Transcutaneous Electric Nerve Stimulation For Pain Control During Office Intra-detrusor Onabotulinumtoxin A Cystoscopy Injection for Overactive Bladder: A Phase III Randomized Controlled Trial
Phase: NA
Conditions: Overactive Bladder
Sponsor: Mayo Clinic

 
 
Transcutaneous Electric Nerve Stimulation For 
Pain Control During Office Intra-detrusor 
Onabotulinumtoxin A Cystoscopy Injection for 
Overactive Bladder: A Phase III Randomized 
Controlled Trial 
 
NCT04448171 
 
08Sep2023 

TENS Units for Pain Control During Office Cystoscopic Botox Injections 
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TRANSCUTANEOUS ELECTRIC NERVE STIMULATION FOR 
PAIN CONTROL DURING OFFICE INTRA-DETRUSOR 
ONABOTULINUMTOXIN A CYSTOSCOPIC INJECTION FOR 
OVERACTIVE BLADDER: A PHASE III RANDOMIZED 
CONTROLLED TRIAL 
 
 
 
Principal Investigator:  
John A Occhino MD MS FPMRS                                         
             
Division of Urogynecology 
             
Department of Gynecologic Surgery  
             
200 First Street SW, Rochester, MN 55905 
 
 
Co-Investigators:  
 
Rubin Raju MD 
John Gebhart MD MS FPMRS 
Brian Linder MD MS FPMRS 
Emanuel Trabuco MD MS FPMRS 
 
 
Statistician:   
 
Megan E. Branda MS 
 
 
 
 
 
 
 
 
Protocol Number: 20-003510 
 
Version 1.0: 06-April-2020 
Version 1.1: 08-Sep-2020 
Version 1.2: 28-April-2021  
Version 1.3: 08-Sep-2023 
 
 
 
 

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Study Summary 
Title 
Transcutaneous Electric Nerve Stimulation For Pain control During 
Office Intra-detrusor Onabotulinumtoxin A Cystoscopy Injection for 
Overactive Bladder: A Phase III Randomized Controlled Trial 
Running Title 
TENS Units for Pain Control During Office Cystoscopic Botox 
Injections 
Protocol Number 
20-003510 
Phase 
Phase III 
Methodology 
Two Arm Phase III Double Blinded Randomized Placebo Controlled 
Trial  
Overall Study 
Duration 
12 months 
Subject Participation 
Duration 
2 days 
Single or Multi-Site  
Single Site 
Objectives 
Primary Objective(s): To determine the effect of  Transcutaneous 
Electric Nerve Stimulation (TENS) units on pain experienced by 
women undergoing office cystoscopic intradetrusor onabotulinumtoxin 
A injection for overactive bladder 
Number of 
Participants 
60 
Diagnosis and Main 
Inclusion Criteria 
1. Age ≥ 18 
2. Scheduled to receive Intradetrusor Onabotulinumtoxin A 
injection for Overactive Bladder 
3. English speaking 
Study Product, 
Dose, Route, 
Regimen 
Product: TENS Unit 
Dose: Asymmetric, balanced, biphasic square waveform at a mixed 
stimulating frequency that randomly varying between 80 and 100 Hz and 
a pulse duration of 300 microseconds 
Route: Transcutaneous using Adhesive Pads 

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Duration of 
Administration 
To start 5 minutes before the procedure and during the procedure  
Reference therapy 
Current Standard of Care: Intra-urethral Lidocaine, Intra-vesicle 
Lidocaine Solution, Distraction techniques, Aromatherapy 
Statistical 
Methodology 
The data will be analyzed using an intention-to-treat approach. In order to 
account for individual participant pain sensitivity profiles through the 
experiment, random effect longitudinal model will be adjusted to the data 
controlling by treatment and selected covariates at baseline. 
 
1 Introduction:  
This document is a protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic research 
policies and procedures.  
1.1 
Background 
Options for adequate pain control during office-based cystoscopy procedures are limited [1]. 
Currently, varying pain control strategies are being used including local anesthesia (intra-urethral 
lidocaine [2], intra-vesicular lidocaine solution[1, 3]), distraction techniques[2, 4] 
(conversation/music/’squeeze balls’), aromatherapy[5], intramuscular analgesia, sedation and a 
combination of these techniques. Despite this, participants often experience pain during the 
procedure. Trans-cutaneous Electrical Nerve Stimulation (TENS) is a non-pharmacologic, non-
invasive and safe method of pain control that involves delivery of electrical impulses to the skin, 
resulting in a reduction in perceived pain. TENS units have been successfully used for 
intraoperative pain control during office hysteroscopy[6] and office colonoscopy[7]. They may 
also help reduce pain during cystoscopy. Overactive bladder (OAB) is a symptom complex 
pronounced by urinary urgency, affecting up to 12% of the adult population, with a significant 
negative impact quality on the life [8]. Cystoscopic Intradetrusor Onabotulinumtoxin A is used for 
the treatment of OAB in participants who do not tolerate or adequately respond to oral 
anticholinergic medications[9]. The response to the onabotulinumtoxin A injection is transient and 
requires repeat injections roughly every 6-7 months. Adequate pain control during this procedure 
is essential for success in the office setting [10, 11]. There is a critical need to assess the 
effectiveness of TENS units for intraoperative pain management during office cystoscopic 
Intradetrusor Onabotulinumtoxin A. In the absence of such knowledge, the realization of the pain 
control potential of TENS units during office cystoscopy will remain unknown. 
 

