AMPLIFY: Amplifying Sensation in Underactive Bladder
Phase: NA
Conditions: Urinary Bladder, Underactive
Sponsor: Duke University

Official Title: AMPLIFY: Amplifying Sensation in Underactive Bladder 
Protocol#: Pro00106457 Version 1.17 
NCT#: NCT04516434 
Document Date: 04/10/2024  

St a n d ar d Rese arc h S u m m ar y
P ur p o s e of t h e St u d y
O bj e cti v es & h y p ot h es es t o b e t est e d
T h e o v er all o bj e cti v e of t hi s st u d y i s t o i m pr o v e l o w er uri n ar y tr a ct s y m pt o m s ( L U T S ) i n a d ult 
n e ur ol o gi c all y -i nt a ct w o m e n wit h u n d er a cti v e bl a d d er t hr o u g h el e ctri c al sti m ul ati o n of bl a d d er s e n s or y 
n er v e s or ur et hr al s e n s or y n er v e s. T h e fir st pri m ar y e n d p oi nt s ar e t h at s e n s or y n er v e fi b er sti m ul ati o n t o 
t h e bl a d d er will d e cr e a s e b ot h er s o m e uri n ar y s y m pt o m s d uri n g filli n g a n d e m pt yi n g, sti m ul ati o n t o t h e 
ur et hr a will d e cr e a s e b ot h er s o m e uri n ar y s y m pt o m s d uri n g e m pt yi n g, a n d t h at bl a d d er sti m ul ati o n will 
i n cr e a s e bl a d d er s e n s ati o n d uri n g filli n g a n d e m pt yi n g, a s d et er mi n e d b y o ur l o w er uri n ar y tr a ct s y m pt o m 
q u e sti o n n air e. T h e s e c o n d pri m ar y e n d p oi nt i s t h at s e n s or y n er v e fi b er sti m ul ati o n t o t h e bl a d d er or 
ur et hr a will i n cr e a s e bl a d d er e m pt yi n g d uri n g pr e s s ur e -fl o w st u di e s i n p arti ci p a nt s wit h p o or b a s eli n e 
bl a d d er f u n cti o n. I n a d diti o n t o t h e s e pri m ar y e n d p oi nt s, w e will al s o o b s er v e s e c o n d ar y e n d p oi nt s t h at will 
b e c o m p ar e d t o p air e d b a s eli n e m e a s ur e m e nt s. S e c o n d ar y e n d p oi nt s i n cl u d e ( a ) i n cr e a s e d bl a d d er or 
ur et hr al c urr e nt p er c e pti o n t hr e s h ol d r el ati v e t o n or m ati v e d at a, ( b ) d e cr e a s e d bl a d d er v ol u m e s at 
c y st o m etri c e n d p oi nt s wit h i ntr a v e si c al ( bl a d d er ) el e ctri c al sti m ul ati o n, a n d ( c ) i n cr e a s e d d etr u s or 
c o ntr a cti o n str e n gt h a n d c o ntr a cti o n d ur ati o n wit h i ntr a ur et hr al el e ctri c al sti m ul ati o n.
B a c k gr o u n d & Si g nifi c a n c e
S h o ul d s u p p ort t h e s ci e ntifi c ai ms of t h e r es e ar c h
T h e st or a g e a n d eli mi n ati o n of uri n e i s r e g ul at e d b y n e ur al cir c uit s i n t h e br ai n a n d s pi n al c or d t o 
c o or di n at e f u n cti o n b et w e e n t h e uri n ar y bl a d d er a n d t h e ur et hr a ( F o wl er et al. 2 0 0 8 ). D uri n g mi ct uriti o n 
( bl a d d er e m pt yi n g ), t h e eli mi n ati o n of uri n e i s f a cilit at e d b y bl a d d er m u s cl e ( d etr u s or ) c o ntr a cti o n a n d 
ur et hr al a n d p el vi c fl o or m u s cl e r el a x ati o n. Uri n e fl o w t hr o u g h t h e ur et hr a al s o a cti v at e s s e n s or y n er v e s t o 
a m plif y bl a d d er c o ntr a cti o n s a n d m ai nt ai n effi ci e nt bl a d d er e m pt yi n g ( J u n g et al. 1 9 9 9, B u m p 2 0 0 0 ). 
I n c o m pl et e e m pt yi n g a n d uri n ar y r et e nti o n o c c ur w h e n t h e s e m e c h a ni s m s ar e di sr u pt e d or p o orl y 
c o or di n at e d.
