Previously Implanted Pudendal Nerve Stimulation
Phase: NA
Conditions: Urinary Retention, Underactive Bladder
Sponsor: University of Michigan

 
Previously Implanted Pudendal Nerve SƟmulaƟon 
 
NCT04473469 
 
Date of IRB Approval: May 13, 2021 

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Previously Implanted Pudendal Nerve Stimulation Study 
 
 
 
 
University of Michigan IRBMED 
 
 Protocol HUM00180124 
 
 
 
 

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Table of Contents 
1. Study Summary ...................................................................................................................................... 4 
1.1 Background and Significance ........................................................................................................ 4 
1.2 Objective ........................................................................................................................................... 6 
1.3 Specific Aims .................................................................................................................................... 6 
1.4 Primary Outcomes ........................................................................................................................... 6 
1.5 Secondary Outcomes ..................................................................................................................... 6 
1.6 Investigative Team .......................................................................................................................... 6 
2. Research Procedures ........................................................................................................................... 6 
2.1 Pre-study Surveys ........................................................................................................................... 6 
2.2 Daily Diaries ..................................................................................................................................... 7 
2.3 Experimental Test Session ............................................................................................................ 7 
2.4 Survey Only Option ......................................................................................................................... 8 
2.5 Patient Timeline ............................................................................................................................... 9 
3. Study Statistics and Data Analysis Plan ............................................................................................ 9 
3.1 Sample Size ..................................................................................................................................... 9 
3.2 Data Analysis Plan .......................................................................................................................... 9 
3.2.1 Bladder Excitation .................................................................................................................. 10 
3.2.2 Strength-Duration Curves ..................................................................................................... 10 
3.2.3 Selectivity Index ...................................................................................................................... 10 
3.2.4 Leak Point Pressure ............................................................................................................... 10 
4. Study Recruitment ............................................................................................................................... 10 
5. Study Population .................................................................................................................................. 11 
5.1 Inclusion Criteria ............................................................................................................................ 11 
5.2 Exclusion Criteria ........................................................................................................................... 11 
6. Study Sites ............................................................................................................................................ 11 
7. Informed Consent ................................................................................................................................ 11 
8. Waiver of Documentation of Informed Consent .............................................................................. 12 
9. Confidentiality of Data ......................................................................................................................... 12 
10. Data Safety and Monitoring ............................................................................................................. 12 
10.1 Data Safety and Monitoring Plan .............................................................................................. 13 
10.2 Severity ......................................................................................................................................... 13 
10.3 Serious Adverse Event ............................................................................................................... 13 

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10.4 Termination of Subjects .............................................................................................................. 14 
10.4.1 Subject Decision ................................................................................................................... 14 
10.4.2 Investigator Decision ........................................................................................................... 14 
11. Protection of Human Subjects ......................................................................................................... 14 
11.1 Potential Benefits of This Research ......................................................................................... 14 
11.1.1 Potential Benefits to Society ............................................................................................... 14 
11.1.2 Potential Benefits to Participants ....................................................................................... 14 
11.2 Risks to Human Subjects ........................................................................................................... 15 
11.2.1 Potential Risks and Protection Against Risks .................................................................. 15 
11.2.2 Identifying Information ......................................................................................................... 15 
11.2.3 Clinical Catheters ................................................................................................................. 15 
11.2.4 Electrical Stimulation ........................................................................................................... 15 
11.2.5 Reasonableness of risks ..................................................................................................... 15 
12. Research Costs ................................................................................................................................. 16 
13. Investigational Drug ........................................................................................................................... 16 
14. Investigational Device ....................................................................................................................... 16 
15. Marketed Drugs/Device .................................................................................................................... 16 
16. Additional Requirements .................................................................................................................. 16 
16.1 Biosafety ....................................................................................................................................... 16 
16.2 Point of care testing .................................................................................................................... 17 
16.3 Tissue procurement .................................................................................................................... 17 
16.4 Clinical research unit ................................................................................................................... 17 
16.5 Nurse or student nurse research .............................................................................................. 17 
16.6 Pregnant women and newborns ............................................................................................... 17 
References ................................................................................................................................................ 17 
 
 
 
 

