Foot Neuromodulation for Nocturnal Enuresis in Children
Phase: NA
Conditions: Bedwetting
Sponsor: Heidi Stephany

Section: Triage
    [reviewer notes¬]  
Provide a short title for this study (200 characters or less): 
Foot Neuromodulation for Nocturnal Enuresis in Children  
T1.0 
Select the type of application: 
New Research Study   
 
 
  
T2.0 
Is the proposed research study limited to the inclusion of deceased individuals?  
* No 
 
T2.1 
 
Are any research activities being conducted at the VA Pittsburgh Healthcare 
System or with VA funds?  
 
* No 
  
  
    [reviewer notes¬]  
T3.0 
What is the anticipated risk to the research participants? 
Minimal Risk 
  
T3.1 
Why do you feel that all aspects of this research study, including screening and 
follow-up, involve no more than minimal risk to the research subjects? 
 
Trans-cutaneous Electrical Nerve Stimulation (TENS) devices are FDA approved and 
commercially available to treat a variety of clinical conditions including pain (migraines, 
musculoskeletal pain and labor pain). The only reported side-effects are local irritation from 
electrode pads and minor cramping of stimulated muscles. Many studies have evaluated the 
use of TENS devices for parasacral neuromodulation in children with no serious adverse 
events reported. 
 
The voltage used for the TENS device will be only as high as is required to stimulate an 
involuntary muscle contraction of at least two toes. In various trials in adults this voltage 
very rarely corresponds to any actual discomfort to the patient. If during the trail 
stimulation at the time of enrollment in the office, the child demonstrates an intolerability 
to this stimulation due to discomfort, he/she will be excluded from the study. 
T4.0 
Does the proposed study qualify for 'exempt' IRB review or for a determination of 
either 'not research' or 'no human subject' involvement? 
* No 
  
T5.0 
Does the proposed research study qualify for 'expedited' IRB review status? 
* No 

Section: Triage
  
Section: Cover Sheet
    [reviewer notes¬]  
CS1.0 
What is the reason for this submission? 
New Research Protocol Submission 
CS1.1 
Has this research study been approved previously by the University of Pittsburgh 
IRB? 
*  No 
CS1.1.1 Has this research study (or a substantially similar research study) been previously 
disapproved by the University of Pittsburgh IRB or, to your knowledge, by any other 
IRB? 
*  No 
  
    [reviewer notes¬]  
CS2.0 
Title of Research Study: 
Foot Neuromodulation for Nocturnal Enuresis in Children 
  
CS2.0.1     
Requested approval letter wording: 
 
  
CS2.1 
Research Protocol Abstract: 
 
Background: Previous animal model studies at the University of Pittsburgh have shown a 
significant impact on inhibiting bladder overactivity and increasing bladder capacity with 
neuromodulation techniques, specifically tibial nerve stimulation. This has been translated into 
adult clinical trials through the department of urology. Through the use of a commercially 
available subcutaneous nerve stimulator placed on the dorsum of the foot, we were able to 
demonstrate a signficant increase in bladder capacity and the delay of voiding sensation for up 
to 5 hours after stimulation in eight healthy subjects. This prompted the clinical trial approved 
under IRB PRO13020474 which is currently enrolling patients.  
 
The incidence of night-time overactive bladder leading to noctural enuresis (bedwetting) is 
very common in the pediatric and teenage population, particularly in patients without daytime 
bladder overactivity symptoms. When behavioral modification (i.e. refraining from night-time 
fluid consumption and bladder irritants, and bedwetting alarms for timed voiding) fails which it 
often does there is a paucity of effective and safe treatment options. Medications can be tried, 
but generally these are from the tricyclic antidepressant family and carry significant side 
effects limiting their use. 
 
Aim: We aim to utilize the same technology currently being studied under IRB PRO13020474 
for pediatric patients with nocturnal enuresis, taking advantage of the possible increase in 
bladder capacity and inhibited bladder activity to potentially help children stay dry at night. 
Electrical stimulation will be applied to the foot via skin surface electrodes for a minimum of 1 
  
  

Section: Cover Sheet
hour before bed for 2 weeks to 25 subjects. Subjects will be required to keep a daily log 
indicating the number of night-time incontinent voids. Subjects will also be asked to complete 
a validated questionnaire prior to treatment, during the two week treatment phase and two 
weeks after treatment. The primary outcomes of this study are improvement in the average 
number of night-time incontinent voids measured by daily log and subjective symptom 
improvement based on questionnaire comparison at the three phases of the study. Subjects 
who feel they are having a positive response to TENS treatment and would like to continue 
participation in the study for an additional 6 weeks may do so. 
CS2.2 
Select the category that best describes your research: 
 
    [reviewer notes¬]  
CS3.0 
Name of the Principal Investigator: 
Heidi Stephany 
Note: Adjunct faculty of the University, including lecturers and instructors, are not 
permitted to serve as a PI or Faculty Mentor but may serve as co-investigators. Refer 
to Chapter 4 on the HRPO website for more information. 
CS3.1 
Affiliation of Principal Investigator: 
UPitt faculty member  
  
If you chose any of the Pitt options, please indicate the specific campus: 
Main Campus - Pittsburgh 
 If you chose the UPitt faculty member option, provide the PI’s University Faculty Title: 
Assistant Professor   
CS3.2 
Address of Principal Investigator: 
 
One Children’s Hospital Drive 
4401 Penn Avenue 
4th Floor Faculty Pavilion 
Pittsburgh, Pa 15224  
CS3.3 
Recorded Primary Affiliation of the Principal Investigator: 
  
U of Pgh | School of Medicine | Urology  
CS3.4 
Identify the School, Department, Division or Center which is responsible for 
oversight of this research study: 
U of Pgh | School of Medicine | Urology  
  
  
CS3.5 
Telephone Number of Principal Investigator: 
412-692-7984  
CS3.6 
Recorded Current E-mail Address of Principal Investigator to which all 
notifications will be sent: 
 
heidi.stephany@chp.edu 
CS3.7 
Fax Number: 

Section: Cover Sheet
412-692-8614 
CS3.8 
Does this study include any personnel from Carnegie Mellon University, and/or 
use any CMU resources or facilities (e.g., Scientific Imaging and Brain Research 
Center (SIBR)? 
*  No 
CS3.9 
Is this your first submission, as PI, to the Pitt IRB?   
*  No 
  
    [reviewer notes¬]  
CS4.0 
List of Co-Investigators:  
 
 
Last 
First 
Organization 
Cannon 
Glenn 
U of Pgh | School of Medicine | Urology 
Chermansky Christopher U of Pgh | School of Medicine | Urology 
Dwyer 
Moira 
U of Pgh | School of Medicine | Urology 
Ferroni 
Matthew 
U of Pgh | School of Medicine | Urology 
Ost 
Michael 
U of Pgh | School of Medicine | Urology 
Reese 
Jeremy 
UPMC | Hospital Divisions | Presbyterian/Shadyside 
Schneck 
Francis 
U of Pgh | School of Medicine | Urology 
Tai 
Changfeng U of Pgh | School of Medicine | Urology 
  
   
   
    [reviewer notes¬]  
CS5.0 
Name of Primary Research Coordinator: 
 
Matthew Ferroni 
   
  
CS5.1 
Address of Primary Research Coordinator: 
One Children’s Hospital Drive 
4401 Penn Avenue 
4th Floor Faculty Pavilion 
Pittsburgh, Pa 15224 
 
CS5.2 
Telephone Number of Primary Research Coordinator: 
617-270-3676 
 
CS6.0 
Name of Secondary Research Coordinator: 
Jennifer Szczepaniak 
 
CS6.1 
Address of Secondary Research Coordinator:  
  
  
 

Section: Cover Sheet
4401 Penn Avenue 
Pittsburgh, PA 15224 
CS6.2 
Telephone Number of Secondary Research Coordinator: 
  
412-692-6203 
 
CS6.3 
Key Personnel/Support Staff (Only list those individuals who require access to 
OSIRIS):  
 
Last 
First 
Organization 
Chermansky Christopher U of Pgh | School of Medicine | Urology 
Ferroni 
Matthew 
U of Pgh | School of Medicine | Urology 
Reese 
Jeremy 
UPMC | Hospital Divisions | Presbyterian/Shadyside 
Stephany 
Heidi 
U of Pgh | School of Medicine | Urology 
Tai 
Changfeng U of Pgh | School of Medicine | Urology 
 
    [reviewer notes¬]  
CS7.0 
Will this research study use any Pediatric PittNet or Clinical and Translational 
Research Center (CTRC) resources? 
No 
  
    [reviewer notes¬]  
CS8.0 
Select the entity responsible for scientific review. 
 