I n c o m pl et e e m pt yi n g d u e t o u n d er a cti v e bl a d d er i s a p o orl y u n d er st o o d h e alt h c o n c er n t h at 
s y m pt o m ati c all y aff e ct s u p t o 4 0 % of t h e p o p ul ati o n, wit h t h e hi g h e st pr e v al e n c e of s y m pt o m s i n ol d er 
m e n a n d w o m e n  ( J e o n g et al. 2 0 1 2, O s m a n et al. 2 0 1 4 ). D e s pit e t h e hi g h pr e v al e n c e of s y m pt o m s, t h e 
di a g n o si s of a n u n d er a cti v e bl a d d er r e m ai n s l o w d u e t o t h e l a c k of c o n si st e nt t er mi n ol o g y a n d 
st a n d ar di z e d di a g n o sti c crit eri a. T hi s r e s ult s i n d efi ni n g u n d er a cti v e bl a d d er b y a s y m pt o m c o m pl e x t h at 
m a y i n v ol v e r e d u c e d m ot or dri v e ( d etr u s or u n d er a cti vit y ) d uri n g bl a d d er e m pt yi n g a n d / or r e d u c e d s e n s or y 
dri v e d uri n g filli n g a n d e m pt yi n g ( C h a p pl e et al. 2 0 1 5 ). S y m pt o m s e x p eri e n c e d b y p er s o n s wit h 
u n d er a cti v e bl a d d er i n cl u d e n o ct uri a, uri n ar y fr e q u e n c y, ur g e n c y, i n c o nti n e n c e, sl o w str e a m, h e sit a n c y, 
str ai ni n g, a n d s e n s ati o n of i n c o m pl et e e m pt yi n g ( G a m mi e et al. 2 0 1 6, Ur e n et al. 2 0 1 7 ). T h e m o st 
c o m m o n s y m pt o m s ar e n o ct uri a, sl o w str e a m, fr e q u e n c y, h e sit a n c y, a n d t h e i m p a ct of t h e s e s y m pt o m s o n 
q u alit y of lif e i s s u b st a nti al f or m a n y p ati e nt s ( G a m mi e et al. 2 0 1 6, Ur e n et al. 2 0 1 7 ). 
T h e m a n a g e m e nt o pti o n s f or p er s o n s wit h u n d er a cti v e bl a d d er i n cl u d e d o u bl e - v oi d, i nt er mitt e nt s elf -
c at h et eri z ati o n, or p h ar m a c ot h er a p y ( Mi y a z at o et al. 2 0 1 3 ). H o w e v er, t h e s e tr e at m e nt s ar e a s s o ci at e d 
wit h p o or q u alit y of lif e a n d p ati e nt s oft e n f ail t o c o m pl et el y r e s ol v e t h e l o w er uri n ar y tr a ct s y m pt o m s 
( L U T S ). T h er e i s a n e e d t o cl arif y t h e p at h ol o gi c al m e c h a ni s m s u n d erl yi n g u n d er a cti v e bl a d d er t o i m pr o v e 
t h er a p e uti c o ut c o m e s. O n e a p pr o a c h t o cl arif y r e d u c e d s e n s or y dri v e i s t o e v al u at e t h e f u n cti o n al i nt e grit y 
of s e n s or y n er v e s wit h q u a ntit ati v e s e n s or y t e sti n g ( U ki m ur a et al. 2 0 0 4, K e nt o n et al. 2 0 0 7 ). C urr e nt 
p er c e pti o n t hr e s h ol d ( C P T ) t e sti n g d eli v er s el e ctri c al sti m ul ati o n t o a cti v at e n er v e fi b er s t h at e v o k e 
s e n s or y p er c e pti o n, a n d c h a n g e s i n bl a d d er s e n s or y p at h w a y s w er e d e m o n str at e d i n p er s o n s wit h di a b eti c 
d etr u s or u n d er a cti vit y ( L e e et al. 2 0 0 9 ). T h e s e di a g n o sti c t e st s, h o w e v er, h a v e n ot b e e n a p pli e d t o 
n e ur ol o gi c all y i nt a ct a d ult w o m e n wit h u n d er a cti v e bl a d d er a n d m a y pr o vi d e i n si g ht i nt o p at h ol o gi c al 
s e n s or y d y sf u n cti o n.
T h e pr o p o s e d r e s e ar c h will q u a ntif y s e n s or y n er v e s e n siti vit y i n t h e bl a d d er a n d ur et hr a i n a d ult w o m e n 
wit h u n d er a cti v e bl a d d er. W e will t h e n a m plif y s e n s or y n er v e a cti vit y vi a c o nti n u o u s el e ctri c al sti m ul ati o n 
t o i m pr o v e L U T S a s s o ci at e d wit h u n d er a cti v e bl a d d er. C o nti n u o u s dir e ct el e ctri c al sti m ul ati o n of t h e 

bladder or urethra is investigational and not standard clinical practice. However, intravesical  (bladder) 
electrical stimulation has been used in persons with detrusor underactivity (Gladh et al. 2003, Deng et al. 