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1. Study Summary 
1.1 Background and Significance 
In general, primary bladder complaints include an inability to maintain urine in the bladder or a 
constant feeling of needing to empty (incontinence and overactive bladder (OAB)) and an 
inability to effectively empty the bladder (underactivity, voiding dysfunction). A significantly 
greater focus in healthcare management and bladder study has been placed on problems with 
maintaining urine in the bladder, likely due to discomfort with and social stigmas of incontinence. 
However, underactivity affects a similarly high percentage of the population and can lead to 
significant conditions including urinary tract infections [1] and urinary retention-driven 
incontinence and OAB, impacting quality of life [2]. Underactive bladder is a symptom often 
indicating detrusor (bladder muscle) underactivity (DUA) and results in prolonged urination and 
urinary retention [2]. These effects may also be due to bladder outlet obstruction (BOO), such 
as for an enlarged prostate, making DUA and BOO challenging to differentiate [3]. The specific 
prevalence of DUA is not known as a wide range has been reported, including 9-28% of men 
under 50, up to 48% of older men [2], [3], and 12-45% of older women [3]. DUA is common for 
cases of damage to or problems with the nervous system, including Parkinson disease, multiple 
sclerosis, and peripheral neuropathies like Guillain-Barré syndrome [2], [3]. Other factors with 
an unclear relationship to DUA include reduced mobility, colorectal dysfunction, various 
medications, and menopause in women [2]. DUA affects tens of millions of Americans, and is 
expected to increase in prevalence as the population ages. 
Many animal studies have demonstrated bladder excitation in response to electrical stimulation 
of pudendal nerve fibers [4]–[7]. Initial studies focused on the use of cuff electrodes to stimulate 
the entire pudendal nerve. Stimulation frequencies within 20-33 Hz are generally micturition-
selective while lower frequencies like 3-10 Hz activate the continence circuit, though there can 
be variation within and across experiments which may depend on nerve activation efficacy. 
Studies have obtained selective activation of micturition through several means, including 
stimulating within the urethra [8], [9] or on distal pudendal branches originating from proximal or 
distal regions of the urethra [10], [11]. Penetrating electrodes within the pudendal nerve [12] or 
spinal roots [13] have been used to selectively activate micturition-driving neurons. Most of 
these studies have focused on exciting the bladder. Only a few have reported clinically-relevant 
bladder emptying [10]. A primary factor in this limited output is the effect of anesthesia, which 
can depress synaptic transmission in spinal circuits and/or maintain sphincter closure or urethral 
tone, depending on the agent used [14]. In general, these studies are performed in rats and 
cats, although other species like mice, pigs and non-human primates have been used 
occasionally. Each of these animals has similar lower urinary tract physiology and primary 
neural control through pudendal, pelvic, and hypogastric nerves [15] and are accepted as 
models for human anatomy and physiology. 
In contrast to animal studies, clinical exploration of pudendal neuromodulation for voiding has 
been limited. Thanks to the pudendal-driven micturition circuit originating within the urethra, 
stimulation with catheter-mounted electrodes has been performed in several pilot clinical 
studies, though the effects are marginal or only explored in a limited fashion [16]–[18]. This 
catheter stimulation approach is an in-clinic tool that is not feasible for at-home use by patients, 
though it allows for patient screening. One study has shown that it is possible to elicit bladder-
excitation responses with an electrode inserted percutaneously near the pudendal nerve, 
however the effects were again marginal due in part to the limited opportunity to explore 

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stimulation paradigms and a lack of nerve-electrode visualization [19]. A recent modeling study 
suggested that it is possible to selectively activate different fascicles with a multi-contact cuff 
placed on the pudendal nerve [20]. While cadaver dissections suggested the surgical feasibility 
of cuff electrode placement to accomplish this selective stimulation [21], the invasive nature of 
the cuff electrode placement surgery has prevented validation of this computational model.   
Sacral neuromodulation (SNM) is a standard clinical treatment. FDA approval was granted for 
the Medtronic Interstim implantable neurostimulator over 20 years ago [22], and over 200,000 
people worldwide have been implanted. The Interstim system consists of an implantable pulse 
generator (IPG) and a stimulation lead. The lead consists of helical-coiled, insulated wires that 
terminate in four ring electrodes near the tip. The Interstim lead has barbs, or tines, along the 
distal end to provide anchoring and limit migration. For an initial evaluation phase (“stage 1 
implant”), the stimulation lead is placed through the third sacral foramen, generally using 
fluoroscopy, and externalized percutaneously to a stimulator worn on the waist [23]. During 
implant, anal bellows and/or patient sensations are typically used to determine relative nerve 
activation for different stimulation amplitudes and electrode combinations. If the patient has had 
sufficient improvement in symptoms (generally > 50%) after a 2- or 3-week observation period, 
the IPG is implanted in the lower back and connected to the stimulation lead, leaving a fully-
implanted system (“stage 2 implant”). Externally, a programmer can communicate with the IPG 
to monitor or modulate stimulation. Stimulation can be delivered bipolar between any pair of the 
four electrodes or monopolar between one electrode and the IPG. Stimulation with the Interstim 
IPG is at a continuous 15 Hz frequency, which differs from the frequencies tested extensively in 
preclinical studies. 
Since 2005, a few clinicians worldwide have started placing the Interstim lead at the pudendal 
nerve [19], [24], [25]. This is often done in patients who failed traditional SNM or who have 
concurrent pelvic symptoms [26]. The clinical steps for this pudendal nerve implant procedure 
follows the steps for SNM, in an off-label use, with fluroscopy and external anal sphincter (EAS) 
electromyogram (EMG) used to determine the proximity of the lead to the pudendal nerve [27], 
[28]. Patients at the University of Michigan health system who have previously received the 
Interstim at the pudendal nerve offer an opportunity to further study how stimulation of this nerve 
can drive bladder responses.  
Stimulation of the pudendal nerve is also a promising minimally invasive solution for the 
mitigation of stress urinary incontinence (SUI). SUI is a form of incontinence in which undesired 
urination occurs in association with physical exertion. SUI profoundly affects quality of life [29] 
and is prevalent in approximately 13% of women aged 19-44 years and 22% of women aged 
45-64 years [30].  There are a number of therapies and treatments for SUI [31], including 
conservative measures and minimally invasive options with varying and limited efficacy [32]. 
Pudendal nerve stimulation may help maintain urethral closure during events that cause SUI, 
such as coughs, however it not been studied directly in patients. 
Thus the goal of this study is to learn more about pudendal nerve stimulation with the patients 
who were previously implanted. These patients will undergo a standard clinical cystometrogram 
in which the bladder is filled to different volumes. Stimulation will be applied at different 
frequencies and during some periods when patients simulate SUI conditions. After the test 
session, the IPG parameters will be set to their normal clinical settings. We will collect surveys 
of patient pelvic organ function and have the participants complete a brief pelvic organ function 