  
 
Department Review - (a dean, department chair, division chief, or center head)  
Note: DoD funded studies require departmental review  
  
  
CS8.1 
Select the school, department or division which is responsible for scientific review 
of this submission. 
U of Pgh | School of Medicine | Urology 
  
 
  
  
    [reviewer notes¬]  
CS9.0 
Does this research study involve the administration of an investigational drug or 
an FDA-approved drug that will be used for research purposes? 
* No   
CS10.0 
Is this research study being conducted under a University of Pittsburgh-based, 
sponsor-investigator IND or IDE application? 
  
 
*  No  
 
If YES, you are required to submit the IND or IDE application and all subsequent FDA 
correspondence through the Office for Investigator-Sponsored IND and IDE Support 
  

Section: Cover Sheet
(O3IS).  Refer to applicable University policies posted on the O3IS 
website  (www.O3IS.pitt.edu). 
  
    [reviewer notes¬]  
CS11.0 
Use the 'Add' button to upload one or more of the following: 
 
the sponsor protocol (including investigator initiated studies) and/or 
other brochures 
 
the multi-center protocol and consent form template, if applicable 
Name Modified Date 
Is this research study supported in whole or in part by industry?  This includes the 
provision of products (drugs or devices).   
  
*  No 
Is this a multi-centered study? 
 
*  No 
  
  
    [reviewer notes¬]  
CS12.0 
Does your research protocol involve the evaluation or use of procedures that emit 
ionizing radiation? 
 
*  No  
  
CS13.0 
Does this research study involve the deliberate transfer of recombinant or 
synthetic nucleic acid molecules into human subjects? 
  
 
*  No 
  
 
Upload Appendix M of NIH Guidelines: 
Name 
Modified Date 
 
  
  
CS14.0 
Are you using UPMC facilities and/or UPMC patients during the conduct of your 
research study? 
  
*  Yes  
 
If Yes, upload completed Research Fiscal Review Form: 
Name 
Modified Date 
Fiscal Review 
8/26/2014 8:24 AM 
  
    [reviewer notes¬]  

Section: Cover Sheet
CS15.0 Indicate the sites where research activities will be performed 
and/or private information will be obtained. 
Choose all sites that apply and/or use Other to include sites not listed: 
 
Sites: 
UPMC 
  
  
 
 
 
UPMC  
 
Sites: 
UPMC Children's Hospital 
  
  
  
 
 
 
If you selected School, International or Other, list the sites: 
 
  
*For research being conducted at non Pitt or UPMC sites, upload 
a site permission letter granting the researcher permission to 
conduct their research at each external site: 
Name Modified Date 
 
  
 
 
CS15.1 Have you, Heidi Stephany , verified that all members of the 
research team have the appropriate expertise, credentials, and if 
applicable, hospital privileges to perform those research 
procedures that are their responsibility as outlined in the IRB 
protocol? 
 
*  Yes 
 
  
CS15.2 Describe the availability of resources and the adequacy of the 
facilities to conduct this study: 
*  We have previously been awarded a $25,000 grant from the Society 
of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction 
(SUFU) which we will use for the purchase of equipment 
(neuromodulators and subcutaneous foot pads). Subjects will be enrolled 
in the urology outpatient clinics at the Children's Hospital of Pittsburgh. 
We anticipate have adequate resources to enroll subjects and perform all 
necessary study tasks. 
  
  
    [reviewer notes¬]  
CS16.0 
Special Research Subject Populations:  
 
Categories 
Children (age < 18 years old) 
 
 

Section: Cover Sheet
    [reviewer notes¬]  
CS17.0 
Does your research involve the experimental use of any type of human stem cell? 
 
*  No 
  
    [reviewer notes¬]  
  
 
NIH Definition of a Clinical Trial 
A research study1 in which one or more human subjects2 are prospectively 
assigned3 to one or more interventions4 (which may include placebo or other control) 
to evaluate the effects of those interventions on health related biomedical or 
behavioral outcomes.5 
1 See Common Rule definition of research at 45 CFR 46.102(d) . 
2 See Common Rule definition of human subject at 45 CFR 46.102(f) . 
3 The term “prospectively assigned” refers to a pre-defined process (e.g., randomization) 
specified in an approved protocol that stipulates the assignment of research subjects 
(individually or in clusters) to one or more arms (e.g., intervention, placebo, or other control) 
of a clinical trial. 
4 An intervention is defined as a manipulation of the subject or subject’s environment for the 
purpose of modifying one or more health-related biomedical or behavioral processes and/or 
endpoints.  Examples include:  drugs/small molecules/compounds; biologics; devices; 
procedures (e.g., surgical techniques); delivery systems (e.g., telemedicine, face-to-face 
interviews); strategies to change health-related behavior (e.g., diet, cognitive therapy, 
exercise, development of new habits); treatment strategies; prevention strategies; and, 
diagnostic strategies. 
5 Health-related biomedical or behavioral outcome is defined as the pre-specified goal(s) or 
condition(s) that reflect the effect of one or more interventions on human subjects’ biomedical 
or behavioral status or quality of life.  Examples include:  positive or negative changes to 
physiological or biological parameters (e.g., improvement of lung capacity, gene expression); 
positive or negative changes to psychological or neurodevelopmental parameters (e.g., mood 
management intervention for smokers; reading comprehension and /or information retention); 
positive or negative changes to disease processes; positive or negative changes to health-
related behaviors; and, positive or negative changes to quality of life. 
CS18.0 * Based on the above information, does this study meet the NIH definition of a 
clinical trial? 
  
Yes 
No  
  
  
If Yes, click Save and then Click Here For Study Team's CITI Training Records .  Please 
ensure all personnel's training is up to date 
Section: Section 1 - Objective, Aims, Background and Significance
    [reviewer notes¬]  

Section: Section 1 - Objective, Aims, Background and Significance
1.1 
Objective: What is the overall purpose of this research study?  (Limit response to 1-
2 sentences.) 
To determine the effects of electrical stimulation of the nerves in the foot on the incidence 
of nocturnal enuresis (bedwetting) in children.  
  
 
  
1.2 
Specific Aims: List the goals of the proposed study (e.g., describe the relevant 
hypotheses or the specific problems or issues that will be addressed by the 
study). 
Aim #1: To determine if foot stimulation can decrease nocturnal enuresis in children as 
measured by daily night-time voiding log. 
 
Aim #2: To determine if foot stimulation can improve quality of life questionnaire scores 
during a 6-week period, with foot stimulation applied during the third and fourth week, as 
measured by a validated quality of life survey. 
 
Aim # 3:Subjects who feel they are having a positive response to TENS treatment and 
would like to continue participation in the study for an additional 6 weeks may do so. By 
collecting this data for an extended period of time we hope to prove long-term efficacy and 
sustainability in symptom relief, and to ensure no unanticipated adverse outcomes with 
continued usage  
  
1.3 
Background: Briefly describe previous findings or observations that provide the 
background leading to this proposal.  
Previous animal model studies at the University of Pittsburgh have shown a significant 
impact on inhibiting bladder overactivity and increasing bladder capacity with 
neuromodulation techniques, specifically tibial nerve stimulation (Tai et al, 2011). This has 
been translated into adult clinical trials through the department of urology. Through the use 
of a commercially available subcutaneous nerve stimulator placed on the dorsum of the 
foot, we were able to demonstrate a significant increase in bladder capacity and the delay 
of voiding sensation for up to 5 hours after stimulation in eight healthy subjects (Chen et 
al, 2014). This prompted the clinical trial approved under IRB PRO13020474 which is 
currently enrolling patients.  
 
The incidence of night-time overactive bladder leading to noctural enuresis (bedwetting) is 
very common in the pediatric and teenage population, particularly in patients without 
daytime bladder overactivity symptoms. When behavioral modification (i.e. refraining from 
night-time fluid consumption and bladder irritants, and bedwetting alarms for timed 
voiding) fails which it often does there is a paucity of effective and safe treatment options. 
Medications can be tried, but generally these are from the tricyclic antidepressant family 
and carry significant side effects limiting their use. 
 