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1.2 
Overactive Bladder and Cystoscopic Intradetrusor Onabotulinumtoxin A 
Overactive bladder (OAB) is a symptom complex that includes urinary urgency, frequency, 
urgency incontinence, and nocturia. It is highly prevalent, affecting up to 12% of the adult 
population, and can significantly impact quality of life (8). In 2013, FDA approved Intradetrusor 
Onabotulinumtoxin A for the treatment of overactive bladder symptoms in patients who do not 
tolerate or adequately respond to oral anticholinergic medications(9). Of note more than 50% 
patients starting medical therapy discontinue medical therapy by 6 months(13). The therapy is 
performed by a cystoscopic injection that can be carried out in an office setting with topical 
analgesia or under sedation in the operating room. The response to the onabotulinumtoxin A 
injection is transient, requiring repeat injections roughly every 6-7 months (10, 11). Due to the 
need for repeat injections, performing this procedure in the office is cost effective (14). Adequate 
pain control during this procedure is essential for success in the office setting. A limited number 
of studies have looked at measures to improve pain control with office cystoscopic 
onabotulinumtoxin A injections. LeClaire et al. (2018), in a randomized control trial of 26 
participants undergoing office cystoscopic onabotulinumtoxin A injection for overactive bladder 
randomized to a belladonna and opiate suppository group (n =13) and a placebo suppository group 
(n = 13), found that the belladonna and opiate did not significantly reduce bladder injection pain(1). 
Nambiar et al. (2016) in a randomized control trial of 54 participants undergoing office cystoscopic 
onabotulinumtoxin A injection for overactive bladder randomized to receive intravesical 
alkalinized lidocaine solution group (n =26) and intravesicle lidocaine gel (n = 28), found that 
alkalinized solution was not superior to lidocaine gel(3).  
 
1.3 
Adequate Pain Control During Office Cystoscopy  
Operative office cystoscopy is a painful procedure and often results in preprocedural anxiety in 
patients (1-4). Flexible cystoscopy maybe less painful than rigid cystoscopy (4). Options for 
adequate pain control during office-based cystoscopy procedures are limited (1). Currently, 
varying pain control strategies are being used including local anesthesia (intra-urethral lidocaine 
(2), 
intra-vesicular 
lidocaine 
solution 
(1, 
3), 
distraction 
techniques 
(2, 
4) 
(conversation/music/’squeeze balls’), aromatherapy(5), intramuscular analgesia, sedation and a 
combination of these techniques. Despite these interventions, patients often experience mild to 
moderate amount of pain during the operative office cystoscopy (1, 3).  
 
1.4 
Trans-cutaneous Electrical Nerve Stimulation (TENS) in an Office Setting 
Trans-cutaneous Electrical Nerve Stimulation (TENS) may provide satisfactory pain control in the 
office setting. It is easy to access and use following proper training. There is a lack of side effects 
compared to existing pharmacology pain control methods and the lack of need for in-office 
anesthesia personnel and prolonged post-procedural monitoring. There are limited studies looking 

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at TENS unit for intraoperative pain management. In order to get the best analgesic effect from 
the TENS unit, it is now known that accurately placement of electrodes, and selection of the 
appropriate current waveform, waveform duration, frequency and intensity are essential [6, 12]. 
With regards to electrode placement, it is important place the electrodes near the nerves that supply 
the area where the analgesic effect is needed [6, 13]. Hruby et al (2016) in a randomized control 
trial of 148 patients in 2006 undergoing flexible cystoscopy showed no difference in mean visual 
analogue pain score between the no analgesia group, placebo TENS group and activated TENS 
(mean visual analogue pain score of 3.73, 3.65, 3.52 respectively, p= 0.97). In this study, the 
electrodes where placed halfway along an imaginary line between the anterior superior iliac spine 
and the pubis. Such a placement has been shown to be suboptimal in achieving pain control for 
pelvic procedures. Also, in this study the pulse duration was set at 180 microsecond pulse width. 
The current consensus is the pulse duration of greater than 250 microseconds is important to 
achieve adequate analgesia [6, 13]. Studies have shown a reduction in pain with the appropriate 
use of TENS units during office hysteroscopy[6] and during colonoscopy[7]. 
 
1.5 
Innovation 
The long term goal is to contribute towards effective pain control strategies for office based 
operative procedures. Our overall objective in this application is to determine how TENS units 
affect pain control during office cystoscopic Intradetrusor Onabotulinumtoxin A injections. This 
is will be the first study looking at the effectiveness of TENS units for pain control during office 
cystoscopic Intradetrusor Onabotulinumtoxin A injections. It was also be the first study looking at 
the effectiveness of TENS units for pain control during office cystoscopy in general, using 
appropriate TENS settings. The knowledge gained from this study will have widespread 
implications for pain control during office based cystoscopic procedures in the field of 
Urogynecology and Urology, and can be extrapolated to other office based procedures in other 
fields as well. If TENS units prove to be effective in pain control for office based procedures, this 
will lead to a paradigm shift. 
 
1.6   Choosing the Specific Aims of this Study: 
Prior to 2017, we performed all cystoscopic Onabotulinum Toxin A injections in the operating 
room at Mayo Clinic in Rochester, Minnesota. Patients with refractory overactive bladder require 
repeat injections and had to return to the operating room on average every 6-7 months. This would 
be almost a whole day’s ordeal for patients. In order to minimize the inconvenience to patients and 
to provide cost effective patient care, Cystoscopic Onabotulinum A injections were transitioned to 
the office setting in 2017.  

