, 2015. 
7. Chapple CR, Khullar V, Gabriel Z et al: The Effects of Antimuscarinic Treatments in 
Overactive Bladder: An Update of a Systematic Review and Meta-Analysis. Eur Urol 
2008; 54: 543. 
8. Brøstrom S and Hallas J: Persistence of Antimuscarinic Drug Use. Eur J Clin Pharmacol 
2009; 65: 309. 
9. Burgio KL, Locher JL, Goode PS.  Behavioral and Drug Treatment for Urge Urinary 
Incontinence in Women.  BJM 2001;5:322:1096-1097. 
10. Gray SL, Anderson ML, Dublin S, et al. Cumulative Use of Strong Anticholinergics and 
Incident Dementia: A Prospective Cohort Study.  JAMA Intern Med. 2015;175(3):401-
407.doi:10.1001/jamainternmed.2014.7663. 
11. Escobar C, Falk K, Mehta S, Hall E, et al: Rethinking Second-Line Therapy for 
Overactive Bladder to Improve Patient Access to Treatment Options.  Obstetrics and 
Gynecology. 2021;137(3):454-460. 
12. Makhani A, Thake M, Gibson W. Mirabegron in the Treatment of Overactive Bladder: 
Safety and Efficacy in the Very Elderly Patient. Clin Interv Aging. 2020;15:575-581. 
Published 2020 Apr 23. doi:10.2147/CIA.S174402. 
13. Kasman A, Stave C, Elliot CS.  Combination Therapy in Overactive Bladder-Untapped 
Research Opportunities:  A Systematic Review of the Literature.  Neurourol Urodyn. 
2019 Nov;38(8):2083-2092. Doi: 10.1002/nau.24158. Epub 2019 Sep 4. PMID. 
31483070. 
14. Kirby A, Park S, Cook S, Odem-Davis K, Gore J, Wolff E.  Practice Patterns for Women 
with Overactive Bladder Syndrome: Time Between Medications and Third-Line 
Treatments. Female Pelvic Medicine & Reconstructive Surgery. 2020;26(7):431-436. 


15. Bhide AA, Tailor V, Fernando R, Khullar V, Digesu GA.  Posterior Tibial Nerve 
Stimulation for Overactive Bladder-Techniques and Efficacy.  Int Urogynecol J. 
2020;31(5):865-870. 
16. Vecchioli-Scaldazza C, Morosetti C.  Effectiveness and Durability of Solifenacin Versus 
Percutaneous Tibial Nerve Stimulation Versus Their Combination for the Treatment of 
Women with Overactive Bladder Syndrome:  A Randomized Controlled Study with a 
Follow-Up of Ten Months.  Int Braz j Urol. 2018; 44(1):102-108.  
https://doi.org/10.1590/S1677-5538.IBJU.2016.0611 
17. Sancaktar M, Ceyhan ST, Akyol I, et al.  The Outcome of Adding Peripheral 
Neuromodulation (Stoller Afferent Neuro-Stimulation) to Anti-Muscarinic Therapy in 
Women with Severe Overactive Bladder.  Gynecol Endocrinol. 2010;26(10):729-732. 
18. Eftekhar T, Teimoory N, Miri E, Nikfallah A, Naeimi M, Ghajarzadeh M.  Posterior Tibial 
Nerve Stimulation for Treating Neurologic Bladder in Women:  a randomized clinical trial.  
Acta Med Iran.  2014;52(11):816-821. 
19. Kizilyel S, Karakkeci A, Ozan T, Unus I, Barut O, Onur R.  Role of Percutaneous 
Posterior Tibial Nerve Stimulation Either Alone or Combined with an Anticholinergic 
Agent in Treating Patients with Overactive Bladder.  Turkish J Urol. 2015;41(4):208-214.  
https://doi.org/10.5152/tud.2015.94210 
20. Moossdorff-Steinhauser HF, Berghmans B. Effects of Percutaneous Tibial Nerve 
Stimulation on Adult Patients with Overactive Bladder Syndrome: A Systematic Review. 
Neurourol Urodyn. 2013 Mar;32(3):206-14. doi: 10.1002/nau.22296. Epub 2012 Aug 20. 
PMID: 22907807. 
21. Rai BP, Cody JD, Alhasso A, Stewart L. Anticholinergic Drugs Versus Non-Drug Active 
Therapies for Non-Neurogenic Overactive Bladder Syndrome in Adults. Cochrane 
Database Syst Rev. 2012 Dec 12;12(12):CD003193. doi: 
10.1002/14651858.CD003193.pub4. PMID: 23235594; PMCID: PMC7017858. 
22. Visco AG, Brubaker L, Richter HE, Nygaard I, Paraiso MF, Menefee SA, et al. 
Anticholinergic Therapy vs. Onabotulinumtoxina for Urgency Urinary Incontinence. N 
Engl J Med. 2012;367:1803-13. 
23. Amundsen CL, Richter HE, Menefee SA, Komesu YM, et al.  OnabotulinumtoxinA vs 
Sacral Neuromodulation on Refractory Urgency Urinary Incontinence in Women: A 
Randomized Clinical Trial.  JAMA. 2016; 316(13): 1366-1374.  
 
Statistical Analysis 
This was a randomized controlled trial Double Blinded (providers and patients) looking at 
PTNS+Myrbetriq vs. PTNS+Placebo.    The original sample size calculation noted that we needed 12-15 in 
each arm.  That was the original one done by Kimberly Martin.  We went ahead and randomized 27 in 
each arm for a total of 54.  We had 7 fall out in the Active Arm and 1 fall out in the Placebo Arm.  The 
reason for fall out was noncompliance with coming to the 12 weeks of visits and not any issues related 
to SAEs.   
We had 20 complete in the Active Arm and 26 complete in the Placebo Arm.  You all have the data 
sheet.  We have complete data for all initial visits.  The 8 patients that we do not have End of Study Data 
for are the ones who fell out after randomization.   
So, for statistical analysis, we have the Demographic Data as I have listed and we want comparisons 
between the two groups as one would do in an RCT.  Secondly, the primary outcome is the change in the 


number of UUIs (urge urinary incontinence episodes) over a 3 day bladder diary pre-trial to the number 
of UUIs post-trial on a 3 day bladder diary.  Then compare them between the two groups.   
Other components of the 3 day bladder diary include number of SUI (stress urinary incontinence) 
episodes changes pre vs. post, number of daytime voids pre vs. post, number of nighttime voids pre vs. 
post, and number of pads used pre vs. post. 
Secondary outcomes also include the questionnaires of IIQ7, UDI 6, and OABQSF changes pre vs. post-
trial and comparing them.   
This should be laid out in the data table.   
Thank you! 
Dr. Stanley