Various clinical trials abroad have studied the impact of transcutaneous parasacral nerve 
stimulation as well as percutaneous tibial nerve stimulation for overactive bladder in 
children with promising results (Sillen et al, 2014; Barroso et al, 2013; DeGannaro et al 
2011; Loredelo et al 2010; Malm-Buatsi et al 2007). These studies have shown good 
efficacy and child tolerability with nerve stimulation in a more invasive approach then we 
are attempting with transcutaneous foot stimulation.  
 
  
 
 
  
1.4 
Significance: Why is it important that this research be conducted? What gaps in 
existing information or knowledge is this research intended to fill?  
Nocturnal Enuresis is a very common and difficult to treat problem in the pediatric 
population which can have significant negative impact on a child's quality of life. Apart from 
medications which can have significant side effects limiting their use, there is a lack of 
effective and safe treatment options for children with frequent nocturnal enuresis. If foot 
  

Section: Section 1 - Objective, Aims, Background and Significance
stimulation prior to bed does indeed improve the frequency of nocturnal enuresis, it may 
provide a safe and non-invasive therapeutic option.  
 
For subjects the would like to continue participation in the study for an additional 6 weeks, 
we would like to explore how durable of a response we can achieve with a longer 
stimulation period 
 
  
Section: Section 2 - Research Design and Methods
    [reviewer notes¬]  
2.1 
Does this research study involve the use or evaluation of a drug, biological, or 
nutritional (e.g., herbal or dietary) supplement? 
*  No 
  
    [reviewer notes¬]  
2.2 
Will this research use or evaluate the safety and/or effectiveness of one or 
more devices? 
  
*  Yes  
  
2.2.1 
Does this research study involve an evaluation of the safety and/or effectiveness 
of one or more devices not currently approved by the FDA for general marketing? 
 
* No 
 
  
  
    [reviewer notes¬]  
2.2.2 
Does this research study involve the use or evaluation of the safety and/or 
effectiveness of one or more devices approved by the FDA for general marketing? 
 
*  Yes 
  
2.2.2.1 
Does this research study involve an evaluation of one or more FDA-approved 
devices for a clinical indication, subject population, and/or operational parameter 
that is not specified in the current FDA-approved product labeling for that device 
(i.e., for an “off-label” indication)?   
* Yes 
2.2.2.1.1 
List each of the devices being evaluated for an “off-label” indication. Specify 
for each listed device the corresponding Investigational Device Exemption (IDE) 
number for this device/research study; or provide a justification for why you feel 
that this device and its “off-label” use, as proposed in this research study (i.e., to 
include potential failure of the device) constitute a non-significant risk to the 
involved research subjects. 
 
  

Section: Section 2 - Research Design and Methods
* 
 
  
Device 
IDE 
# 
Non-significant risk justification 
View 
TRANSCUTANEOUS 
ELECTRICAL NERVE 
STIMULATOR (TENS) 
  
The TRANSCUTANEOUS ELECTRICAL NERVE STIMULATOR 
(TENS) is a battery powered stimulator that is 
commercially available and FDA-approved for individual 
use at home to stimulate muscles/nerves. 1. It is not an 
implant. 2. It is not used in supporting or sustaining 
human life. 3. It does not aid in diagnosing, curing, 
mitigating, or treating disease. 4. It does not present a 
potential for serious risk to the health, safety, or welfare 
of a subject. TENS will be used in this study to deliver 
electrical stimulation via adhesive pad electrodes attached 
to the skin surface of the foot. The proposed use parallels 
the safety parameters of TENS already approved by the 
FDA. The investigators, Drs. Tai, Reese, and Ferroni, have 
many years of experience with electrical stimulation and 
neurophysiology. They are qualified in using the TENS 
stimulator correctly. Furthermore, the FDA approves of 
TENS use at home for muscle/back pain and neuropathy. 
Therefore, we believe this is a non-significant risk device. 
  
    [reviewer notes¬]  
2.3 
Summarize the general classification (e.g., descriptive, experimental) and 
methodological design (e.g., observational, cross-sectional, longitudinal, 
randomized, open-label single-blind, double-blind, placebo-controlled, active 
treatment controlled, parallel arm, cross-over arm) of the proposed research 
study, as applicable. 
  
 
This is an experimental, open-label study. Both the subject and the investigator will be 
informed about the foot stimulation. The results obtained before and after the treatment will 
be compared in the same subject. 
  
2.3.1 
Does this research study involve a placebo-controlled arm? 
*  No 
    [reviewer notes¬]  
2.4 
Will any research subjects be withdrawn from known effective therapy for the 
purpose of participating in this research study? 
*  No  
  
  
    [reviewer notes¬]  

Section: Section 2 - Research Design and Methods
2.5 
Will screening procedures (i.e., procedures to determine research subject 
eligibility) be performed specifically for the purpose of this research study? 
*  Yes 
2.5.1 
List the screening procedures that will be performed for the purpose of this 
research study.  Do NOT include the inclusion/exclusion criteria in this section as 
they will be addressed in section 3; questions 3.13 and 3.14. 
The screening procedure only includes a review of patient's medical records and performing 
an office based urinalysis to rule out concern for urinary tract infection. No other procedures 
will be performed. Patient's medical record has all the information we need to determine the 
idiopathic nocturnal enuresis condition. A urinalysis is normally done as part of standard of 
care for all office visits. The standard office visit questions, which is also available in the 
medical record and includes questions about neurological disorders, spinal cord injuries, and 
so forth will be used to rule out those who may have a neurological reason for nocturnal 
enuresis. Drs. Stephany, Ost, Schneck, and Cannon who have clinical responsibilities to the 
patient will review the medical records for eligibility. We also request a waive of consent for 
this review on section 4.7. 
  
    [reviewer notes¬]  
 
  
2.6 
Provide a detailed description of all research activities (e.g., all drugs or devices; 
psychosocial interventions or measures) that will be performed for the purpose of 
this research study.  
 
This description of activities should be complete and of sufficient detail to permit 
an assessment of associated risks.   
 
At a minimum the description should include: 
 
all research activities 
 
personnel (by role) performing the procedures 
 
location of procedures 
 
duration of procedures 
 
timeline of study procedures 
Night-time voiding log: 
The subject/parents will be instructed to record a night-time voiding log specifying the 
number of incontinent episodes per night. This log is included in the IRB application. 
Subjects/parents will fill out the log for a two week period prior to foot stimulation to 
determine a baseline average of nocturnal enuresis episodes, during the two week foot 
stimulation period to measure any acute effect on nocturnal enuresis episodes and finally 
during the two weeks after stimulation to evaluate any post-stimulation residual benefit. 
 
 
Neuromodulation: 
In the office to calibrate TENS device - skin surface electrodes will be attached to the 
bottom of one foot for electrical stimulation. The stimulator and electrodes are FDA-
approved devices for TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION (TENS) and are 
commercially available. The stimulation characteristics include a continuous frequency of 5 
Hz, pulsewidth 0.2 ms, and intensity 2-4 times the threshold voltage required for inducing 
 
  

Section: Section 2 - Research Design and Methods
toe twitching - or the intensity that the subject feels comfortable with. The subjects will 
also be instructed how to use the stimulator and where to attach the electrodes on the foot 
at the beginning of the study. The investigator will provide the stimulator and electrodes. 
The subjects will be asked to wear socks to prevent the electrodes from detachment and to 
stop the stimulation during walking or in any non-resting situation. Subjects will be 
provided a TENS device and disposable foot pads for two weeks of treatment. Subjects will 
be asked to use the stimulator for a MINIMUM of 60 minutes in the evening prior to 
bedtime at home for two weeks. They will be encouraged to use the stimulator for more 
time than the minimum as long as they accurately record the total duration. Stimulation 
will be performed during the second and third weeks of the study only.  
 
TENS Unit Training: 
The training session will take place in a patient room in the office of pediatric urology. The 
training will be conducted in person by Dr. Stephany with the parent(s) and child in the 
room. Dr. Stephany will explain the device, how it works and how to use it to the parent(s) 
along with a detailed user manual that is provided with the stimulator. The parent(s) will be 
instructed how to place the stimulation pads on the child's foot (most distal covering the 
planar bridge of the foot and more proximal pad over the medial edge of the foot). The 
parent(s) will then be instructed on how to connect the two electrode wires to the device 
and turn it on. The device settings are preprogrammed at time of sale, so no frequency 
change adjustments need to be made. The parent(s) will incrementally increase the voltage 
on the device until the child elicits a response of involuntary contraction of at least two toes 
of the foot including the great toe. Stimulation will be continuous for 5 minutes assessing 
the child's comfort level. If the child is obviously uncomfortable at the level of voltage 
required for involuntary motor movement and does not perceive they would be able to 
stimulate in this fashion at home for periods of up to one hour, they will not be eligible for 
the study.  
 