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survey in the days before and after the study day. This study is not studying or establishing the 
efficacy of the Interstim system at the pudendal nerve. 
1.2 Objective 
The goal of this study is to examine the response of the bladder and urethra to different 
pudendal nerve stimulation frequencies, by studying previously-implanted patients. 
1.3 Specific Aims 
The aims of this study are to: 
• 
Specific Aim 1: Determine the bladder’s response to different pudendal nerve stimulation 
parameters in an acute setting. 
• 
Specific Aim 2: Determine the change in urethral leak point pressure (ULPP) with pudendal 
nerve stimulation 
1.4 Primary Outcomes 
The primary outcome measure in this study is an evoked bladder contractions of at least 20 
centimeters of water (cmH2O) in at least 50% of participants. 
1.5 Secondary Outcomes 
1) Selective stimulation of pudendal nerve branches for external urethral sphincter closure 
determined by comparing sensor recordings from distal pudendal nerve branches. 2) 
Measurement of effect of selective PNS on urethral leak point pressure (ULPP) using PNS 
configured for external urethral sphincter selectivity.  
1.6 Investigative Team 
Tim Bruns, PhD, is an Associate Professor of Biomedical Engineering. He leads a research 
group that develops interfaces with the peripheral nervous system to restore function while 
focusing on autonomic organs like the bladder. He has over ten years of experience in studying 
neuromodulation for bladder control, including preclinical feline studies at the pudendal nerve 
and dorsal root ganglia and pilot clinical studies investigating intraurethral and genital nerve 
stimulation. At the University of Michigan, he was PI on a completed clinical study investigating 
skin-surface neuromodulation for female sexual dysfunction (HUM00101713). Dr. Bruns is PI 
with Dr. Gupta on a study to prospectively examine new patients receiving an Interstim IPG at 
the pudendal nerve (HUM00165005). 
Priyanka Gupta, MD, is an Assistant Professor of Urology. She has extensive training in the 
use of neuromodulation for bladder conditions. In her clinical practice she regularly uses sacral 
neuromodulation, posterior tibial nerve stimulation, and pudendal neuromodulation to improve 
the bladder symptoms of her patients. Dr. Gupta is the only clinician at the University of 
Michigan implanting Interstim IPGs at the pudendal nerve. Dr. Gupta is the clinical lead 
investigator on a study with Dr. Bruns to prospectively study new patients in whom she implants 
stimulators at the pudendal nerve (HUM00165005) and previously participated in 
HUM00101713. 
2. Research Procedures 
We will conduct the proposed study in accordance with the requirements of the University of 
Michigan Medical School Institutional Review Board (IRBMED). All study visits will be conducted 
at University of Michigan Health System locations.  
2.1 Pre-study Surveys 