2017), overactive bladder (Yune et al. 2018), and neurogenic non-obstructive urinary retention (Lombardi 
et al. 2013). Intraurethral electrical stimulation has also been used in persons with spinal cord injury (Yoo 
et al. 2011), as well as in women with urgency urinary incontinence (Pro00084173). Achieving the 
proposed objectives will establish a prognostic marker for rationally guided electrical stimulation in women 
with underactive bladder. Understanding how these mechanisms contribute to impaired emptying in 
underactive bladder will enable the development of novel therapeutics to enhance quality of life.
There are no patents, conflicts of interest, or FDA submissions in the works related to this study.
Design & Procedures
Describe the study, providing details regarding the study intervention (drug, device, physical 
procedures, manipulation of the subject or the subject’s environment, etc.). Discuss justifications for 
placebo control, discontinuation or delay of standard therapies, and washout periods if applicable. 
Identify procedures, tests and interventions performed exclusively for research purposes or more 
frequently than standard of care. Include alternative therapies, concurrent therapies discontinued per 
protocol, risk benefit ratio, and use of tissue/specimens. Discuss monitoring during washout periods if 
applicable. Include brief description of follow-up, if any.
We will only be evaluating adult women in this proposal. Men are excluded from this pilot study due to the 
high incidence of similar symptoms caused to a degree by prostatic hyperplasia and not necessarily an 
underactive bladder. Patients will be screened through Chart Review and on the phone to determine 
eligibility, and if found eligible, will be scheduled for an in-person study procedure visit at the Duke 
Urogynecology Office at Patterson Place, Durham, NC under the supervision of Dr. Cindy L. Amundsen, MD.
Design
Screening: Established patients with underactive bladder will be identified by MaestroCare chart review. 
New patients with underactive bladder will be identified by Duke urogynecologists who see patients at one 
of two urogynecologic offices (Navaho Clinic in Raleigh or Patterson Place in Durham). Providers or study 
staff may hand out a brochure describing the AMPLIFY study, and who to contact. Providers will notify 
study personnel by secure email or MyChart of potential patients who may met the study criteria and 
patient names will be transcribed into a database stored behind an enterprise-grade firewall in a shared 
folder on password protected Duke PIN stations. After the patients have undergone urodynamic testing 
(uroflowmetry, cystometry, pressure-flow) as part of their routine workup, study personnel will review 
urodynamic criteria to see if they meet inclusion and exclusion criteria. If they meet these criteria, patients 
will be contacted by study personnel via phone call to determine their interest in participating in the study. 
If the patient is interested, they will be screened by answering 5 questions from the Lower Urinary Tract 
Dysfunction Research Network Symptom Index-29 (LURN SI-29) (Cella et al. 2019) to determine 
bothersome urinary symptoms. After confirmation of inclusion and exclusion criteria, the participant will be 
scheduled for the in person study procedure.
Electronic informed consent: Electronic informed consent will be collected via REDCap survey on a clinic-
provided portable device. Participants will be asked if they would prefer self-guided or coordinator-led 
electronic informed consent. Study personnel will be available for questions before, during, or after the 
consent. Study personnel will confirm if participants have unresolved questions or concerns. Signed 
electronic informed consent will be emailed by REDCap Auto-Archiver + e-Consent Framework. In the 
event participants are not comfortable with electronic data capture, paper informed consent will be made 
available.
Study procedure visit: Participants will be reminded by phone call or email 48 hours before the study visit 
to withdraw from medications affecting urination per our inclusion criteria. On the day of the visit, 
participants will sign and date the informed consent document and complete a compensation form, LURN 
SI-29 questionnaire survey, and demographics questionnaire survey. Pre-procedure vital signs, point of 
care urinalysis, and a pregnancy test will be obtained. Participants will be excluded with a positive 
pregnancy test or delayed until resolution of infection with a positive urinalysis (per exclusion criteria). If 
participants have negative urinalysis, negative pregnancy test, and meet inclusion/exclusion criteria they 
will undergo current perception threshold (CPT) testing in the bladder and urethra.