Questionnaire: 
Subjects will complete the quality of life questionnaire attached to this application at the 
start of the study (prior to week 1) to establish a baseline, after the second week of 
treatment period (week 4 of study) to determine a treatment effect, and after the sixth 
week to determine any residual post-treatment effect. 
 
The subjects can call or email the investigators anytime during the 6-week at-home test 
for questions or any problems encountered. At the end of the 6-week study, the subjects 
are 
asked to return the stimulator and night-time voiding log to the investigator's office. 
 
 
Subjects who feel they are having a positive response to TENS treatment and would like to 
continue participation in the study for an additional 6 weeks may do so. We will ask that 
they continue to keep their logs and answer the questionnaires 
 
2.6.1 
Will blood samples be obtained as part of this research study? 
*  No  
 
*If submitting a protocol for expedited review, it should be clear that the planned blood 
draws are within the parameters described 
here: http://www.hhs.gov/ohrp/policy/expedited98.html  (see Expedited Research 
Category #2) 

Section: Section 2 - Research Design and Methods
If Yes, address the frequency, volume per withdrawal, the total volume per visit, and the 
qualifications of the individual performing the procedure: 
 
  
  
 
Study Flow Chart: 
 
Name 
Modified Date 
    [reviewer notes¬]  
2.7 
Will follow-up procedures be performed specifically for research 
purposes?  Follow-up procedures may include phone calls, interviews, biomedical 
tests or other monitoring procedures. 
 
*  No 
  
    [reviewer notes¬]  
2.8 
Does this research study involve the use of any questionnaires, interview or 
survey instruments? 
 
*  Yes 
 
  
 
  
Upload a copy of all materials except for the SCID or KSADS which are on file at 
the IRB.  The use of all instruments must be addressed in question 2.6 and/or 
question 2.7 (except for an exempt submission where they should be addressed 
on the appropriate uploaded exempt form). 
 
 
Name 
Modified Date 
Quality of Life Survey  
8/12/2014 8:56 PM 
Night-time Voiding Log 
8/12/2014 8:53 PM 
Previously the name and publisher for commercially available materials 
were listed in the textbox below but effective 9/1/2015, all materials (except for 
the SCID and KSADS) must be uploaded using the Add button above. 
 
    [reviewer notes¬]  
2.9 
If subjects are also patients, will any clinical procedures that are being used for 
their conventional medical care also be used for research purposes? 
 
*  yes 
 
  

Section: Section 2 - Research Design and Methods
If Yes, describe the clinical procedures (and, if applicable, their frequency) that will be 
used for research purposes:  
We will not perform a urinalysis specifically for this research project. However, the result of 
urinalysis as part of standard clinical care will be reviewed in the medical record and used 
to 
screen the patients for eligibility.  
2.10 
The blood sample question was moved to 2.6.1. 
    [reviewer notes¬]  
2.11 
What is the total duration of the subject's participation in this research study 
across all visits, including follow-up surveillance? 
 
*  6 to 12 weeks 
    [reviewer notes¬]  
  
2.12 
Does this research study involve any type of planned deception?  
If Yes, you are required to request an alteration of the informed consent process (question 
4.7) 
 
*  No 
  
  
    [reviewer notes¬]  
  
2.13 
Does this research study involve the use of UPMC/Pitt protected health 
information that will be de-identified by an IRB approved "honest broker" 
system? 
 
  
*  No 
  
    [reviewer notes¬]  
 
  
2.14 
Will protected health information from a UPMC/Pitt HIPAA covered entity 
be accessed for research purposes or will research data be placed in the UPMC/Pitt 
medical record? 
 
*  Yes 
  
 
 
If you answer Yes, you are required to submit this study to the Center for Assistance in 
Research using e-Record (CARe).  Per UPMC Policy HS-RS0005, all research projects that access 
or involve UPMC electronic protected health information (e-PHI) must be submitted to CARe, 
with the exception of clinical trials that are contracted through the UPMC Office of Sponsored 
Programs and Research Support (OSPARS).   
 
Complete the online submission form at https://care.upmc.com/request.aspx.  After the study is 
submitted in OSIRIS, a CARe representative will conduct a review. You will be notified once your 
 
 
 
 

Section: Section 2 - Research Design and Methods
CARe review is complete or if anything further is needed.  
 
Studies that will access only paper-based medical records (not in combination with any 
electronic records) do not need to be submitted to CARe. 
 
For additional information, please see https://care.upmc.com. 
 
Describe the medical record information that will be collected from the UPMC/Pitt 
HIPAA covered entity and/or the research-derived information that will be placed in 
the medical records. 
 
Medical records will be accessed for screening the patients for eligibility and information 
concerning the child’s diagnosis, age, past medical history, and diagnostic procedures that were 
already done as part of their standard medical evaluations will be retained for this study. A 
urinalysis is normally done as part of standard of care and will be checked in the medical record 
for evidence of urinary tract infection. The standard office visit questions, which is also available 
in the medical record and includes questions about prior neurological disorders, spinal cord 
injuries, and so forth, will be reviewed to rule out those who may have a neurological reason for 
nocturnal enuresis. No research data will be placed in the medical record. 
2.14.1 Will protected health information from a non-UPMC/Pitt HIPAA covered entity be 
obtained for research purposes or will research data be placed in the non-UPMC/Pitt 
medical record?   
 
*  No 
I, Heidi   Stephany , certify that any member of my research team accessing, reviewing 
and/or recording information from medical records have completed the CITI Privacy & 
Information Security course or, if completed within the past year, the Internet-Based 
Studies in Education and Research (ISER) HIPAA for Researchers (Formerly RPF 
Module 6). The HIPAA certificates must be available for review if audited but do not 
need to be uploaded into this OSIRIS application. 
* Yes 
2.14.2 Are you requesting a waiver of the requirement to obtain written HIPAA authorization 
for the collection of the PHI? 
 
* No 
  
    [reviewer notes¬]  
2.15 
Does this research study involve the long-term storage (banking) of biological 
specimens?  
  
*  No 
  
    [reviewer notes¬]  
2.16 
Will research participants be asked to provide information about their family 
members or acquaintances? 
  

Section: Section 2 - Research Design and Methods
*  No 
  
    [reviewer notes¬]  
2.17 
What are the main outcome variables that will be evaluated in this study? 
1) Number of night-time incontinent episodes per two week period comparing baseline 
number of voids (first two weeks of study), number during two-week stimulation period 
(weeks 3-4), and number during two-week after-stimulation period (weeks 5-6). 
 
2) Subjective quality of life measures as recorded by validated quality of life questionnaire 
prior to study start, after week 4 and after week 6 to evaluate for any differences.  
 
3) For the subjects who continue participation for an additional 6 weeks, we hope to prove 
long-term efficacy and sustainability in symptom relief, and to ensure no unanticipated 
adverse outcomes with continued usage  
  
2.18 
Describe the statistical approaches that will be used to analyze the study data. 
*  Addressed below: 
 
The data will be statistically analyzed using student t-test and ANOVA 
  
    [reviewer notes¬]  
2.19 Will this research be conducted in (a) a foreign country and/or (b) at a site (e.g., 
Navajo Nation) where the cultural background of the subject population differs 
substantially from that of Pittsburgh and its surrounding communities? 
 
*  No 
Note that copies of training records, licenses, certificates should be maintained in the study 
regulatory binder and are subject to audit by the Research Conduct and Compliance Office 
(RCCO). 
In addition, individuals planning to conduct human subject research outside the United States 
must complete an optional module on the CITI training website: International Studies.  Click 
here to access the instruction sheet for accessing optional CITI modules. 
  
 
  
    [reviewer notes¬]  
2.21 Will this research study be conducted within a nursing home located in Pennsylvania? 
*  No  
  
  

Section: Section 3 - Human Subjects
    [reviewer notes¬]  
Section 3 - Human Subjects 
3.1 
What is the age range of the subject population? 
 
5 to 18 years old  
   
3.2 
What is their gender? 
 
*  Both males and females  
 
 Provide a justification if single gender selected: 
 
 
3.3 
Will any racial or ethnic subgroups be explicitly excluded from participation? 
 
*  No   
 
If Yes, identify subgroups and provide a justification:  
 
  
 
3.4 
For studies conducted in the U.S., do you expect that all subjects will be able to 
comprehend English? 
*  Yes  
 
  
    [reviewer notes¬]  
3.5 
Participation of Children: Will children less than 18 years of age be studied? 
 