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Once enrolled in the study, participants will complete surveys to assess their pelvic organ 
function. The participants will five complete clinically-validated surveys on: 
1 
Bladder health: American Urological Association Symptom Index (AUASI) also called 
International Prostate Symptom Score (IPSS) [33], [34] 
2 
Bladder health: Michigan Incontinence Symptom Index (M-ISI) [35] 
3 
Sexual function: Female Sexual Function Index short form (FSFI-6) for women [36] 
and the International Index of Erectile Function (IEEF-5) also called Sexual Health 
Inventory for Men (SHIM) for men [37], [38] 
4 
Bowel function: Colorectal-Anal Distress Inventory 8 (CRAD-8) [39] 
5 
Pelvic pain: Female GenitoUrinary Pain Index (FGUPI) for women and Male 
GenitoUrinary Pain Index (MGUPI) for men [40].  
The AUASI and M-ISI surveys were already part of the normal clinical care for these patients 
before they received the implant and the F/MGUPI are sometimes also given already. All 
surveys will be given to the participants during this study, even if participants have completed 
any of them previously. Participants will also complete a questionnaire on demographics. All of 
these surveys are loaded in section 29 of the IRB application. Surveys will be completed by 
phone, on paper, either in person, and/or mailed to participants before study visits, and/or 
online, through REDCAP or a similar, clinically approved interface.  
2.2 Daily Diaries 
From two days before until two days after the study visit (five total days), participants will 
complete a pelvic function diary (included as Daily Diary in section 44.1). Observations in these 
diaries will be added to the research data set for each participant. 
2.3 Experimental Test Session 
In the primary part of this study, participants will visit the clinic to undergo a cystometrogram 
(bladder filling) in a urodynamics suite. This test will occur at the University of Michigan main 
hospital or a local UMHS clinic, as determined by the clinical schedule, in a urology cystometry 
suite. Prior to the test, women capable of becoming pregnant will undergo a urine pregnancy 
test to detect pregnancy. A research staff member (i.e. study investigator/coordinator/research 
staff) will administer the test by providing participants with a specimen cup. Participants will then 
provide a urine sample; a research staff member will read the results by placing a dip stick 
inside the specimen cup. This test will be covered by the research study and clinical staff will 
obtain the results.  
Patients will be situated for a normal cystometrogram, in a reclining position as shown in Figure 
1 Top (from [41]), or in an upright sitting position. It is standard clinical practice to offer patients 
an antibiotic right before the cystometrogram. The antibiotic pill will be provided by and 
administered by the clinical staff. Clinical staff will insert standard urodynamic catheters into the 
urethra, bladder, and bowel (or vagina), and place standard urodynamic EMG surface 
electrodes by the external anal sphincter and perineal region, as done during the standard 
stage-1 implant surgery. The primary urethra catheters will be a standard clinical-use Covidien 
Manoscan manometry catheter, to provide high-resolution urethra pressure data [42], [43], and 
a standard urodynamics catheter for infusing fluid into the bladder (2 urethra catheters in total). 
If the manometry catheter is unavailable one or two standard urodynamics catheters may be 
used to measure proximal and distal urethra pressures. At an empty bladder, thresholds to 
activate each of the distal catheter sensors will be determined for each electrode to generating a 

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standard strength-duration response curve [44] for each electrode. Warm saline will be used to 
fill the bladder (~30-50 mL/min) through the bladder catheter until the participant just perceives 
filling. This is a standard clinical step in a cystometrogram, using a standard clinical 
urodynamics instrument. Normal cystometrograms continue infusion until voiding (Figure 3 
Bottom, from [41]), however stopping at a not-full state will allow for the assessment of 
stimulation effects on the bladder. Various stimulation paradigms will be applied via the 
implanted neurostimulator until stimulation-driven voiding occurs or the participant expresses a 
very strong desire to void. At that point, the patient will be allowed to void and/or residual saline 
will be removed from the bladder via the bladder catheter. Approximately half of patients 
normally do not void around the catheter during a cystometrogram. For any participant like this, 
they will have the catheters removed and will empty their bladder on to a void scale or into a 
toilet. This sequence will be repeated up to three times.  
At two time points within a cystometrogram, the urethral leak point pressure (ULPP) may be 
measured during Valsalva and/or forceful coughing. This will occur after infusing saline into the 
bladder to an intermediate volume(s) below the sensation of fullness and then pausing. Urethral 
leakage may not be observed; however, urethral pressures will be recorded and compared to 
pressures during pudendal nerve stimulation.  If leakage is observed, an equal amount of saline 
may then be reinfused.  Pudendal nerve stimulation will be turned on to a stimulation paradigm 
for maximum EUS activation at a comfortable level, for a maximum of a 60-second pulse train 
while the ULPP measurement is repeated using Valsalva and/or forceful coughing.  The saline 
infusion will then be resumed until the participant perceives fullness and then will be stopped. 
Leak point pressure will be again assessed without and then with pudendal nerve stimulation as 
before.  Each assessment of leak point pressure may be performed with stimulation on and then 
repeated with stimulation off, or with stimulation off and then repeated with stimulation on.  The 
ULPP testing may be repeated at the investigator’s discretion and participant’s agreement.  The 
ULPP measurements and stimulation-driven voiding experiments may be integrated in a fill 
sequence, such that both assessments may be completed at the same fullness sensation 
bladder volumes, using the respective stimulation parameters for each assessment. 
All stimulation parameters used will be within the normal hard-coded limits of the IPG. We will 
not be testing new paradigms that the IPG is not capable of performing. We may vary the 
combination of lead contacts that are active, the pulse width of applied stimulation (i.e. duration 
of each pulse), the frequency of applied pulses (i.e. cycles per second), and the amplitude (i.e. 
volts or milliamps) of the applied stimulation. If any stimulation paradigms are perceived as 
uncomfortable by the participant, they will be stopped and alternate paradigms will be 
attempted. Once testing is completed, the IPG will be returned to the clinically-determined 
stimulation settings for the patient. 
2.4 Survey Only Option 
As part of the research procedure, potential study participants have the option of completing the 
surveys only. This optional study, HUM00169761 is a survey only study conducted by Dr. Gupta 
and colleagues. 
During the initial recruitment phone call, participants will be informed of both studies and given 
the option to participant in one or both studies. In the event a participant is only interested in 
completing the surveys, the study coordinator or a clinical team member will consent the 
participant and administer the surveys. For participants interested in the experimental test 
session, the study coordinator will proceed with consenting and scheduling the study visit. 