Participants will be assigned to the intervention arm based on CPT. CPT data will be analyzed immediately 
by percentage change against normative data to stratify investigational allocation to intravesical (bladder) 
electrical stimulation or intraurethral electrical stimulation (Kenton et al. 2007). The allocation will be as 
follows: 1) if percentage change of urethral CPT > percentage change of bladder CPT then participants will 
receive intraurethral electrical stimulation, 2) if percentage change of bladder CPT > percentage change of 

urethral CPT then participants will receive intravesical electrical stimulation, or 3) if percentage change of 
urethral CPT = percentage change of bladder CPT then participants will receive intravesical stimulation 
when cystometry “first desire to void” > 275ml or intraurethral stimulation when pressure-flow detrusor 
pressure at maximum flow < 30 cmH2O and maximum flow < 10 ml/s. After the investigational session of 
stimulation, participants will undergo post-study urodynamic studies which will include cystometry and 
pressure-flow studies. At the completion of these procedures, participants will be given standard 
urogynecology post urodynamic study instructions. They will also be instructed to complete remotely a 
post-study condition LURN SI-29 questionnaire that will be emailed via RedCap 7 days after the study visit. 
At that time, they will be considered to have completed the study.
Devices: A single Gaeltec electrode catheter will be used to stimulate both the bladder (intravesical) or 
urethra (intraurethral). The Gaeltec catheter will be smaller in diameter than the Neurometer to facilitate 
easier voiding. The Neurotron devices are comprised of a CPT device to generate current and the 
automated paradigms, and a Neurometer catheter to deliver stimulation to the tissues. While the 
Neurotron devices are from the same manufacturer, the CPT device may be used with different electrode 
catheters. Neurotron devices and Gaeltec catheters are commercially available. Everyway Medical 
Instruments Ultra 9000 stimulation device will be used as a backup to the Neurotron CPT device during 
investigational sessions of intravesical and intraurethral stimulation (not CPT) if the Neurotron device 
cannot generate our selected stimulation parameters. The Ultra 9000 will be run on a 9V Battery, and will 
be used on TENS mode "normal" or EMS mode "constant" with an adjustable frequency, amplitude, and 
timer.
Specifics of each Procedure
Current perception threshold (CPT): All participants will undergo CPT testing. Participants will be instructed 
to empty their bladder prior to instrumentation. They will then be moved to a semi lithotomy position and 
a Neurotron catheter (12-French) with electrode will be inserted through the urethra into the bladder. 
Lidocaine will not be used for this catheter insertion because we want to preserve sensory reflexes. The 
catheter balloon will be inflated and positioned at the urethrovesical junction to stimulate the urethra 10-
14 mm from the bladder neck. The catheter and electrode leads will be secured to the participant’s leg 
with medical tape. The urethral electrode will then deliver sine wave stimulus pulses at 5, 250, and 2,000 
Hz. For each frequency, the stimulation amplitude will be increased until first perception and then 
decreased until it is no longer perceptible. CPT will be established using an automated forced choice 
paradigm by the method of levels, where random triplicates of A/B/Rest stimuli will be presented. The A/B
/Rest paradigm is defined as a true stimulus, a placebo stimulus, and a rest trial, where the participant 
must indicate verbally or by handheld monitor whether they can detect stimulation during the three 
sessions. Based on their response, the device adjusts stimulation output and randomizes testing order. 
The final CPT value determined by the device is defined as the average of the minimum amplitude of the 
stimulus consistently detected and the stimulus 40 µA lower that was consistently not detected. For 
bladder stimulation, the catheter balloon will be deflated and the catheter will be advanced into the 
bladder. We will perform CPT testing in the bladder using a forced choice paradigm as described above. 
Bladder pressure will be monitored from a lumen of the Neurotron catheter electrode but we are not 
retrograde filling so we do not expect overdistention within the 30 minutes of CPT testing. Testing order of 
the bladder and urethra will be randomized between patients. Participants will be instructed to inform the 
study staff of any unpleasant sensations they may experience and may elect to terminate stimulation and 
participation at any point.
Intravesical (bladder) electrical stimulation This procedure is specific to participants in the bladder 
stimulation arm. A sterile stimulation catheter (Gaeltec custom catheter, 7-French) will be placed in the 
bladder through the urethra and the electrode contacts will be positioned to be floating within the bladder. 
The electrode contacts will be surrounded by ~30 ml of saline infused through the catheter. Impedance 
measurements will be recorded to monitor electrode integrity. A single return electrode will also be placed 
on the abdominal skin above the pubic bone. Stimuli will be delivered as 0.2 ms charge-balanced biphasic 
rectangular current pulses applied between the catheter electrode and the return surface electrode. 