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For successful adoption of office cystoscopic Onabotulinum Toxin A injection, the procedure has 
to be an acceptable option to patients. As noted earlier, office cystoscopy in itself is an 
uncomfortable procedure and the addition bladder injections make it painful. The pain patients 
experience during the procedure can deter them from wanting a repeat cystoscopic injection in 
office setting. Currently we use local anesthesia (intra-urethral lidocaine), intra-vesicular lidocaine 
solution, distraction techniques (conversation/music/’squeeze balls’), and aromatherapy for pain 
control during this procedure. Despite this, a preliminary review of 91 office Cystoscopic 
Onabotulinum A injections performed at our institution from 2017 to 2019 showed that the average 
intra-procedural pain score was 5 on a numerical pain scale of 0 to 10.  
Therefore, we chose the pain experienced during the office Cystoscopic Onabotulinum Toxin A 
injection and the patient’s satisfaction from the procedure as the specific aims for this study.  
 
2 Study Objective(s)/Aims(s): 
2.1 
Specific Aim #1: To assess whether the TENS units are effective for intraoperative pain 
management during office cystoscopic Intradetrusor Onabotulinumtoxin A in women 
with OAB.  
We plan to compare participant reported pain using a 0-10 numerical pain scale at baseline, during 
and after cystoscopic intradetrusor onabotulinumtoxin A injection in patients randomized to active 
TENS units and placebo TENS units. We will compare the change in numerical pain scale from 
baseline to intraoperatively and intraoperatively to postoperatively between both groups. 
2.2 
Specific Aim #2: To evaluate the effect of TENS units on participant satisfaction 
following cystoscopic intradetrusor onabotulinumtoxin A injection in women with 
OAB.  
We plan to evaluate participant satisfaction on a 10 point Likert scale immediately after the 
procedure in participants randomized to activated TENS units and placebo TENS units.  
 
3 Study Design 
3.1 
General Description 
The study is a two arm phase III double blinded randomized placebo control trial looking at the 
effect of TENS unit on pain in participants receiving Office based Cystoscopic Onabotulinum 
Toxin A injection for Overactive bladder at the Mayo Clinic in Rochester, Minnesota.  

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3.2 
Number of Subjects: 60 subjects 
3.3 
Duration of Participation: From accrual to the end of the Cystoscopic Onabotulinum 
Toxin A injection office visit 
3.4 
Study Schema and Flow: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Women ≥ 18 years of age, diagnosed with Overactive Bladder, 
scheduled for Office Based Cystoscopic Intra-detrusor 
Onabotulinumtoxin A  Injection at  the Division of 
Urogynecology, Mayo Clinic, Rochester, English speaking 
Eligible Patient given baseline questionnaires pre-procedure: 
Generalized Anxiety Disorder Screen (GAD-7 Questionnaire) 
and Depression Screen (PHQ-9); History of Sexual Abuse: 
History of Chronic Pain 
Randomization: Permutated Block Randomization (1:1 Ratio) 
using a computerized sequence generator 
Activated TENS Unit with 
standard pain control 
measures during Office 
Based Cystoscopic Intra-
detrusor Onabotulinumtoxin 
A  Injection 
Sham TENS Unit with 
standard pain control 
measures during Office 
Based Cystoscopic Intra-
detrusor 
Onabotulinumtoxin A 
Injection  
Standardized Questionnaire Verbally Administered and 
Completed by Registered Nurse assessing: 
1. Numerical Pain Scale (0-10): before, during and post-
procedural (within 5-10 minutes of completion) 
2. Participant Satisfaction (10 point Likert Scale): post-
procedural 
Exclusion Criteria:  
1. Unable/Decline to Give 
Informed Consent 
2. Previously Received TENS 
therapy  within 1 year 
prior to study enrollment. 
3. Currently fitted with 
Pacemakers/automatic 
implanted cardiac 
defibrillator 
4. History of Epilepsy 
5. Pregnancy or within 12 
weeks Postpartum 
Participant withdrawal from study 

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3.5 
Primary endpoints  
• Numeric Analog Pain Score (0-10) at Baseline before Office Cystoscopic Onabotulinum 
Toxin A injection (collected after the participant changes into procedural grown)  
• Numeric Analog Pain Score (0-10) during Office Cystoscopic Onabotulinum Toxin A 
injection (collected during middle of the procedure, after the 10th injection) 
• Numeric Analog Pain Score (0-10) after Office Cystoscopic Onabotulinum Toxin A 
injection (collected 5-10  minutes after the procedure) 
Source: The Numerical Analog Pain Score will be documented by the study coordinator into 
the case report forms and later transferred in the Red Caps Data Management system.  
 
3.6 
Secondary Endpoints 
• Participant satisfaction on a Likert Scale of 1 - 10 (10 = Completely satisfied and 1 = 
Completely Dissatisfied) after the Office Cystoscopic Onabotulinum Toxin A injection 
(collected 5-10 minutes after the procedure) 
• Depression Screen Score (PHQ 9) 
• Anxiety Screen Score (GAD 7) 
• History of Sexual Abuse 
• History of Chronic Pelvic Pain 
• Participant Demographics: Age, Ethnicity, Basal Metabolic Index (BMI), Insurance 
• Co-morbid conditions 
• Current Medications 
• Smoking Status 
• Past or Current Illicit Drug Abuse 
• Presence of Chronic Pain  
• Number of Previous Onabotulinum Toxin A injection 
• Previous Therapies for OAB (Lifestyle, Medication, Peripheral Tibial Nerve Stimulation, 
Sacral neuromodulation) 
Source: The Participant Satisfaction Score, PHQ 9 score and GAD 7 score will be 
documented by the study coordinator into the case report forms and later transferred in the 
REDCap Data Management system. The participant demographics, co-morbid condition, 
current medications, smoking status, history of past or current illicit drug abuse, presence of 
chronic pain, number of previous Onabotulinum Toxin A injections, and previous therapies 
for OAB will be extracted from the electronic medical records. This information will be 
transferred to the REDCap Data Management System by the Principal and Co-investigators 
on the study. 