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2.5 Patient Timeline 
Figure 2 gives a summary 
of the timeline for each 
study participant. 
3. Study Statistics and 
Data Analysis Plan 
3.1 Sample Size 
We plan to recruit at least 
10 of Dr. Gupta’s patients. 
This sample size is 
comparable to prior human 
subject studies stimulating 
the pudendal nerve or its 
branches (N=10 pudendal 
implant after sacral implant 
[45], N=12 cutaneous 
genital nerve [46], N=21 
percutaneous genital 
nerve [47], N=30 pudendal 
versus sacral implant [25]). 
Dr. Gupta has implanted 
more than fifteen patients 
as part of her clinical 
duties at the University of 
Michigan. We will reach 
out to all of these patients 
but do not expect all to 
participate. 
3.2 Data Analysis Plan 
The primary outcome 
measures in this study will 
be evoked bladder 
contractions of at least 20 
centimeters of water 
(cmH2O) during nerve 
stimulation in at least 50% 
of participants. The 
secondary outcome 
measure will be 
identification of ULPP with 
and without stimulation. 
Results of the patient 
surveys (demographics, pelvic organ function surveys as defined above) and voiding diaries will 
be compared to our ability to stimulate and cause bladder excitation and ULPP measures to 
determine if there are any trends or relationships to participant characteristics.  
 
 
Figure 1. Top: Standard cystometrogram (CMG) setup, with a pump to 
infuse saline, bladder and rectal pressure catheters and sensors, and 
a flowmeter for voiding. From [37]. Our study will add one or more 
urethra catheters, anal sphincter and perineal EMG, and will not use 
fluoroscopy. Bottom: Standard CMG outputs, with in-bladder pressure 
(Pves; blue), abdominal (rectal) pressure (Pabd; red), bladder muscle 
pressure (Pdet=Pbes-Pabd; green), EMG, urine flow (black), and 
volume (infused, voided). From [37].  

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3.2.1 Bladder Excitation 
The primary metric of successful 
bladder excitation will be a target 
evoked bladder contraction of at 
least 20 cmH2O during the 
cystometrogram in at least 50% of 
participants. Additionally, any 
stimulation-driven or participant-
driven voiding efficiency will be 
calculated as [volume voided] / 
[volume voided + residual 
measured still in bladder]. 
3.2.2 Strength-Duration Curves 
For each electrode strength-
duration curves will be created [44]. These data plots will show the minimum stimulation 
amplitudes that recruit each distal sensor location, for each tested stimulus pulsewidth. The 
response curves will be compared within and across participants for each distal sensor location, 
to see if there are trends, and will be fitted with standard strength-duration equations [48].  
3.2.3 Selectivity Index 
For a given stimulation electrode (among the four on an implanted stimulation lead), a 
Selectivity Index (SI) will be calculated for each catheter or electromyogram sensor recording 
from distal pudendal nerve branches. This includes sensors in the proximal urethra (proximal 
perineal branch - PPB), distal urethra (distal perineal branch - DPB), perineal EMG (PEMG), 
and anal EMG (ischeal rectal nerve - IRN).  
𝑆𝐼𝑛𝑒𝑟𝑣𝑒 𝑋=
𝑋
𝑃𝑃𝐵+ 𝐷𝑃𝐵+ 𝑃𝐸𝑀𝐺+ 𝐼𝑅𝑁 
The PPB and DPB are the maximal intraurethral pressures measured at proximal and distal 
urethra catheter locations. PEMG is the maximum, normalized perineal EMG response. IRN is 
the maximum, normalized rectal nerve response. This SI will be used to determine whether any 
stimulation electrode combinations have selective recruitment of any individual pudendal nerve 
branches (SI > 0.67, for example). The SI calculation may be modified in some patients, as 
necessary, for factors such as the presence of a short urethra that only allows for a single 
intraurethral pressure measure (female urethras < male urethras in length) and/or an inability to 
place all EMG sensors. The SI for each electrode will be calculated to help us understand the 
relationship between the implanted electrodes and the pudendal nerve, and not as a measure of 
any sort of stimulation efficacy. 
3.2.4 Leak Point Pressure 
The ULPP will be determined as the maximum urethra pressure during any Valsalva and 
forceful coughing events from the urethra catheter sensors. The ULPP during pudendal nerve 
stimulation will be compared to the ULPP without stimulation at each volume level tested. 
4. Study Recruitment  
We will recruit patients from Dr. Gupta’s clinical practice who have previously received a 
pudendal nerve implant. Generally, these patients are very willing to help, as they failed a series 
 
Figure 2. Per-participant study timeline. The interval between 
patient surveys and the test session is not fixed. 