Stimulation frequency will be set at 20 Hz and amplitude will be adjusted individually to 80% of the 
maximum tolerable intensity (Jiang and Lindstrom 1999, Gladh et al. 2003). Participants will be instructed 
to inform the study staff of any unpleasant sensations they may experience and may elect to terminate 
stimulation at any point. Electrical stimulation will be applied to bladder sensory nerves for up to 60 
minutes prior to the start of urodynamic studies (Gladh et al. 2003, Deng et al. 2017).
Intraurethral electrical stimulation This procedure is specific to participants in the urethral stimulation arm. 
A sterile stimulation catheter (Gaeltec custom catheter, 7-French) will be placed in the urethra and 
positioned with the electrode contact 10-14 mm from the bladder neck to stimulate the proximal urethral 
sensory nerves. The catheter and electrode leads will be secured to the participant’s leg with medical tape. 
Impedance measurements will be recorded to monitor electrode integrity. A single return electrode will 
also be placed on the abdominal skin above the pubic bone. Stimuli will be delivered as 0.2 ms charge-
balanced biphasic rectangular current pulses applied between the catheter electrode and the neutral 
surface electrode. Stimulation frequency will be 10 Hz (may switch 2 or 20 Hz in subsequent participants if 
unresponsive) and amplitude will be adjusted individually to 80% of the maximum tolerable intensity 
(Gustafson et al. 2004, Yoo et al. 2011). Electrical stimulation will be applied to urethral sensory nerves at 
“strong desire to void” during cystometry. The participant will then be given permission to void at 

“maximum cystometric capacity” with continuous intraurethral stimulation. Participants will be instructed 
to inform the study staff of any unpleasant sensations they may experience and may elect to terminate 
stimulation and participation at any point.
Cystometry After bladder stimulation or during intraurethral stimulation, standard urodynamics will be 
performed to assess bladder sensation and storage. Residual urine volume in the bladder will be removed 
by catheterization prior to cystometry. A dual-chamber 8-French catheter will be passed through the 
urethra into the bladder for retrograde filling. A second 8-French catheter will be placed in the vagina to 
measure intra-abdominal pressure. A stimulation electrode catheter will only be inserted in the 
intraurethral stimulation arm per the above methods. EMG pads will then be placed at 3 and 9 o’clock on 
each side of the perineum in an area not obstructed by hair or skin folds. These pads each have adhesive, 
which allows them to adhere in place through the study. Both the urethral and vaginal catheters will be 
zeroed to atmospheric pressure. The bladder will then be filled with room-temperature sterile saline 
solution in a retrograde fashion using a pump. Bladder sensation and urgency will be assessed while filling. 
Bladder pressure will be continuously observed and recorded during the study for evidence of involuntary 
detrusor contractions. The following values will be recorded from this portion of the study: volume of first 
sensation during bladder filling, first desire to void, strong desire to void, maximum cystometric capacity, 
presence or absence of detrusor overactivity.
Pressure-flow study A standard pressure flow study will be performed to evaluate voiding function after 
stimulation. The transurethral and intra-vaginal catheters are left in place after cystometry and the 
participant will be asked to void around them, into a commode. Bladder and abdominal pressures will be 
recorded, as well as urine flow over time. Variables that will be recorded in this portion of the study include 
the following: voided volume, postvoid residual volume, pressure at maximum flow, flow time, abdominal 
pressure during voiding, interrupted versus continuous flow, and pelvic floor muscle activity during 
micturition (as determined by EMG activity).
Uroflowmetry This standard procedure may be performed if participants are unable to void past the 
catheters in pressure flow studies. The dual chamber bladder catheter will be removed, and the participant 
will be instructed to void while sitting on a commode chair. A postvoid residual volume will be measured by 
straight catheterization. Variables that will be recorded include the following: voided volume, postvoid 
residual volume, flow rate, flow quality, and voided percentage. While this test sacrifices our secondary 
study objectives, we will still be able to fulfill our primary objectives of improved sensation and improved 
voiding function if the participant can void without catheters.
Selection of Subjects
List inclusion/exclusion criteria and how subjects will be identified.
Inclusion Criteria:
- Females ages 18 and older
- Able to provide informed consent and agree to the study risks
- Willing to withdraw from medications affecting urination for the 48 hours prior to the procedure (e.g.,
alpha-adrenergic antagonists, cholinergic agonists, cholinesterase inhibitors)
- Has the below response to 2 of the 3 bulleted questions:
Questions regarding self-reported poor sensation during bladder filling or emptying (one or more of 
the below)
 Question: In the past 7 days, where did you feel sensations when you felt you needed to urinate?