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4 Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
• Age 18 and older 
• Scheduled to receive Intradetrusor Onabotulinumtoxin A injection 
• English speaking 
 
4.2 
Exclusion Criteria 
• Unable or Declining to Give Informed Consent 
• Allergy to adhesives 
• Participant self-report of previous use of TENS Unit within 1 year prior to study 
enrollment. 
• Fitted with pacemaker or automatic implanted cardiac defibrillator 
• History of Epilepsy 
• Pregnancy and Postpartum period (within 12 weeks postpartum) 
 
4.3 
Subject Recruitment, Enrollment 
All women with a diagnosis of Overactive bladder who are pursuing Office Cystoscopic 
Onabotulinum Toxin A for treatment and receiving care at the Division of Urogynecology, Mayo 
Clinic in Rochester, Minnesota will be approached for this study. Fellows, residents, Advanced 
level providers and Urogynecologists can offer these participants to talk with the study 
coordinator. The study coordinator will then be notified of women with Overactive Bladder 
interested in office based Cystoscopic Intra-detrusor Onabotulinum Toxin A injections by the 
care provider/Registered Nurse during the office visits following their appointment. The study 
coordinator will then approach the women interested in the study immediately following this 
appointment. The study coordinator will make sure that the participant meets the inclusion and 
exclusion criteria for the study. A written informed consent will be obtained from all eligible 
women who chose to participate using a standardized consent form approved by the Mayo Clinic 
Institutional Review Board. We will allow for 1 year from the start of recruitment for accrual of 
participants, expecting to enroll approximately 5 participants per month. A total of 60 
participants will be recruited with 30 participants in each group (Active TENS group and Sham 
TENS group). 
4.4 
Withdrawal of Subjects and Follow up 
A participant can chose to withdraw from the study at any point. A verbal request is all that is 
needed and can be conveyed to anyone of the team members taking care of the participant. This 
information will then be relayed to the study coordinator by the person receiving the request. No 
further follow up is needed.  
 

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5 Study Procedures 
A flow chart of study activities is provided in Protocol Section 3.4 
5.1 
Visit 1: 
Participants will be recruited from the Division of Urogynecology at Mayo Clinic, where care is 
being provided. Care providers will determine whether women are interested in learning about the 
study. The study coordinator will then be notified of women with Overactive Bladder interested in 
office based Cystoscopic Intra-detrusor Onabotulinum Toxin A injections by the care 
provider/Registered Nurse during the office visit following their appointment. The study 
coordinator will then approach the women interested in the study immediately following this 
appointment. A written informed consent will be obtained from all eligible women who chose to 
participate using a standardized consent form approved by the Mayo Clinic Institutional Review 
Board. We will allow for 1 year from the start of recruitment for accrual of participants.  
5.2 
Outpatient Procedure Visit: Cystoscopic Onabotulinum Toxin A Injection 
On the day of the scheduled procedural visit, all participants will receive a Generalized Anxiety 
Disorder 7 (GAD -7) and Depression screening questionnaire (PHQ-9). Those women screening 
positive for anxiety (GAD 7 score ≥ 10) or depression (PHQ-9 score ≥ 10), will be offered referral 
to their primary care provider for further management. These women can continue to remain in 
the study and will not be excluded. In the same questionnaire, the participants will be asked “Have 
you ever experienced sexual abuse?” in order to assess for a history of sexual abuse. Participants 
will also be asked “Have you experienced chronic, unrelenting pain for 6 months or more 
duration?” in order to assess for a history of chronic pain. 
Participants will be randomized to two groups using a computerized sequence generator based on 
permuted block randomization (1:1 allocation ratio) on the day of the procedure by the registered 
nurse (RN) taking care of the participant. Participants in Group 1 will receive an Activated TENS 
unit for pain control. Participants in Group 2 will have a Sham, inactive TENS unit for pain control. 
Both groups will be blinded to the type of TENS unit received. The nursing team taking care of 
the participant will know about the randomization. The care providers performing the procedure 
and the study coordinator will not be notified about the randomization. 
 
On the day of the procedure, after baseline questionnaires and randomization, the participant will 
receive intraurethral lidocaine jelly as part of the standard pain control measures. Her bladder is 
then emptied using a Foley Catheter, and at the same time the bladder is then backfilled with 30 
ml (300 mg/30 ml) of 1 % plain lidocaine solution. A waiting period of 30-50 minutes duration is 
allowed for the intravesicle lidocaine to take effect. During this wait period, participant is asked to 
lie supine for 10-15 minutes, then roll to the left side for 10-15 minutes and then to right side for 
about 10-15 minutes.  