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of prior conservative treatments before receiving the pudendal nerve implant. Dr. Gupta or her 
clinical staff will identify patients from her clinical history chart review and will provide their 
contact information to the study coordinator. The study coordinator will send a letter to the 
patient and follow up with a phone call to recruit the patient. Patient information will not be 
shared outside of direct clinical conversations or inquiries by the study coordinator. The study 
coordinator will maintain regular contact with each participant, reminding them of the 
appointment to help retain subjects. 
5. Study Population 
We will recruit 10 participants for this study. If greater than 10 patients are willing to participate 
then we will recruit as many as are willing. We expect that 90% of participants will be women 
(N=9) and 10% men (N=1), based on the demographics of the patients in whom Dr. Gupta has 
performed this procedure. Within that, we anticipate 9 Caucasian (8 women; 1 men) of which 
none will be Hispanic and 1 African American (woman). We will not decline any participants 
based on their group membership.  
5.1 Inclusion Criteria 
• 
Previously received an implanted neurostimulator at the pudendal nerve. 
• 
Adult (18 or older), capable of providing own informed consent and communicating clearly 
with research team. 
• 
Capable of speaking, reading, and understanding English, as all study questionnaires are 
standardized assessments only available in English. 
• 
Capable of attending the experimental session. 
5.2 Exclusion Criteria 
• 
Pregnant or planning to become pregnant during study. If a woman of child-bearing potential 
wishes to participate in this study, they will be pre-screened with a test to detect pregnancy. 
• 
Currently has a urinary tract infection (UTI). 
• 
Currently has or tested positive in the last 14 days for COVID-19, or is symptomatic for 
COVID-19. 
• 
Unwilling to allow de-identified data to be stored for future use or shared with other 
researchers.   
6. Study Sites 
All research activities will be performed at University of Michigan Health System locations, also 
known as Michigan Medicine. All participants will be normal patients at Michigan Medicine. The 
study visit will be performed at the main Ann Arbor Michigan Medicine hospital or at a nearby 
satellite Michigan Medicine location, as scheduling permits. These sites are normal clinical 
sites for studies of this nature. Dr. Gupta has full clinical privileges at these locations and sees 
patients across these locations. All members of the research team hold primary appoints within 
the University of Michigan Medical School. Data analysis will occur in the research lab of Dr. 
Bruns, which is in the University of Michigan North Campus Research Complex (NCRC), which 
is primarily filled with Michigan Medicine research institutes, research labs, and core facilities. 
NCRC is a short drive or bus ride from the main Michigan Medicine hospital and not far from 
other Michigan Medicine sites such as in Livonia and Brighton. 
7. Informed Consent  
Full, written or electronic consent will be obtained by Dr. Gupta or the study coordinator. For 

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participants who are available in-clinic prior to the test session, a normal recruitment and 
consent by Dr. Gupta or the study coordinator will be performed. Typically, Dr. Gupta will 
introduce an eligible patient to the study coordinator who will then continue recruitment and 
discussion of the study, if necessary, and will then obtain informed consent. Otherwise, Dr. 
Gupta will perform the consent herself. Typically, the informed consent document will be sent to 
a participant prior to the test session for their review.  
The research team will adopt an optional electronic informed consent procedure using SignNow. 
This option will be our preferred method for obtaining consent. Once Dr. Gupta identifies an 
eligible participant, she will notify the study coordinator who will reach out to the participant over 
the telephone to discuss the study and either obtain consent or schedule a time to call the 
participant after they have had a time to review the consent form. In the instance a potential 
participant does not have access to the internet or is not inclined to use the internet, research 
staff will revert back to using the standard procedures for obtaining consent on paper during the 
first study visit. 
Additionally, during the consenting process the study coordinator will explain to all potential 
participants the option to participate in the experimental test session, complete the surveys only 
or both. Should a participant only want to complete the surveys, either the study coordinator or a 
clinical team member on HUM00169761 will consent the participant and send the surveys.  
8. Waiver of Documentation of Informed Consent  
We are seeking a waiver of documentation of informed consent. There are a set of surveys that 
get completed at the start of the study. There are also daily diaries for the participants to 
complete in the days prior to the session. It is likely that participants will not be in the clinic for 
normal healthcare prior to their visit for the test session. It would be simplest to send the 
participants the surveys and diary, along with the consent form for review, if they agree to take 
part in the research during the recruitment process with the study coordinator. This means, 
though, that participants may be completing surveys and diaries before formally signing the 
consent form. Then we will have participants sign the full consent at the start of the test session. 
9. Confidentiality of Data 
Proper, standard procedures will be followed to protect participant identities. Patient information 
will be saved on a secure server and password protected. Experimental data will have coded 
references to each participant and will be stored separately on a secure M-Box folder. The code 
key will be kept with the patient information. The study coordinator will have access to the 
patient information and code key. The study coordinator's office will have a locked door. Paper 
research records will be stored in a locked cabinet in the study coordinator's office. No patient-
identifying information will be shared outside the research team. 
Additionally, data from HUM00169761 will be keep separate from the data collected for this 
study. In other words, data will not be linked between studies. If a participant takes a survey that 
is part of both studies, then a duplicate will be placed in each record. The two data sets will be 
kept separate so that data for participants who are only in one study are not accidentally 
corrupted or included in the wrong study. 
10. Data Safety and Monitoring 