Answer: “No” response for Bladder Area
Question: In the past 7 days, how often did you have no sensation of urine flow while you were 
urinating?
Answer: “Most of the time” or “Every time” response
Question: In the past 7 days, how often did you feel that your bladder was not completely empty 
after urination?
Answer: “Most of the time” or “Every time” response
Questions regarding self-reported bothersome urinary symptoms (one or more of the below)
Question: In the past 7 days, how satisfied were you with your bladder function?
Answer: “Not at all satisfied” or “Somewhat satisfied” response
Question: In the past 7 days, how bothered were you by urinary symptoms?

Answer: “Very bothered” or “Extremely bothered” response
Standard uroflowmetry with a voiding efficiency (voided volume / voided volume + residual 
volume) of < 80%, voided volume + residual volume must be >150ml for measurement
Exclusion Criteria:
- Preexisting neurological impairment (e.g., spinal cord injury, multiple sclerosis, Guillain-Barre, cauda
equina syndrome, cerebrovascular accident, Parkinson’s disease, traumatic brain injury)
- Functional obstruction demonstrated by either elevated pelvic floor activity on EMG during standard
pressure flow study or high tone pelvic floor on clinical exam)
- Pelvic organ prolapse beyond introitus
- Active urinary tract infection (candidate would be deferred until treated)
- Positive pregnancy test
- Less than 6 weeks postpartum
- Unevaluated hematuria
- Urethral stricture/stenosis
- Surgical obstruction i.e., urinary retention due to obstructive sling or other anti incontinence procedure
- Surgical procedures to increase bladder capacity (e.g., augmentation cystoplasty)
- Active sacral neuromodulation or ongoing posterior tibial nerve stimulation sessions
- Botulinum toxin injection in the past six months
- History of genitourinary or gastrointestinal cancer
Subject Identification Patient name and contact information will be recorded for eligibility screening. They 
will be considered enrolled once they complete the informed consent process and sign the consent form at 
their study procedure visit. Ineligible participants will be given a number SF001-100, whereas eligible 
participants will be given a number AMPLIFY01-20. An electronic enrollee log book will be kept by study 
personnel and will serve as the master list for enrolled participants. After being logged in the log book, the 
participant’s name will no longer be used on case report forms; instead, their subject number will be used 
on case report forms. Each study participant will have a study folder. These will be managed by the 
research coordinator and kept under lock and key at the Duke Urogynecology Office.
Subject Recruitment and Compensation
Describe recruitment procedures, including who will introduce the study to potential subjects. Describe 
how you will ensure that subject selection is equitable and all relevant demographic groups have access 
to study participation (per 45 CFR 46.111(a) (3)). Include information about approximately how many 
DUHS subjects will be recruited. If subjects are to be compensated, provide specific prorated amounts 
to be provided for expenses such as travel and/or lost wages, and/or for inducement to participate.
Subject Recruitment Participants will primarily be recruited from Duke Urogynecology offices (Navaho and 
Patterson Place). Advertisement brochures will be used provide contact information and a snapshot of the 
AMPLIFY study. MaestroCare and DEDUCE will also be used to identify established patients previously seen 
by providers that meet study eligibility criteria. We will contact patients via email, phone, or the MyChart 
portal to determine their interest in participating in the study. If they are interested, research personnel 
will perform a screening questionnaire and schedule a study procedure visit.
Subject Compensation There will be no direct cost to subjects participating in the study. They may incur 
costs for travel to the Urogynecology Clinic. 
Compensation is pro-rated as follows:
$20 for completing informed consent
$60 for completing any part of the procedure visit
$60 for completing the entire procedure visit
$60 for completing the final questionnaire
Consent Process
Complete the consent section in the iRIS Submission Form.

Subject’s Capacity to Give Legally Effective Consent
If subjects who do not have the capacity to give legally effective consent are included, describe how 
diminished capacity will be assessed. Will a periodic reassessment occur? If so, when? Will the subject 
be consented if the decisional capacity improves?
Participants will be competent to give consent. The study personnel will determine competency.
Study Interventions
If not already presented in #4 above, describe study-related treatment or use of an investigational 
drug or biologic (with dosages), or device, or use of another form of intervention (i.e., either physical 
procedures or manipulation of the subject or the subject’s environment) for research purposes.
Risk/Benefit Assessment
Include a thorough description of how risks and discomforts will be minimized (per 45 CFR 46.111(a) (1 
and 2)). Consider physical, psychological, legal, economic and social risks as applicable. If vulnerable 
populations are to be included (such as children, pregnant individuals, imprisoned persons or 
cognitively impaired adults), what special precautions will be used to minimize risks to these subjects? 