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The participant, the provider taking care of the participant and the study coordinator assigned to 
the study will be blinded to the randomization. Both groups of participants will receive the TENS 
unit electrode placement during this wait period by the RN.  
In participants randomized to the Active TENS group, the TENS unit will be initiated on standard 
setting (see ‘TENS, Electrode Placement, and Settings’) 5 minutes before starting the cystoscopy 
and will last the duration of the cystoscopy. The device intensity (amplitude) will be individually 
adjusted to each participant’s maximum sensory level, which is the strongest reported tingling 
feeling without pain and muscle contractions and kept at this setting for the duration of the 
procedure. 
Participants randomized to the Sham TENS group will not receive the TENS therapy. Instead, they 
will receive electrode placement followed by initiation of the TENS unit until the participant feels 
the tingling sensation, following which the TENS unit will be immediately turned off by the RN. 
The participant will be notified by the RN that the TENS stimulus has been turned down such that 
they are not able to feel the tingling sensation anymore.  
Following the initiation/placement of the TENS unit, the study coordinator and fellowship trained 
Urogynecologist will enter the room. Rigid cystoscopic Intradetrusor Onabotulinumtoxin A 
injection will be performed by a fellowship trained Urogynecologist. This involves 100 units of 
Onabotulinumtoxin A injected in roughly 20 aliquots throughout the bladder. After the procedure 
participants are discharged home.  
Care providers performing the injection will only be allowed into the procedure room once the 
TENS units has been activated. The nursing staff will assess the pad placement sites for any skin 
irritation, and or burns. If so, this will be documented on the participant’s electronic medical 
record. The study coordinator will ask the participant and the provider separately (in the absence 
of the other) whether they felt the participant was in the Active TENS group versus the Sham 
TENS group at the end of the procedure. Participants will be advised to call and inform the clinic 
if they experience any burns, skin irritation or muscle soreness/pain. 
 
 
 
 
 
5.2.1 TENS Unit, Electrode Placement and Settings  
The nursing team will be provided with official training on the appropriate use of TENS unit, prior 
to its implementation. The nurse taking care of the participant will place the electrodes and manage 
the TENS unit. An iStim EV804 TENS unit along with 4 AUVON TENS self-adhering stimulating 
electrodes will be used for each participant. 

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Electrode Placement:  Two sets of two self-adhesive electrodes 
to be placed parallel to the spinal cord at the T10–L1 and S2–
S4 levels as shown in Figure 1.  
 
 
Activated TENS Output Parameters: Based on randomization 
the TENS unit will be either activated or left inactive (after a 
brief initial activation to avoid the unblinding of the 
participant) 5 minutes prior to and for the duration of the 
cystoscopic injection procedure. Active parameters are: 
asymmetric, balanced, biphasic square waveform at a mixed 
stimulating frequency that randomly varying between 80 and 100 Hz and a pulse duration of 300 
microseconds.  
 
5.3 
Masking/Blinding 
Participants in both arms of the study will be blinded to whether they received Active TENS unit 
or Sham TENS unit. Only the nursing team will be notified about the randomization. The care 
providers performing the procedure and the study coordinator will not be notified about the 
randomization. The study coordinator will ask the participant and the provider separately (in the 
absence of the other) whether they felt the participant was in the Active TENS group versus the 
Sham TENS group at the end of the procedure.  
 
Schedule of Events 
 
 
Study Activity 
Visit 1  
Outpatient Clinic 
Visit 2 Outpatient Procedure 
Cystoscopic Onabotulinum Toxin A 
Injection 
Screening and Informed Consent 
X 
 
 Depression and Anxiety Screen 
    
X 
Randomization 
  
X 
Numerical Pain Score assessment 
 
X 
Participant  Satisfaction Assessment 
 
X 
Participant and Provider Perception 
regarding Arm of study 
 
X 
 
Figure 1: Electrode Placement 
Lisόn et al (2017). Pain Relief During Office 
Hysteroscopy. Obstet Gynecol 

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6 Statistical Plan 
6.1 
Sample Size Determination: 
Based on our baseline preliminary data and the study ‘Transcutaneous Nerve Stimulation for Pain 
Relief During Office Hysteroscopy’ by Lison et al (2017)[6], power calculations were performed. 
As estimates of the mean and variance of the pain scale we used table 2 from the Lison et al (2017) 
study and our preliminary data. Group sample sizes of 27 and 27 achieve 80.53% power to reject 
the null hypothesis of equal means when the population mean difference is μ1 - μ2 = 4.0 - 2.0 = 
2.0 with standard deviations of 2.0 for group 1 and 3 for group 2, and with a significance level 
(alpha) of 0.050 using a two-sided two-sample unequal-variance t-test. With a 10% possible 
dropout rate, we plan to have 30 participants in each of the study. 
 
6.2 
Statistical Methods: 
6.2.1 
 Specific Aim #1: To assess whether the TENS units is effective for intraoperative pain 
management during office cystoscopic Intradetrusor Onabotulinumtoxin A in women 
with OAB.  
We plan to compare participant reported pain using a 0-10 numerical pain scale at baseline, during 
and after cystoscopic intradetrusor onabotulinumtoxin A injection in participants randomized to 
active TENS units and placebo TENS units. We will compare the change in numerical pain scale 
from baseline to intraoperatively and intraoperatively to postoperatively between both groups. 
Hypothesis: We hypothesize that there will be a clinically significant pain reduction in the Active 
TENS group.  
Interpretation: Assuming that pain as measured is decreased in the Active TENS group when 
compared to the placebo TENS group, then we will accept our hypothesis. If not, we will perform 
a subgroup analysis of our data to see if certain groups of people that have better pain reduction 
with the Active TENs unit and an analysis of risk factors that might contribute to pain with 
Intradetrusor Onabotulinumtoxin A injection.  
Power Calculation: Based on our baseline preliminary data and the study ‘Transcutaneous Nerve 
Stimulation for Pain Relief During Office Hysteroscopy’ by Lison et al (2017)(6), power 
calculations were performed. As estimates of the mean and variance of the pain scale we used table 
2 from the Lison et al (2017) study and our preliminary data. Group sample sizes of 27 and 27 
achieve 80.53% power to reject the null hypothesis of equal means when the population mean 
difference is μ1 - μ2 = 4.0 - 2.0 = 2.0 with standard deviations of 2.0 for group 1 and 3 for group 
2, and with a significance level (alpha) of 0.050 using a two-sided two-sample unequal-variance 
t-test. 
 