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10.1 Data Safety and Monitoring Plan  
A full Data and Safety Monitoring Board will not be used for this study as it is a small study with 
minimal risks. Once data collection has begun, Drs. Bruns and Gupta will discuss project 
progression, participant safety, and overall data on a monthly basis via phone, video 
conference, email correspondence, or an in-person meeting. Adverse Events (AEs) will be 
reported promptly to the IRB.  
All research personnel involved in any way in this project will have completed training in the 
protection of human research participants per guidelines issued by the U.S. Department of 
Health and Human Services, Office for Human Research Protection. The protocol will undergo 
review and approval by the IRBMED and other necessary regulatory and oversight entities prior 
to implementation.  
10.2 Severity  
Drs. Gupta and Bruns will grade any Adverse Event signs and symptoms as mild, moderate, 
severe, or life threatening according to the following definitions in Table 1. 
Table 1. Adverse events severity scale. 
Grade 
Definition 
0 
None: 
No adverse event 
1 
Mild: 
Causing no limitation of usual activity with no treatment needed 
2 
Moderate: 
Causing some limitations of usual activities and resolved with 
treatment 
3 
Severe: 
Causing inability to carry out usual activities and requiring 
professional medical attention 
4 
Life Threatening: 
Patient was at immediate risk of death from the event  
5 
Fatal: 
Causing death 
 
10.3 Serious Adverse Event  
Serious Adverse Events (SAEs) will be identified as any adverse event (AE) that: 
• 
Is fatal; 
• 
Is life threatening, meaning the patient was, in the view of the investigator, at  
• 
immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction 
that, had it occurred in a more serious form or progressed, might have caused death; 
• 
Causes a persistent or significant disability or incapacity; 
• 
Requires or prolongs inpatient hospitalization. Inpatient hospitalization will be considered a 
hospitalization if is longer than 24 hours or requires an intervention to treat emergent 
symptomatology (non-diagnostic); 
• 
Is a congenital anomaly or birth defect; 
Other important medical events may be considered SAEs when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 

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intervention to prevent one of the outcomes as listed in this definition. We will report all SAEs to 
the IRBMED, including death, due to any cause which occurs during this study and until 30 days 
after the last participation in the study, whether or not expected and regardless of causality.   
10.4 Termination of Subjects  
10.4.1 Subject Decision 
Subject participation is strictly voluntary and the research strictly knowledge driven; therefore, a 
subject may withdraw from further participation in the study without penalty or harm. Any 
reason(s) the subject may give for terminating his or her participation will be kept confidential. 
We will store the study documents according to the procedures outlined in the Confidentiality of 
Data section of this protocol (Section 9). We will require no further information of the subject and 
the subject will be compensated if they have completed the study visit prior to termination. 
10.4.2 Investigator Decision 
Study personnel (principal investigator, co-investigators, and study coordinator) will be 
authorized to release a subject from further study participation according to the following 
guidelines: 
• 
The researcher believes that it is not in the subject’s best interest to stay in the study. 
• 
Subject becomes ineligible to participate. 
• 
Subject’s condition changes such that he or she needs treatment that is not allowed while 
taking part in the study. 
• 
Subject does not follow instructions from the researchers. 
• 
The study is suspended or canceled. 
Upon termination of a subject, the investigators will ensure the subject is dismissed with any 
study documents to which he or she is entitled, as well as guidance for resuming medications 
safely. Subjects will be compensated if they completed the study visits prior to termination. 
Investigators will require no further obligation or participation from a terminated subject. 
11. Protection of Human Subjects 
11.1 Potential Benefits of This Research  
11.1.1 Potential Benefits to Society 
Bladder dysfunction affects a large percentage of the population, well over 10%, leading to 
significant healthcare impacts. The knowledge gained here will provide key insights into function 
of a primary nerve in the bladder system, potentially leading to improvements in future 
technologies, and will also investigate the potential for directly controlling the bladder with 
pudendal stimulation. Direct pudendal stimulation for bladder voiding has been repeatedly 
studied in animal studies but only limited studies in humans. These patients provide an ideal 
opportunity to explore whether this preclinically validated approach has clinical merit, benefiting 
future candidates for this implant.  Similarly, these patients also provide an opportunity to 
assess whether pudendal nerve stimulation may offer the potential to treat stress urinary 
incontinence through improvements in urethral leak point pressures. 
11.1.2 Potential Benefits to Participants  
Participants will not directly benefit from this study. The findings of the study will not be used to 
modify the healthcare of any patients. Through this study we will gain new knowledge about 
how the pudendal nerve controls the lower urinary tract. This knowledge may benefit future 