*  Yes 
 
  
3.5.1 
Specify the age range of the children to be studied.   
(Check all that apply below:) 
* 
 
Choices 
0-6 years of age 
7-13 years of age 
14-17 years of age 
3.5.2 
Provide a rationale for the specific age ranges of the children to be studied: 
 
Child needs to be adequately potty trained with daytime dryness and be able to 
communicate quality of life subjective information to parents. 
3.5.3 
Describe the expertise of the study team for conducting research with children 
within this age range: 
 
The study team has significant clinical experience in the pediatric population as Drs. 
Stephany, Cannon, Ost, and Schneck are board certified urologic pediatricians and have 
  

Section: Section 3 - Human Subjects
facilitated a number of research studies through the Children's Hospital of Pittsburgh 
urology department. 
3.5.3.1 
Have you obtained the following clearances from all research staff who may have 
direct contact with children under the age of 18?  Direct contact under the law 
includes face-to-face, and telephonic or electronic, contact with minors.  Please 
see the Child Clearances guidance document for further explanation? 
Pennsylvania Department of Public Welfare Child Abuse History Clearance; 
Pennsylvania State Police Criminal Record Check; and 
FBI Criminal Background Check 
 
Yes 
Note: If No, once all clearances are obtained, a modification must be submitted. 
 
If you selected N/A, please explain:  
 
It is important to note that “direct contact” refers not only to face-to-face meetings but 
also extends to communication via phone (including text messaging), social media or 
internet.   Direct contact also includes the care, guidance, supervision or control, or routine 
interaction with, minors.  Conversely, a participating investigator or support staff member 
who does not have direct contact, either electronically or in person, with children does not 
need to obtain clearances (e.g., statistician, non-clinical laboratory personnel, etc.).  If 
your research study provides babysitting services, the babysitters must have the required 
child clearances.  
 
* Note: It is the responsibility of the principal investigator to ensure that all research 
staff have these clearances prior to any interaction with children. Contact Human 
Resources at 412-624-8150 for assistance with this process.  
 
 
  
  
3.5.4 
Describe the adequacy of the research facilities to accommodate children within 
this age range:* 
Addressed below: 
The department of urology at the Children's Hospital of Pittsburgh outpatient clinic has all 
of the necessary resources to implement this research study. 
3.5.5 
Permitted Categories of Research: The Federal Policy and FDA regulations 
governing human subject protections specify that research involving children 
must fall into one of the following permitted categories.  
* 
The research does not involve greater than minimal risk [45 CFR 46.404/21 CFR 50.51]. 
45 CFR 46.406 
 
The risk represents only a minor increase over minimal risk. 
 
The research procedures present experiences to the subjects that are reasonably 
commensurate with those inherent in their actual or expected medical, dental, 
psychological, social, or educational situations. 
  
  

Section: Section 3 - Human Subjects
 
The research procedures are likely to yield generalizable knowledge about the 
subjects’ disorder or condition which is of vital importance for understanding or 
amelioration of the subjects’ disorder or condition. 
45 CFR 46.407 
 
The risk is justified by the anticipated benefit to the subjects; and the relation of 
the anticipated benefit to the risk is at least as favorable to the subjects as that 
presented by available alternative approaches. 
Provide a justification which must address all considerations related to the 
designated category of research: 
 
At stated prior we feel this study provided minimal risk based on the rarity and minority of 
side effects from previous TENS studies in adults. We will use a voltage only high enough 
to elicit an involuntary twitch of the toes, which is generally non-painful.  
 
Although the electrical stimulation may help subjects with nocturnal enuresis, this benefit 
is not known or guaranteed. However, information learned from this study will help 
investigators learn how to better treat children with nocturnal enuresis in the future. 
  
    [reviewer notes¬]  
3.6 
Does this research study involve prisoners, or is it anticipated that the research 
study may involve prisoners? 
 
*  No 
  
  
    [reviewer notes¬]  
3.7 
Will pregnant women be knowingly and purposely included in this research study? 
*  No 
  
    [reviewer notes¬]  
3.8 
Does this research study involve neonates of uncertain viability or nonviable 
neonates? 
*  No 
  
  
    [reviewer notes¬]  
3.9 
Fetal Tissues: Does this research involve the use of fetal tissues or organs? 
 
*  No 
  

Section: Section 3 - Human Subjects
  
    [reviewer notes¬]  
---> 
3.10 
What is the total number of subjects to be studied at this site, including subjects 
to be screened for eligibility? 
 
Note: The number below is calculated by summing the data entered in question 3.11. Any 
additions or changes to the values entered in 3.11 will be reflected in 3.10. 
 
*  40 
  
3.11 
Identify each of the disease or condition specific subgroups (include healthy 
volunteers, if applicable) that will be studied.   
Click on the "Add" button and specify for each subgroup: 
1) how many subjects will undergo research related procedures at this site; and 
2) if applicable, how many subjects will be required to undergo screening 
procedures (e.g., blood work, EKG, x-rays, etc.) to establish eligibility.  Do Not 
include subjects who will undergo preliminary telephone screening. 
 
*  
  
Subgroup 
Number to undergo research 
procedures 
Number to undergo screening 
procedures 
 
View Pilot study of tibial nerve 
stimulation 
25 
40 
 
 
  
  
  
3.12 
Provide a statistical justification for the total number of subjects to be enrolled 
into this research study at the multicenter sites or this site. 
 
*  Described below:  
  
This is a pilot study to determine if foot stimulation has any effect on nocturnal enuresis. 
The study is designed through the use of an objective night-time voiding log and subjective 
quality of life questionnaires to determine the effect of foot stimulation. As the variations on 
these symptom parameters is unknown, it is difficult to to determine the total number of 
subjects based on statistical analysis. Therefore, we decided on 25 subjects in this pilot 
study. Once statistical significance is reached , we will stop recruiting additional subjects in 
order to maintain the subject number at a minimum. 
  
    [reviewer notes¬]  
3.13 
Inclusion Criteria: List the specific criteria for inclusion of potential subjects. 
 
1. Children ages 5 to 16 years old without any specific neurological disorder or urinary tract 
infection, clinically diagnosed as having nocturnal enuresis AT LEAST 4 episodes per month 
by history 
 
2. Currently having no daytime overactive bladder symptoms, i.e. urinary frequency, 
  

Section: Section 3 - Human Subjects
urgency, or daytime incontinence 
 
3. Having been assessed for and treated if applicable for behavioral etiologies of nocturnal 
enuresis - consuming excess fluids or specific bladder irritants 
 
4. Having been assessed for and treated if applicable for constipation  
  
3.14 
Exclusion Criteria: List the specific criteria for exclusion of potential subjects from 
participation. 
 
1. Children with known neurological disorders which may be contributing to nocturnal 
enuresis episodes 
 
2. Children found through history to have significant behavioral causes of nocturnal 
enuresis including consumption of excessive fluids or known bladder irritants 
 
3. Children with chronic constipation who are non-compliant with previous pharmacologic 
efforts to treat. 
 
4. Children who are not adequately potty trained 
 
5. Children with significant daytime symptoms of overactive bladder including frequency, 
urgency, and daytime incontinence 
 
5. Children who do not tolerate initial stimulation training session in the urology clinic upon 
enrollment 
 
6. Children with any implantable medical devices such as a pacemaker will be excluded 
from the study 
 
Note: Any patient currently taking medication such as an anti-muscarinic or a tricyclic 
antidepressant for overactive bladder at time of enrolllment will be eligibale to participate 
and will be continued on their usual medication and dosage throughout the study.  
3.15 
Will HIV serostatus be evaluated specifically for the purpose of participation in 
this research study? 
 
*  No  
 
 
If Yes, provide a justification: 
 
  
Section: Section 4 - Recruitment and Informed Consent Procedures
    [reviewer notes¬]  
4.1 
Select all recruitment methods to be used to identify potential subjects: 
Other Strategies: Described below 
  
  
 
  
  
 
  
  
 
  
  
 
  

Section: Section 4 - Recruitment and Informed Consent Procedures
4.2 
Provide a detailed description of your recruitment methods, including identifying 
and initiating contact with participants:   
Children will be assessed during clinic visit to department of pediatric urology for nocturnal 
enuresis for eligibility in this study. Medical record and detailed history will be reviewed to 
ensure no confirmed neurological diagnosis or other known etiologies of nocturnal enuresis 
including bladder irritants or constipation which would make child ineligible. Routine 
urinalysis will be reviewed to rule out any urinary tract infection. 
  