Data Analysis: The data will be analyzed using an intention-to-treat approach. In order to account 
for individual participant pain sensitivity profiles through the experiment, random effect 
longitudinal model will be adjusted to the data controlling by treatment and selected covariates at 
baseline. 
 

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6.2.2 Specific Aim # 2: To evaluate the effect of TENS units on participant satisfaction 
following cystoscopic intradetrusor onabotulinumtoxin A injection in women with 
OAB.  
We plan to evaluate participant satisfaction on a 10 point Likert scale immediately after the 
procedure in participants randomized to activated TENS units and placebo TENS units.  
Hypothesis: There will be a high level of participant satisfaction on a 10 point Likert scale in the 
active TENS group. 
Interpretation: Assuming that the participant satisfaction as measured is high in the Active TENS 
group, then we will accept our hypothesis. If not, we plan to do a subgroup analysis to see if there 
are factors that contribute to higher participant satisfaction in certain groups of people in both the 
Active TENS and Placebo TENS group. 
 
Data Analysis: The data will be analyzed using an intention-to-treat approach. Baseline differences 
between both groups will be analyzed using Cochran-Mantel-Haenszel test with an Alpha level of 
0.05. Spearman rank correlation coefficients between Likert scales will be using to assess the 
strength of the relationship. 
 
 
7 Safety and Adverse Events 
7.1 
Definitions 
 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  
• Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: (1) 
death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth defect/anomaly; (6) 
breach of confidentiality and (7) other problems, events, or new information (i.e. 
publications, DSMB reports, interim findings, product labeling change) that in the opinion 
of the local investigator may adversely affect the rights, safety, or welfare of the subjects 
or others, or substantially compromise the research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the research procedures. 
 

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Adverse Event 
An untoward or undesirable experience associated with the use of a medical product (i.e. drug, 
device, biologic) in a patient or research subject. 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  Serious problems/events can be well 
defined and include: 
• death 
• life threatening adverse experience 
• hospitalization 
• inpatient, new, or prolonged; disability/incapacity 
• persistent or significant disability or incapacity 
 
And/or per protocol may be problems/events that in the opinion of the sponsor-investigator may 
have adversely affected the rights, safety, or welfare of the subjects or others, or substantially 
compromised the research data. 
Other important medical events are those that may not be immediately life threatening, but are 
clearly of major clinical significance include: 
• Burns  
• Skin Irritation 
• Muscle Pain or Soreness 
All adverse events that do not meet any of the criteria for serious, should be regarded as non-
serious adverse events.  
 
Adverse Event Reporting Period  
For this study, the study treatment follow-up period is defined as from enrollment to 1 week after 
receiving the cystoscopic Onabotulinum Toxin A injection. 
 
 
 

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Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event.  
Post-study Adverse Event 
All unresolved adverse events should be followed by the sponsor-investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the sponsor-investigator should instruct each subject to report, to the sponsor-
investigator, any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study.  
Abnormal Laboratory Values   
No abnormal laboratory values are related to the administration of the TENS Unit 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for an adverse event.  
 
7.2 
Recording of Adverse Events 
At each contact with the subject, the study team must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event section of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic, laboratory or procedure results should recorded in the source document. 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been ultimately 
determined that the study treatment or participation is not the probable cause.  Serious adverse 

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events that are still ongoing at the end of the study period must be followed up, to determine the 
final outcome.  Any serious adverse event that occurs during the Adverse Event Reporting 
Period and is considered to be at least possibly related to the study treatment or study 
participation should be recorded and reported immediately. 
CTCAE Version 5.0 (November 27, 2017) will be used for classification and grading of Adverse 
Events: 
 
 
7.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event section of 
the Case Report Form.  The sponsor-investigator will evaluate the event and determine the 
necessary follow-up and reporting required. 
 
7.3.1 Investigator reporting: notifying the Mayo IRB 
The study coordinator will promptly report to the Principal Investigator and co- investigators of 
“any unanticipated problems involving risk to subjects or others” (UPIRTSO) as defined by the 
Code of Federal Regulations [45 CFR 46.103(b)(5) and 21 CFR 56.108(b)(1)]. The adverse 
events will be documented on the CRF and the data management system. 
The investigator will review all adverse event reports to determine if specific reports need to be 
made to the IRB.  The investigator will sign and date the adverse event report when it is 
reviewed.  For this protocol, only directly related SAEs/UPIRTSOs will be reported to the IRB.  
Investigators will collect, assess, and report all adverse events that occur during a clinical trial. 
The investigators will review each event and ensure the appropriate information is added to the 
case report form (CRF). If the event is serious, the internal reviewer (as appointment by the 
Mayo Clinic Obstetrics and Gynecology Department Research chair) and the Mayo Clinic IRB 
must be informed within 24 hours of the occurrence of the event. Non-serious events will also be 
reported to the internal reviewer and the Mayo Clinic IRB sponsor through documentation on the 
CRF and database updates. Any adverse event will be reported to the Mayo IRB, in the manner 
prescribed by Mayo’s policy. [IRB Policy Document No. 10049, Procedure for the Investigator]. 
Once reported, the Mayo Clinic IRB will determine what constitutes an unanticipated problem 
involving risk to subjects or others (UPIRTSO) and will report to appropriate institutional 
officials, OHRP, and other relevant Federal agencies as set forth in IRB Policy III.C.  