Also identify what available alternatives the person has if he/she chooses not to participate in the 
study. Describe the possible benefits to the subject. What is the importance of the knowledge expected 
to result from the research?
The potential benefits of the proposed study to research participants are as follows:
- Participants will experience standard procedural risks involved with invasive urodynamics and electrical
stimulation. The potential acute benefit of decreased lower urinary tract symptoms (LUTS) and increased
bladder emptying is reasonable relative to the risks of additional urodynamic testing that they may have
otherwise undergone.
The potential risks for the study are as follows:
- The risk for breach of confidentiality of personally identifiable information. There is minimal risk given our
Data and Safety Monitoring Plan but this risk will result in loss of confidentiality of study participation.
- Risk for breach of confidentiality with electronic informed consent. Participants will receive a signed copy
of their consent via the email address they provide and this risk is disclosed in the informed consent form.
- Participants will be asked to withdraw medications (e.g., alpha-adrenergic antagonists, cholinergic
agonists, cholinesterase inhibitors) that affect urination for 48 hours prior to study participation. This will
create a risk of them being untreated for the medicated condition. We do not expect significant
complications other than decreased quality of life from 48 hours of medication withdrawal. We will protect
against the risk of significant adverse events during medication withdrawal by instructing participants to
contact study personnel in the event of adverse effects.
- During invasive urodynamic testing, there is a risk of irritation and infection with catheterization.
Participants may develop a urinary tract infection, hematuria, or pain and discomfort. We will minimize the
risk of urethral irritation by lubricating the catheter with K-Y jelly and having the fewest de novo
catheterizations possible Additionally, we will minimize the risk of infection by using sterile preparation
techniques, as well as antiseptic cleaning of the working area.
- There is a risk of painful sensations from electrical stimulation to the bladder and urethra. Participants
can elect to decrease or terminate stimulation at any point during the study. We will minimize the risk of
activating nerve fibers carrying painful stimuli by individually adjusting current amplitude to 80% of their
maximum tolerable intensity. Every subject will be titrated down from a stimulation parameter that they
feel is uncomfortable. The stimulation amplitude will be guided by the values obtained from the Current
Perception Threshold forced choice paradigm, where a baseline intensity alignment automatically increases
amplitude until the participant reports detection. Participants will be informed of any sensations they may
perceive as unpleasant and may elect to terminate stimulation at any point.
- Participating in this study while pregnant may expose the unborn child to unknown risks. There is no risk
level because we have excluded pregnant women.

- There may be some unknown and unforeseeable risks related to the study. Participants will be informed
of any significant new information learned during the study that might cause them to change their mind
about participating in the study. Significant new findings developed during the research, which may relate
to their willingness to participate will also be provided to them.
Costs to the Subject
Describe and justify any costs that the subject will incur as a result of participation; ordinarily, subjects 
should not be expected to pay for research without receiving direct benefit.
There will be no cost to the subject as a result of the participation.
Data Analysis & Statistical Considerations
Describe endpoints and power calculations. Provide a detailed description of how study data will be 
analyzed, including statistical methods used, and how ineligible subjects will be handled and which 
subjects will be included for analysis. Include planned sample size justification. Provide estimated time 
to target accrual and accrual rate. Describe interim analysis including plans to stop accrual during 
monitoring. Phase I studies, include dose escalation schema and criteria for dose escalation with 
definition of MTD and DLT.
Expected enrollment n = 20 neurologically-intact women with underactive bladder
Expected effect size (dz) = 0.67
 
Power (1 – β) = 0.8
Time to Target Accrual 2 years
To account for participants failing to meet our eligibility criteria, it is anticipated that a total of 100 adult 
women will be screened to achieve n=20 total study participants. We expect to screen all patients with ICD 
codes suggestive of underactive bladder because a DEDUCE query revealed that in 2019 Duke 
Urogynecology clinics saw 34 patients meeting our criteria and approximately 10 of those patients went on 
for urodynamic studies. It is our expectation that the lack of consistent terminology and diagnostic 
parameters for underactive bladder will result in a large patient population failing to meet our eligibility 
criteria. Our expected enrollment will enable detection of a 7.5% change in voided percentage after 
stimulation with power (1-beta) of 0.8.
Statistical Methods
Primary Aim 1: Use of intraurethral electrical stimulation or intravesical electrical stimulation to assess 
increase in voided percentage during pressure-flow studies
Hypothesis: Electrical stimulation will increase voided percentage, and this hypothesis will be evaluated 
with non-parametric tests.