Note: Questions jump from 4.2 to 4.6 as questions 4.3-4.5 have been removed and the information is now 
captured in 4.1 
    [reviewer notes¬]  
4.6 
Are you requesting a waiver to document informed consent for any or all 
participants, for any or all procedures? (e.g., a verbal or computerized consent 
script will be used, but the subjects will not be required to sign a written informed 
consent document.  This is not a waiver to obtain consent. 
*  No 
  
    [reviewer notes¬]  
4.7 
Are you requesting a waiver to obtain informed consent or an alteration of the 
informed consent process for any of the following?  
 
  
* Yes 
  
4.7.1 
If Yes, select the reason(s) for your request: 
Medical record review for ONLY the identification of potential subjects 
 
General Requirements: The Federal Policy [45 CFR 46.116 (d)] specifies in order for a 
waiver of consent to be approved, the request must meet four criteria. For each request, 
you will be asked to provide a justification addressing how each of these criterion is met. 
  
  
 
  
Medical record review for the identification of potential subjects: 
The research involves no 
more than minimal risk to 
the subjects;  
[45 CFR 46.116 (d)(1)] 
We will only review medical records to identify potential 
subjects. We will not extract or record any information from 
the medical record. This review procedure imposes no physical 
or psychological risks to the patients. Therefore, we believe it 
has no more than minimal risk. 
The waiver or alteration will 
not adversely affect the 
rights and welfare of the 
subjects; 
[45 CFR 46.116 (d)(2)] 
The rights and welfare of these patients will not be negatively 
affected because this research team is comprised of pediatric 
urologists who already have legitimate access to the medical 
records by virtue of their clinical responsibilities. 

Section: Section 4 - Recruitment and Informed Consent Procedures
The research could not 
practicably be carried out 
without the waiver or 
alteration; 
[45 CFR 46.116 (d)(3)] 
 
It would not be practical to obtain the full consent of the 
urology patient without first reviewing the medical record. 
Medical record review is intended to determine whether or not 
the patient meets the eligibility criteria, which can not be used 
to replace the patient consent. A full consent will be 
conducted as described in this application. 
Whenever appropriate, the 
subjects will be provided 
with additional pertinent 
information after 
participation;  
[45 CFR 46.116 (d)(4)] 
 
We will not obtain any pertinent information from the medical 
record review. 
  
 
  
  
 
  
  
 
  
  
 
  
  
 
  
4.7.2 
Under what circumstances (if any) will you obtain consent from some of these 
subjects? 
Under no circumstances will we obtain consent for medical record review. However, we will 
obtain a full consent from the patient's parent or guardian for the study to be performed. 
  
  
    [reviewer notes¬]  
4.8 
Are you requesting an exception to the requirement to obtain informed consent 
for research involving the evaluation of an 'emergency' procedure? 
 
Note: This exception allows research on life-threatening conditions for which available 
treatments are unproven or unsatisfactory and where it is not possible to obtain informed 
consent. 
 
*  No 
  
    [reviewer notes¬]  
 
4.9 
Upload all consent documents for watermarking: 
 
 
Draft Consent Forms for editing: 
 
Name 
Modified Date 
New Consent  5/13/2015 12:01 PM 
 
 
 
  
      

Section: Section 4 - Recruitment and Informed Consent Procedures
 
Approved Consent Form(s): 
Name Modified Date 
    [reviewer notes¬]  
4.10 
Will all potential adult subjects be capable of providing direct consent for study 
participation?  
 
*  
Not applicable  
 
 
  
Indicate why direct consent is not possible: 
Study participants will all be children < age 18 years old and therefore consent will be 
obtained from a parent or legal guardian. 
  
    [reviewer notes¬]  
4.11 
At what point will you obtain the informed consent of potential research subjects 
or their authorized representative? 
 
After performing certain of the screening procedures, but prior to performing any of the 
research interventions/interactions  
  
4.11.1 
Address why you feel that it is acceptable to defer obtaining written informed 
consent until after the screening procedures have been performed. 
 
Our screening procedure only includes a review of patient medical record. We have a 
requested a waiver of consent for assessing medical record and provided the reasons for the 
waiver on section 4.7 
  
4.11.2 
Taking into account the nature of the study and subject population, indicate how 
the research team will ensure that subjects have sufficient time to decide whether 
to participate in this study.  In addition, describe the steps that will be taken to 
minimize the possibility of coercion or undue influence. 
The research study will be discussed in detail with the child's parent or guardian in the 
outpatient clinic by the pediatric urologist. If the parent is immediately interested in 
enrolling the child in the study, informed consent will take place during the clinic visit as will 
the providing of the TENS equipment will all necessary teaching on the use of the device. If 
the parent would like additional time to consider participation, we will wait for them to 
contact us at a later date. The intention for participation will always be initiated by the 
parent, thus we will make no attempts to call or email them if they do not contact us after 
the clinic visit. 
  
  
    [reviewer notes¬]  
4.12 
Describe the process that you will employ to ensure the subjects are fully 
informed about this research study.  
 
 
  

Section: Section 4 - Recruitment and Informed Consent Procedures
*  Addressed below:  
This description must include the following elements: 
 
who from the research team will be involved in the consent process (both 
the discussion and documentation); 
 
person who will provide consent or permission;  
 
information communicated; and 
 
any waiting period between informing the prospective participant about the study 
and obtaining consent 
In addition, address the following if applicable based on your subject population: 
 
process for child assent and parental permission 
o 
continued participation if a child subject turns 18 during participation 
 
process for obtaining proxy consent and assent for decisionally impaired subjects 
o 
continued participation if subject regains capacity to consent 
 
Drs. Stephany, Cannon, Ost, or Schneck will be involved in the consent process to discuss 
the study in detail with the parent including all of the potential risks. The consent form will 
be provided and the parent will be free to ask any questions related to the study. We will 
provide the parent with the option to sign the consent form at a later date if they choose to 
do so. 
 
Legal guardians may provide consent only if they have a court order specifically indicating 
their authority.  
4.13 
Are you requesting an exception to either IRB policy related to the informed 
consent process? 
 
For studies involving a drug, device or surgical procedures, a listed 
physicianinvestigator is required to obtain the written informed consent unless an 
exception to this policy has been approved by the IRB  
 
For all other studies, a listed investigator is required to obtain consent (Note: In 
order to request an exception to this policy, the study must be minimal risk) 
 
*  No 
If Yes, provide a justification and describe the qualifications of the individual who will 
obtain consent: 
 
  
  
4.14 
Will you inform research subjects about the outcome of this research study 
following its completion? 
 
*  No  
  
If Yes, describe the process to inform subjects of the results: 
 
Section: Section 5 - Potential Risks and Benefits
    [reviewer notes¬]  

Section: Section 5 - Potential Risks and Benefits
5.1 
Describe potential risks (physical, psychological, social, legal, economic or 
other) associated with screening procedures, research interventions/interactions, 
and follow-up/monitoring procedures performed specifically for this study:  
 
*  
View 
Research Activity: 
Electrical Stimulation of the Foot  
Common Risks: 
Common risks may include potential foot cramp, skin irritation, 
redness, or rash.   
Infrequent Risks: 
N/A  
Other Risks: 
N/A  
View 
Research Activity: 
Medical Record Review  
Common Risks: 
No Value Entered  
Infrequent Risks: 
No Value Entered  
Other Risks: 
Potential for breach of confidentially   
  
  
5.1.1 
Describe the steps that will be taken to prevent or to minimize the severity of the 
potential risks: 
 
  
To minimize foot cramping, the lowest threshold voltage required (to induce spontaneous 
movement of the toes) will be used for actual stimulation. To minimize the risks, the 
research procedures will be conducted by experienced personnel. The subjects will be 
appropriately trained on how to use the TENS stimulator and attach the electrodes. The 
subjects will also be told that they can call the investigators anytime with any questions or 
problems. 
  
5.2 
What steps will be taken in the event that a clinically significant, unexpected 
disease or condition is identified during the conduct of the study? 
 
*  Addressed below: 
The study will be stopped immediately in the event that a clinically significant, unexpected 
condition is identified. The subject will also be referred to appropriate care for the 
unexpected condition. 
5.3 
All the risk questions (screening, intervention/interaction, follow-up) have been merged 
into one question (5.1). 
    [reviewer notes¬]  
5.4 
Do any of the research procedures pose a physical or clinically significant 
psychological risk to women who are or may be pregnant or to a fetus? 
 