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Information collected on the adverse event worksheet (and entered in the research database):  
• Subject name:  
• Medical record number:  
• Disease/histology (if applicable):  
• The date the adverse event occurred:  
• Description of the adverse event:  
• Relationship of the adverse event to the research (drug, procedure, or intervention*):  
• If the adverse event was expected:  
• The severity of the adverse event: (use a table to define severity scale 1-5**) 
• If any intervention was necessary:  
• Resolution: (was the incident resolved spontaneously, or after discontinuing treatment) 
• Date of Resolution:  
 
The relationship of an AE to the Investigational Drug is a clinical decision by the sponsor-
investigator (PI) based on all available information at the time of the completion of the CRF and 
is graded as follows: 
1. Not related: a reaction for which sufficient information exists to indicate that the etiology is 
unrelated to the study drug; the subject did not receive the study medication or the temporal 
sequence of the AE onset relative to administration of the study medication is not reasonable or 
the event is c1early related to other factors such as the subject’s clinical state, therapeutic 
intervention or concomitant therapy. 
2. Unlikely: a clinical event, including laboratory test abnormality, with a temporal relationship 
to drug administration which makes a causal relationship improbable and in which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
3. Possible: a clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug but which could also be explained by concurrent disease 
or other drugs or chemicals; information on drug withdrawals may be lacking are unclear. 
4. Probable: a clinical event including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent disease or other 
drugs or chemicals and which follows a clinically reasonable response on withdrawal (de-
challenge): re-challenge information is not required to fulfi1 this definition. 
5. Definite: a reaction that follows a reasonable temporal sequence from administration of the 
drug, or in which the drug level has been established in body fluids or tissues, that follows a 
known or expected response pattern to the suspected drug, and that is confirmed by improvement 
on stopping or reducing the dosage of the drug, and reappearance of the reaction on repeated 
exposure (re-challenge). 

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The maximum intensity of an AE during a day should be graded according to the definitions 
below and recorded in details as indicated on the CRF. If the intensity of an AE changes over a 
number of days, then separate entries should be made having distinct onset dates.  
1. Mild: AEs are usually transient, requiring no special treatment, and do not interfere with 
patient’s daily activities. 
2. Moderate: AEs typically introduce a low level of inconvenience or concern to the patient and 
may interfere with daily activities, but are usually ameliorated by simple therapeutic measures. 
3. Severe: AEs interrupt a patient's usual daily activity and traditionally require systemic drug 
therapy or other treatment. 
 
7.1 
Stopping Rules  
An interim analysis will be performed after 30 participants have undergone cystoscopic 
Onabotulinum Toxin A injection as part of the study. The information will also be sent to an 
internal reviewer (as appointment by the Mayo Clinic Obstetrics and Gynecology Department 
Research chair). At this point a meeting between the investigators and internal reviewer will be 
convened to discuss the existing data, the efficacy and any safety issues including serious 
adverse events that have taken place. A decision will be made as to whether to continue with the 
study or to prematurely terminate the study based on any safety issues.  
If there are greater than 3 serious adverse (i.e. severe skin reactions, burns, muscle weakness) 
events reported in the 30 participants reviewed, further recruitment and administration of the 
TENS unit will be stopped. The study will be put on hold with the IRB and each of the adverse 
events will be carefully looked into for any causal relation to the TENS unit. If no causal 
relationship is proved then the will re-approach IRB for restarting the study.  
 
7.2 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his site.  
This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see section 10  “Study Monitoring, Auditing, and Inspecting”).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
 

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7.2.1 Internal Data and Safety Monitoring Board 
An internal reviewer with Urogynecolgic expertise will be appointed by the Obstetrics and 
Gynecology Research Chair who will participate in review of any serious adverse events 
associated with the trial. A meeting convened with the internal reviewer will be performed after 
30 participants have undergone cystoscopic Onabotulinum Toxin A injection as part of the study. 
 
8 Data Handling and Reporting 
8.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (long term survival status that 
the subject is alive) at the end of their scheduled study period. 
8.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Original documents and data records include but are not 
limited to: hospital records, clinical and office charts, laboratory notes, memoranda, subject 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
8.3 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded in the RedCaps Database.  All missing data will be 
explained.   

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8.3.1 Data Management 
Any data not collected on a study case report form will be manually abstracted from the 
electronic medical record and recorded in the Data Management System by the Principal and Co-
Investigators. 
8.3.1.1 Data Processing 
The REDCap Data Management System will contain information captured from the Case Report 
Form and from the Electronic Medical Records. The Data Management system will be reviewed 
once a month by the investigators and the study coordinator for missing information. If missing 
data is noted in the data management system that can be captured from the Electronic Medical 
Records, the electronic medical records will be reviewed to capture this information. 
8.3.2 Data Security and Confidentiality 
Collected study data collected on case report forms will recorded in pen and will be stored in 
restricted access areas when not actively being used in the study. Only necessary research team 
members will have access to the data for data entry or analysis. All data collection and analysis 
will be performed behind the Mayo firewall.  
8.3.3 Data Quality Assurance 
The Case Report Forms will be cross checked by the study coordinator for completion at the end 
of the 24 hours after cystoscopic Onabotulinum Toxin A injection. At the completion of the 
study, the data in the Case Report Forms will be crossed with the data entered into the RedCaps 
Data Management System for accuracy.  For the data entered from the electronic medical records 
into the Data Management System, a second Co-investigator will be assigned to randomly select 
a patient monthly and review the data entered into the Data Management System from the 
Electronic Medical Records. 
8.3.4 Data Clarification Process 
The case report forms will be checked for missing data before the patient leaves home from their 
procedure visit.  
8.4 
Records Retention 
The sponsor-investigator will maintain records and essential documents related to the conduct of 
the study.  These will include subject case histories and regulatory documents. 
Subject-specific data and Case Report Forms will be identified by the patient medical record 
number and a unique coded number given to it; the patient name will not be included. The 
subject identification list will be stored behind the Mayo firewall.  
Subject names and other directly identifiable information will not appear on any reports, 
publication, or other disclosures of clinical study outcomes.  