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recipients of neurostimulators for pelvic organ function.  
11.2 Risks to Human Subjects 
Potential risks include release of identifying information, infection, and shock or burn due to 
electrical stimulation. 
11.2.1 Potential Risks and Protection Against Risks 
Participants will already have received the neurostimulator implant as part of their clinical care 
and thus all risks inherent to it are separate from what this study will add. 
11.2.2 Identifying Information 
The primary risk of participation in this experimental study is the release of identifying 
information. The potential harm is release of research data leads to temporary embarrassment 
over the need of the patient to require treatment for bladder or other pelvic problems. The 
likelihood of this risk is Rare. Proper, standard procedures will be followed to protect participant 
identities. Patient information will be saved on a secure server and password protected. 
Experimental data will have coded references to each participant, and will be stored separately 
on a secure Box folder. The code key will be kept with the patient information. The study 
coordinator will have access to the patient information and code key. 
11.2.3 Clinical Catheters 
The standard urodynamic urethra and rectal catheters and manometry catheter added during 
the cystometrogram testing have a risk of temporary infection (e.g. urinary tract infection), 
similar to any foreign object being placed in the body, even if temporarily. The likelihood of this 
Risk is Infrequent. Standard sterilization and handling techniques will be used to mitigate 
against the risk of urinary tract infections or other infections due to placement of catheters 
during testing. Additionally, research participants will be offered an antibiotic medication before 
the testing begins to mitigate against any risk of infection.  
11.2.4 Electrical Stimulation 
During the cystometrogram testing of stimulation from the implanted stimulator, the electrical 
current may be tested over a range of amplitudes and pulse widths, providing a range of total 
charge delivered to the participant. Side effects related to higher currents, such as muscle 
contractions or discomfort, may occur, but are known to be reversible by either reducing the 
amplitude of the stimulation or stopping the stimulation entirely. Whenever using electricity to 
stimulate tissue, there is also the possibility of a shock hazard, including an electrical burn. 
However, only electrical stimulators approved by the United States Food and Drug 
Administration will be used in this study and all stimulation parameters will be within the limits of 
the stimulator. Therefore, the risk of tissue damage or electrical shock during the electrical 
stimulation is minimal. 
11.2.5 Reasonableness of risks 
The risks of study participation are minimal beyond risks that patients have undergone as part of 
their normal clinical care prior to and including the implant of the neurostimulator. Release of 
personal information and risks of infections due to catheter placement are all overlapping in 
scope and occurrence with activities that happen during normal clinical care of these patients. 
While the participants may not normally undergo a cystometrogram test, it is a standard clinical 
tool that is commonly used to assess bladder problems. With these subject's participation, we 
anticipate greatly increasing the knowledge of a critical nerve's anatomy and ability of a 3rd line 
treatment (implantable neurostimulator) to interact with it. This study may lead to improved 

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future treatments that will improve upon the treatment that patients like these are able to 
receive.  
12. Research Costs 
All research-specific costs will be covered by NIH award OT2OD028191 and 
 
, under direction of study Investigators Tim Bruns and Priyanka Gupta. Study 
participants will not be billed for any research study procedures, such as the cystometrogram 
testing or pregnancy test, if required. 
13. Investigational Drug 
There is no involvement of any investigational drug in this study. 
14. Investigational Device 
There is no involvement of any investigational device in this study. 
15. Marketed Drugs/Device  
The Medtronic Interstim implantable neurostimulator has no restrictions on its availability. It is 
commonly used at Michigan Medicine and worldwide for regulatory-approved implantation at a 
sacral nerve or at the off-label pudendal nerve location to be used in this study. We have 
discussed a related pudendal nerve project (HUM00165005) with the University of Michigan 
MICHR IND/IDE Investigator Assistance Program (MIAP), which provides comprehensive 
regulatory support to U-M investigators involved in regulated clinical research. In 
HUM00165005, new pudendal implant patients undergo the same cystometrogram test as here, 
as well as additional testing. MIAP's assessment was that study is not testing the safety or 
efficacy of the device (Interstim) and it also does not have a control arm. This is also true of this 
study, HUM00180124. In both studies we are testing our ability to stimulate and map the nerve. 
For HUM00165005 the MIAP assessment was that there is not a requirement for an 
Investigational Device Exemption (IDE), which is also our expectation for HUM00180124. The 
U-M IRB consults with MIAP when determining final IDE requirements. In the unlikely event that 
the IRB reverses this no-IDE assessment we will promptly work with MIAP to receive an IDE 
from the FDA. 
A Manoscan ESO High-Resolution Manometry system will be used in this study. 
Covidien/Medtronic is the supplier. The manufacturer is Given Imaging, which is a company that 
was was purchased by Medtronic. The device provides high-resolution pressure measurements 
along the length of its catheter. It is a standard clinical diagnostic system for measuring 
esophageal pressure profiles and other measures in the gastrointestinal tract. The Michigan 
Medicine GI Lab has a Manoscan of its own for this purpose. In this study we will use a 
pediatric-sized Manoscan catheter to obtain high-resolution pressure data in the urethra and 
bladder of participants. The pediatric catheter is the same size as standard clinical-use urethra 
catheters. This manometry system will significantly improve our ability to map pudendal nerve 
control over the urethra in the participants. This system is purely being used for diagnostic 
purposes. 
16. Additional Requirements 
16.1 Biosafety 
This research does not involve the use of infectious agents, recombinant DNA, or gene transfer. 

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16.2 Point of care testing 
This research does not involve laboratory testing of the patient. 
16.3 Tissue procurement 
This research does not involve use of redundant/residual biological specimens. 
16.4 Clinical research unit 
This research does not involve the use of the Michigan Clinical Research Unit (MCRU). 
16.5 Nurse or student nurse research 
No one participating in this research study is a nurse or student nurse. 
16.6 Pregnant women and newborns 
This research does not involve laboring women and/or newborns. 
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