* No 
  
    [reviewer notes¬]  

Section: Section 5 - Potential Risks and Benefits
5.5 Do any of the research procedures pose a potential risk of causing genetic mutations that 
could lead to birth defects? 
 
*  No 
  
    [reviewer notes¬]  
5.6 
Are there any alternative procedures or courses of treatment which may be of 
benefit to the subject if they choose not to participate in this study? 
 
*  Not applicable 
 
If Yes, describe in detail: 
 
  
  
    [reviewer notes¬]  
5.7 
Describe the specific endpoints (e.g., adverse reactions/events, failure to 
demonstrate effectiveness, disease progression) or other circumstances 
(e.g., subject's failure to follow study procedures) that will result in discontinuing 
a subject’s participation? 
 
*  Describe below: 
 
The study is expected to end when the six weeks have been completed with associated 
completion of weekly night-time voiding log and quality of life questionnaires. However, if 
the subject can not follow the study procedures such as an inability to tolerate foot 
stimulation or non-compliance with completing night-time voiding logs and/or quality of life 
questionnaires, the subject's participation will be discontinued and the study will be ended. 
 
We expect some electrodes to detach from the foot. However, occasional unattached 
electrodes will not end the study, since the data will be collected in a week period and a few 
occurrences of detachment should not change the results. Also, if skin irritation is caused by 
the electrodes, the study will continue by using the other foot and giving the irritated foot a 
day or two to recover. However, if unexpected serious irritation occurs that cannot be 
avoided by changing feet, the study will be terminated for that subject. 
 
 
  
  
    [reviewer notes¬]  
5.8 
Will any individuals other than the investigators/research staff involved in the 
conduct of this research study and authorized representatives of the University 
Research Conduct and Compliance Office (RCCO) be permitted access to research 
data/documents (including medical record information) associated with the 
conduct of this research study? 
 
*  No 
 
   

Section: Section 5 - Potential Risks and Benefits
5.9 
Has or will a Federal Certificate of Confidentiality be obtained for this research 
study? 
*  No 
  
5.10 
Question has been moved to 5.17 
5.11 
Question has been moved to 5.16 
  
    [reviewer notes¬]  
5.12 
Does participation in this research study offer the potential for direct benefit to 
the research subjects? 
 
No - Describe the general benefits to society (e.g., increased knowledge; improved safety; 
better health; technological advancement) that may result from the conduct of this 
research study.  
  
Describe the benefit: 
The subject may not receive direct benefit from participation in this research study. 
Although the electrical stimulation may help with nocturnal enuresis, this benefit is not 
known or guaranteed. However, information learned from this study will help investigators 
learn how to better manage the conditions of nocturnal enuresis.  
  
5.13 
Describe the data and safety monitoring plan associated with this study. If the 
research study involves multiple sites, the plan must address both a local and 
central review process. 
 
11. Drs. Stephany, Tai and Ferroni will be responsible for the data and safety monitoring. 
 
2. After the ADDITIONAL 3 WEEKS OF ONGOING stimulation, parents will be called on the 
telephone by either Dr. Stephany or Dr. Ferroni to inquire if any issues and assess the 
child's tolerability to continue treatments. All questions will be addressed as well. If no 
issues, the patient will continue the EXTENDED study and follow-up in clinic at the 
conclusion to submit their completed log and return the stimulation device. If during the 
monitoring telephone call an issue is detected, Drs. Ferroni or Stephany will attempt to 
troubleshoot issues related to device usage over the telephone. A follow-up phone call will 
be scheduled on an as needed basis (2-3 days later) if any adjustments are made to the 
parents' technique of providing the stimulation or adjustments to the device settings. If at 
the monitoring phone call it is determined that the child is not reasonably tolerating the 
stimulation and/or they have developed concerning side effects, a prompt clinic 
appointment will be made to assess the child in person and remove them from the study. 
 
3. The investigators will monitor the progress of the study and the efficacy of the treatment 
after collecting data from the first 10 subjects. Any unexpected adverse effect will be 
addressed immediately and reported to the IRB committee. In addition to the monitoring of 
every 10 subjects, an annual review of the study will also be conducted to assure the 
experimental design, identify any unexpected adverse effects for reporting, and review the 
progress of subject recruitment 
 
4. The data will be locked in the urology office by the investigators for safety and privacy. 
An annual review of the safety and privacy of the data will be performed. If any problem 
occurs, it will also be addressed immediately during any time of the year. 
 
5. The following will be reported to IRB annually: a list of persons who monitored the data 
 
  
  

Section: Section 5 - Potential Risks and Benefits
and safety; the date when the monitoring/review occurs; a summary of any problems 
detected; final decisions about changes of the study based on the annual review. 
 
6. The potential adverse events may be reported to IRB including: 
Use of TENS stimulator: Foot skin irritation, redness, or rash, or foot cramp. 
 
    [reviewer notes¬]  
 
Section 5 - Potential Risks and Benefits of Study Participation 
5.14 What precautions will be used to ensure subject privacy is respected? (e.g. the research 
intervention will be conducted in a private room; the collection of sensitive information about 
subjects is limited to the amount necessary to achieve the aims of the research, so that no 
unneeded sensitive information is being collected, drapes or other barriers will be used for 
subjects who are required to disrobe) 
  
The initial instruction of the TENS device will be conducted in a private examination room in the 
urology clinic. The 6 to 12-week voiding diaries and quality of life questionnaires will be 
conducted by the subjects/parents at home without privacy concerns. 
  
 
5.15 What precautions will be used to maintain the confidentiality of identifiable 
information? (e.g., paper-based records will be kept in a secure location and only be accessible 
to personnel involved in the study, computer-based files will only be made available to personnel 
involved in the study through the use of access privileges and passwords, prior to access to any 
study-related information, personnel will be required to sign statements agreeing to protect the 
security and confidentiality of identifiable information, whenever feasible, identifiers will be 
removed from study-related information, precautions are in place to ensure the data is secure by 
using passwords and encryption, because the research involves web-based surveys, audio 
and/or video recordings of subjects will be transcribed and then destroyed to eliminate audible 
identification of subjects) 
  
The subject's name will only be used for screening and scheduling purposes. Once the subject 
enters the experiment, an ID number will be assigned to each subject in place of his/her name 
and only the subject's age and gender will be recorded for privacy reasons. Subject name will 
not appear on data collection forms.  
 
The information linking the ID number with the subject's name will be stored in a separate 
secure location during the study, and will be destroyed at the end of the study. We will not keep 
any document to link the subject's name to the ID number. After the study is finished, we will 
have consent forms with subjects names and data forms with ID numbers. Since the link 
between names and ID numbers are not kept, there will be no identifiable information that could 
be released. However, the data on papers will still be locked for safety reasons and the 
electronic data will be stored in password-protected, fire-walled computers. 
 
  
  
  
  
  
 
5.16 If the subject withdraws from the study, describe what, if anything, will happen to the 
subject’s research data or biological specimens. 
If a subject requests withdrawal or is withdrawn by the PI, no further data should be collected, 
but all data obtained prior to withdraw will be retained and analyzed for the study purposes.   
 
5.17 Following the required data retention period, describe the procedures utilized to 
protect subject confidentiality. (e.g., destruction of research records; removal of identifiers; 
destruction of linkage code information; secured long-term retention) 
  
 

Section: Section 5 - Potential Risks and Benefits
After the required data retention period, all data and subject information will be destroyed. 
  
Section: Section 6 - Costs and Payments
    [reviewer notes¬]  
  
6.1 
Will research subjects or their insurance providers be charged for any of the 
procedures (e.g., screening procedures, research procedures, follow-up 
procedures) performed for the purpose of this research study? 
*   
No  
  
    [reviewer notes¬]  
6.2 
Will subjects be compensated in any way for their participation in this research 
study? 
 
*  Yes 
6.2.1 
Describe the amount of payment or other remuneration offered for 
complete participation in this research study. 
$200 for complete participation involving the completion of 6-week night-time voiding log 
and quality of life questionnaires as well as the ability to tolerate foot stimulation during the 
third and fourth week of the study. Upon receipt of all completed forms and return of the 
TENS equipment, compensation will be distributed. 
There will be no additional compensation for the subjects who wish to continue with the 
study for an additional 6 weeks 
  
6.2.2 
Describe the amount and term of payment or other remuneration that will be 
provided for partial completion of this research study. 
$50 for partial completion. Partial completion is defined as that the subject has signed the 
consent form and the study has begun, but the data collection is not finished. 
  