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The sponsor-investigator will retain the specified records and reports: 
1. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy”  
 
9 Study Monitoring, Auditing, and Inspecting 
9.1 
Study Monitoring Plan 
The investigator will allocate adequate time for such monitoring activities.  The Investigator will 
also ensure that the monitor or other compliance or quality assurance reviewer is given access to 
all study-related documents, study related facilities (research pharmacy), and has adequate space 
to conduct the monitoring visit. 
9.2 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, inspections by the IRB, and 
government regulatory agencies, of all study related documents.   The investigator will ensure 
the capability for inspections of applicable study-related facilities (research pharmacy).  
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
10 Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted local Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study.  The decision of the IRB concerning the conduct of the study will be made in writing to 
the sponsor-investigator before commencement of this study. 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the approved IRB consent form, must be 
obtained before that subject undergoes any study procedure.  The consent form must be signed 
by the subject or the subject’s legally authorized representative, and the individual obtaining the 
informed consent. 
This study does not involve any vulnerable populations. 
 

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11 Study Finances 
Planned source of funding is the fellow research fund from the Division of Urogynecology, 
Mayo Clinic, Rochester, Minnesota allotted. 
12 Publication Plan 
The primary responsibility for publication is in the hands of the principal investigator and co-
investigators. Permission will be needed from the primary responsible party before any 
information can be used or passed on to a third party.  The study will be registered in 
ClinicalTrials.gov and the results will be posted to ClinicalTrials.gov within 12 months of final 
data collection for the primary outcome.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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13 References 
1. 
LeClaire, E.L., et al., Randomized controlled trial of belladonna and opiate suppository during 
intravesical onabotulinum toxin A injection. Am J Obstet Gynecol, 2018. 219(5): p. 488 e1-488 
e7. 
2. 
Gupta, S., et al., Distraction during cystoscopy to reduce pain and increase satisfaction: 
Randomized control study between real-time visualization versus listening to music versus 
combined music and real-time visualization. Urol Ann, 2019. 11(1): p. 33-38. 
3. 
Nambiar, A.K., et al., Alkalinized lidocaine versus lidocaine gel as local anesthesia prior to intra-
vesical botulinum toxin (BoNTA) injections: A prospective, single center, randomized, double-
blind, parallel group trial of efficacy and morbidity. Neurourol Urodyn, 2016. 35(4): p. 522-7. 
4. 
Gezginci, E., et al., Three Distraction Methods for Pain Reduction During Cystoscopy: A 
Randomized Controlled Trial Evaluating the Effects on Pain, Anxiety, and Satisfaction. J Endourol, 
2018. 32(11): p. 1078-1084. 
5. 
Lakhan, S.E., H. Sheafer, and D. Tepper, The Effectiveness of Aromatherapy in Reducing Pain: A 
Systematic Review and Meta-Analysis. Pain Res Treat, 2016. 2016: p. 8158693. 
6. 
Lison, J.F., et al., Transcutaneous Nerve Stimulation for Pain Relief During Office Hysteroscopy: A 
Randomized Controlled Trial. Obstet Gynecol, 2017. 129(2): p. 363-370. 
7. 
Amer-Cuenca, J.J., et al., Pain relief by applying transcutaneous electrical nerve stimulation 
(TENS) during unsedated colonoscopy: a randomized double-blind placebo-controlled trial. Eur J 
Pain, 2011. 15(1): p. 29-35. 
8. 
Irwin, D.E., et al., Population-based survey of urinary incontinence, overactive bladder, and other 
lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol, 2006. 50(6): p. 
1306-14; discussion 1314-5. 
9. 
Nitti, V.W., Botulinum toxin for the treatment of idiopathic and neurogenic overactive bladder: 
state of the art. Rev Urol, 2006. 8(4): p. 198-208. 
10. 
Nitti, V.W., et al., Durable Efficacy and Safety of Long-Term OnabotulinumtoxinA Treatment in 
Patients with Overactive Bladder Syndrome: Final Results of a 3.5-Year Study. J Urol, 2016. 
196(3): p. 791-800. 
11. 
Dmochowski, R., et al., Efficacy and safety of onabotulinumtoxinA for idiopathic overactive 
bladder: a double-blind, placebo controlled, randomized, dose ranging trial. J Urol, 2010. 184(6): 
p. 2416-22. 
12. 
Vance, C.G., et al., Using TENS for pain control: the state of the evidence. Pain Manag, 2014. 
4(3): p. 197-209. 
13. 
Sluka, K.A. and D. Walsh, Transcutaneous electrical nerve stimulation: basic science mechanisms 
and clinical effectiveness. J Pain, 2003. 4(3): p. 109-21.