Method: Data will be analyzed by Wilcoxon signed-rank test to determine the influence of intravesical 
and intraurethral stimulation on bladder emptying.
Primary Aim 2: Use of LURN SI-29 questionnaire to assess whether electrical stimulation decreases urinary 
bothersome symptoms and increase bladder sensation during filling and emptying
Hypothesis: Intravesical (bladder) stimulation will decrease affirmatory responses to bothersome 
urinary symptoms and increase affirmatory responses to sensation during filling and emptying, 
whereas intraurethral stimulation will decrease affirmatory responses to bothersome symptoms during 
emptying.
Method: Data will be analyzed by the McNemar Exact Test or the Wilcoxon signed-rank test to 
determine the influence of intravesical or intraurethral stimulation on sensation.   
Secondary Aim 1: Assess bladder or urethral current perception threshold (CPT) in women with 
underactive bladders
Hypothesis: Women with underactive bladder will have increased bladder CPT and increased urethral 
CPT (reduced sensory nerve activity) compared to normative data in asymptomatic women, and this 
hypothesis will be evaluated with the Dunn’s multiple comparisons test.
Method: Data will be analyzed by the Kruskall-Wallis test to determine the CPT distribution between 
women with underactive bladder and asymptomatic women.
Secondary Aim 2: Use of intravesical electrical stimulation to assess volumes at cystometric endpoints
Hypothesis: Intravesical stimulation decrease cystometric volume endpoints, and this will be evaluated 
with the Bonferroni multiple comparisons correction.

Method: Data will be analyzed by repeated measures ANOVA to determine the influence of intravesical 
on perceptions of bladder filling.
Secondary Aim 3: Use of intraurethral electrical stimulation to assess contraction strength and contraction 
duration
Hypothesis: Intraurethral stimulation will increase detrusor contraction strength and contraction 
duration, and this will be evaluated with non-parametric tests.
Method: Data will be analyzed by Wilcoxon signed-rank test to determine the influence of intraurethral 
stimulation on detrusor function.
Data & Safety Monitoring
Summarize safety concerns, and describe the methods to monitor research subjects and their data to 
ensure their safety, including who will monitor the data, and the frequency of such monitoring. If a 
data monitoring committee will be used, describe its operation, including stopping rules and frequency 
of review, and if it is independent of the sponsor (per 45 CFR 46.111(a) (6)).
The paper informed consent and case report forms will be placed in individual participant binders, which 
will be stored under lock and key in the Duke Urogynecology office. Electronic informed consent will be 
stored in the REDCap project's File Repository. The regulatory binder will be an electronic regulatory binder 
in the Forte eRegulatory Management System (eReg). The research study staff will have access to these 
documents. The staff processing the participant reimbursement will have contact with the reimbursement 
form, which requires the participant provide a SSN. These forms will be kept in an opaque envelope and 
handled only by the research coordinator. Electronic data will be stored behind an enterprise-grade firewall 
in a shared folder on the password protected Duke PIN stations. It will not be placed on personal laptops, 
phones, or thumb drives.
Participant privacy will be maintained through confidential phone screens and consultation behind closed 
doors in the Urogynecology Clinic. Participant information will be recorded in their subject binder and 
stored for six years per Duke protocol. Their electronic personal health information will be behind an 
enterprise-grade firewall and will not be shared with outside entities unless required by the sponsor.
Research study participants will be given contact information to Em Abbott, PhD and will be allowed access 
during working hours (9am-5pm) to answer questions related to study risks and procedures. To maintain 
patient safety oversight, Em Abbott, PhD will submit Adverse Event reports to an independent safety 
monitor after 5 participants have been evaluated with the intervention. The independent safety monitor is 
Dr. Nazema Siddiqui, M.D., a Duke Urogynecologist. We also have a Clinical Quality Management Plan 
where a Quality Management Reviewer will review all safety events during the review of the participant 
charts to ensure appropriate reporting according to DUHS IRB policy. If any Serious Adverse Events, 
Protocol Deviations/Violations, and/or Unanticipated Problem are observed during the review, these will be 
communicated to the study team promptly. The QM reviewers are Bonnie Thiele, Caroline Nagle, or Jessie 
Paradis. In addition to the Clinical Quality Management Plan, study staff will review participants' charts 30 
days after the study visit to identify safety/adverse events and facilitate timely reporting. All protocol 
deviations and adverse events will be promptly reported to the Institutional Review Board in accordance 
with institution and Human Research Protection Program policies. All additional regulatory and monitoring 
requirements of the Investigational Device Exemptions will be carried out by the study team in accordance 
with 21 CFR 812.2(b)(1).