  
Section: Section 7 - Qualifications and Source(s) of Support
    [reviewer notes¬]  
7.1 
Summarize the qualifications and expertise of the principal investigator and listed 
co-investigators to perform the procedures outlined in this research 
study.                
 
Heidi A. Stephany, MD, is an assistant professor of urology at the University of Pittsburgh 
School of Medicine. She received her medical DEGREE from the University of Kansas School 
of Medicine, where she also completed a residency in urology. Dr. Stephany completed a 
fellowship in pediatric urology at Vanderbilt University in Nashville, Tenn., and specializes in 
pediatric urology. 
 
Changfeng Tai, PhD, Assistant Professor Dr. Tai has many years of experience in electrical 
stimulation, neurophysiology, and urologic studies. The TENS stimulator is a FDA-approved 
device for rountine use by individuals at home for muscle and back pain. Therefore, he is 
  

Section: Section 7 - Qualifications and Source(s) of Support
qualified for performing the non-invasive electrical stimulation of the foot using skin surface 
electrodes and the TENS stimulator during the initial instruction period for the subjects. 
 
Matthew C. Ferroni, MD, is a urologic surgery resident at the University of Pittsburgh School 
of Medicine. He received his medical DEGREE FROM Thomas Jefferson University in 
Philadelphia, PA. Prior to his current career in medicine, Dr. Ferroni spent five years 
working in financial services after graduating from Boston College in 2001. His interests 
within the field of urology center around minimally invasive surgery and oncology. 
 
Michael C. Ost, MD, is an associate professor of urology and vice chairman of the 
Department of Urology, University of Pittsburgh School of Medicine and chief of the division 
of pediatric urology at Children's Hospital of Pittsburgh of UPMC. He is a graduate of the 
University of Michigan and earned his MEDICAL DEGREE at Mount Sinai School of Medicine. 
Following surgical and urologic residencies at Mount Sinai, Dr. Ost completed fellowship 
training in endourology at the North Shore — Long Island Jewish Medical Center and in 
pediatric urology at Children’s Hospital of Pittsburgh of UPMC. Dr. Ost’s clinical interests 
include adult and pediatric minimally-invasive urologic surgery, robotic treatment of 
urologic diseases and complex stone disease. He is a member of the American Urological 
Association and the Endourological Society.  
 
Glenn M. Cannon, MD, is an assistant professor of urology at the University of Pittsburgh 
School of Medicine. A graduate from Thomas Jefferson University Medical College, Dr. 
Cannon completed residencies in urology at the University of Pittsburgh, and in surgery at 
Barnes-Jewish Hospital in St. Louis. He also completed a fellowship in pediatric urology at 
the Children’s Hospital of Boston 
 
Francis X. Schneck, MD, is an associate professor of urology at the University of Pittsburgh 
School of Medicine. He earned his medical DEGREE FROM the Georgetown University School 
of Medicine in 1987, and completed a residency in urology at the University of Pittsburgh 
School of Medicine in 1993 and a pediatric urology fellowship at the Harvard Medical School 
and Children's Hospital in 1995. He joined UPMC upon completion of his fellowship. He is 
the author of numerous articles and book chapters in the field of pediatric urology. Dr. 
Schneck is board certified by the American Board of Urology. 
    [reviewer notes¬]  
7.2 Indicate all sources of support for this research study. 
 
*  
Selections 
Foundation: Upload a copy of the research plan that was submitted to the agency 
 
  
 
 
If Federal support, provide the sponsor information: 
  Federal sponsor Grant Title Grant number Awardee institution 
Federal grant application 
 
  
 
 
 
 
 
For projects not supported by a federal grant, upload the research plan that was submitted for 
funding: 
 
Name Modified Date 

Section: Section 7 - Qualifications and Source(s) of Support
 
If Industry support, provide the sponsor information and level of support: 
 
 
 
If Foundation support, provide the sponsor information: 
A grant of $25,000 was received by Dr. Tai from the Society of Urodynamics and Female Urology in 
order to proceed with research studies evaluating the clinical impact of neuromodulation. This grant 
will cover all equipment costs, and patient compensation required for completion. 
 
 
If Other support, provide the support information and level of support: 
 
    [reviewer notes¬]  
  
7.3 
Is this study funded in part or whole by a PHS Agency? 
 *  No  
  
 
Does any investigator* involved in this study (select all that apply): 
 
  
Name 
 
 
A. Have equity in a publicly-traded entity that either sponsors** this research or 
owns the technology being evaluated or developed that exceeds a 5% ownership 
interest or a current value of $10,000? 
 
 
B. Have equity in a non-publicly-traded entity that either sponsors this research or 
owns the technology being evaluated or developed? 
 
 
C. Receive salary, consulting fees, honoraria, royalties or other remuneration from an 
entity that either sponsors this research or owns the technology being evaluated or 
developed that is expected to exceed $10,000 during the past or next 12 months? 
 
 
D. Have rights as either the author or inventor of intellectual property being 
evaluated or developed in this research that is the subject of an issued patent or has 
been optioned or licensed to an entity? 
 
 
E. Have an officer or management position**** with a Licensed Start-up 
Companyoverseen by the COI Committee that either sponsors this research or owns 
the technology being evaluated or developed? 
 
 
F. Receive compensation of any amount when the value of the compensation would 
be affected by the outcome of this research, such as compensation that is explicitly 
greater for a favorable outcome than for an unfavorable outcome or compensation in 
the form of an equity interest in the entity that either sponsors this research or owns 
the technology being evaluated or developed? 
 
 
None of the above options apply and there are no other financial conflicts of 
interest in the conduct of this research. 
*Investigator means the PI, co-investigators, and any other member of the study team, 
regardless of title, who participates in the design, conduct, or reporting of this research, as 
well as his/her spouse, registered domestic partner, dependents, or other members of 
  

Section: Section 7 - Qualifications and Source(s) of Support
his/her household. The PI is responsible for ensuring that s/he and all other 
relevant members of the study team review the above questions describing 
Significant Financial Interests.  
**through the provision of funds, drugs, devices, or other support for this research 
****Such as serving on the Board of Directors or Board of Managers or a position that 
carries a fiduciary responsibility to the company (e.g., CEO, CFO, CTO, or CMO). 
  
Section: Supporting Documentation
    [reviewer notes¬]  
  
Supporting Documentation Section 
References and Other Attachments 
  
 
Additional documents: 
Name 
Modified Date 
Version 
Grant Approval 
Letter 
8/26/2014 8:24 
AM 
0.01 
Reference List 
9/15/2014 12:15 
PM 
0.01 
 
  
 
Please use the Add button to the left to upload additional 
documents if needed. 
 
    [reviewer notes¬]  
ClinicalTrials.gov is a registry and results database of publicly and privately supported 
clinical studies of human participants conducted around the world. 
"Applicable clinical trials" are required by federal law to be registered in ClinicalTrials.gov. 
Applicable Clinical Trials (ACTs) are studies that meet the following criteria: 
 
The study is an interventional study AND  
 
The study intervention is a drug, biologic, medical device, radiation or genetic AND 
 
The Study is not Phase 0 or 1 AND 
 
The study has at least one site in the United States or is conducted under an investigational 
new drug application or investigational device exemption 
NIH Policy 
Effective January 18, 2017, revised NIH Policy requires that all clinical trials funded in whole or in part 
by the NIH be registered and results information posted on ClinicalTrials.gov.  

Section: Supporting Documentation
As defined by the NIH, a clinical trial is: 
A research study in which one or more human subjects are prospectively assigned to one or more 
interventions (which may include placebo or other control) to evaluate the effects of those interventions 
on health related biomedical or behavioral outcomes. 
The NIH Policy extends beyond the Food and Drug Administration Amendment Act (FDAAA 801) 
requirements in that it requires registration and results reporting of: 
 
clinical trials of behavioral, surgical and other types of health and medical interventions 
 
phase 1 studies of drugs and biological products 
 
small feasibility studies of device products  
Failure to submit all required registration and results information requested on ClinicalTrials.gov can 
jeopardize University grant funding, the future funding of the grantee and subject the University of 
Pittsburgh to future monetary penalties. 
In addition, to promote transparency of the clinical trials process, the International Committee of 
Medical Journal Editors (ICMJE) has established a policy requiring the entry of clinical trials in a public 
registry, such as ClinicalTrials.gov, prior to subject enrollment as a condition of consideration for 
publication of the trial results. 
* Based on the above information, will this study be registered in ClinicalTrials.gov?