Clinical Feasibility Study, Implantable Tibial Nerve Stimulator (ITNS)
Phase: NA
Conditions: Overactive Bladder
Sponsor: Nine Continents Medical, Inc.

NCT04115228 Study Protocol and Statistical Analysis Plan 
 
 
Nine Continents Medical, Inc 
Revision date 2020-05-21 
Page 1 of 19 
 
 
 
 
 
 
 
 
 
 
 
Clinical feasibility study, implantable tibial nerve stimulator (ITNS) 
 
 

NCT04115228 Study Protocol and Statistical Analysis Plan 
 
 
Nine Continents Medical, Inc 
Revision date 2020-05-21 
Page 2 of 19 
 
Contents 
1 
Introduction ............................................................................................................................. 3 
2 
Study design ............................................................................................................................ 3 
2.1 
Inclusion and exclusion criteria........................................................................................ 3 
2.2 
Medicare beneficiaries ..................................................................................................... 5 
2.3 
Endpoints .......................................................................................................................... 5 
3 
Methods for assessing and recording variables ....................................................................... 6 
3.1 
Procedures ........................................................................................................................ 6 
3.2 
Study devices and equipment ........................................................................................... 8 
3.3 
Subjects ............................................................................................................................ 9 
3.4 
Procedure timing requirements ...................................................................................... 10 
3.5 
Adverse events and device deficiency definitions ......................................................... 11 
3.6 
Activities performed by sponsor .................................................................................... 13 
3.7 
Investigator selection and training ................................................................................. 13 
4 
Data management .................................................................................................................. 13 
4.1 
Case report forms (CRFs) .............................................................................................. 13 
4.2 
Procedures used for data review, database cleaning, and issuing and resolving data 
queries ....................................................................................................................................... 13 
4.3 
Procedures for verification, validation and securing of electronic clinical data systems, 
if applicable. .............................................................................................................................. 13 
4.4 
Procedures for data retention and specified retention period ......................................... 13 
4.5 
Other aspects of clinical quality assurance, as appropriate ............................................ 13 
4.6 
Study report .................................................................................................................... 14 
5 
Rationales for endpoints ........................................................................................................ 15 
5.1 
Rationale for the criterion for improvement in frequency ............................................. 15 
5.2 
Rationale for the criterion for worsening ....................................................................... 15 
5.3 
Dichotomous and continuous criteria ............................................................................. 16 
5.4 
Effectiveness data from prior studies ............................................................................. 16 
6 
Rationale for type of design ................................................................................................... 17 
7 
Future pivotal study ............................................................................................................... 18 
8 
Deviations from clinical protocol .......................................................................................... 18 
9 
Suspension or premature termination of the clinical investigation ....................................... 18 
10 
Amendments ...................................................................................................................... 18 
11 
Device accountability......................................................................................................... 19 
12 
Statements of compliance .................................................................................................. 19 

NCT04115228 Study Protocol and Statistical Analysis Plan 
 
 
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Revision date 2020-05-21 
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13 
Publication policy .............................................................................................................. 19 
 
1 
Introduction 
Study title: Clinical feasibility study, implantable tibial nerve stimulator (ITNS); ITNS-01.  
Study sponsor: Nine Continents Medical, Inc., 302 Alden Lane, Livermore, CA 94550 USA. 
Study objectives: To report feasibility data for safety and effectiveness of the study device.  
Study device: Nine Continents Medical implantable tibial nerve stimulator (ITNS) model 9C-680 
with programmer model 9C-580. 
Intended use: The study device is intended for treatment of the symptoms of overactive bladder 
(OAB), including urinary urge incontinence and significant symptoms of urgency-frequency 
alone or in combination, in patients who have failed or could not tolerate more conservative 
treatments. 
2 
Study design 
Type of design: Single-arm longitudinal design with no implanted comparator.  
Study sites: Single site, in the United States. 
Number of subjects: The investigator will implant a study device in each of 10 subjects, to permit 
gathering meaningful data for evaluating study endpoints while constraining the number of 
subjects exposed to residual risks. This sample size conforms to FDA recommendations (FDA, 
2013-10-01). 
Study duration: One year total, comprising six months for enrolling and implanting 10 subjects, 
and 26 weeks for follow-up. The follow-up period allows for biological stabilization at the 
implant site and for assessing the effect of neuromodulation therapy on OAB symptoms. 
To minimize or avoid bias: This protocol specifies inclusion and exclusion criteria and 
standardized methods and timing for assessing variables. It requires standardized case report 
forms for recording variables, and it specifies methods for analyzing variables. 
2.1 
Inclusion and exclusion criteria 
The target population is the population indicated for third-line therapy for OAB. To avoid 
exposing subjects to risks in the absence of any anticipated benefit, exclusion criteria are 
intended to prevent implantation in subjects for whom success is unlikely due to general health 
issues. Any exclusion criterion disqualifies a subject from further participation in the study. 
Although this is a feasibility study, it uses the same inclusion and exclusion criteria planned for a 
pivotal study. The purpose is to gain experience evaluating potential subjects with these criteria 
and to select a study population representative of the intended target population. 
Type of criteria 
List of criteria 
Inclusion criteria 
assessed at pre-
screening evaluation. 
Each subject must 
meet all. 
Age 18 years or older 
Documented diagnosis of overactive bladder 
Documented failed behavioral intervention and/or physical therapy  
Documented failed first drug for overactive bladder 
Documented failed second drug for overactive bladder 

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Type of criteria 
List of criteria 
Inclusion criteria 
assessed at screening 
visit. Each subject 
must meet all. 
Life expectancy of at least one year 
Capable of tolerating the implantation procedure 
Ambulatory and able to use the toilet independently and without 
difficulty 
Able to sense and tolerate posterior tibial nerve stimulation 
(transcutaneous test) 
Inclusion criteria 
based on 3-day pre-
therapy diary. Each 
subject must meet at 
least one. 
Average daily voids during waking hours ≥ 11 
Average daily voids interrupting sleep ≥ 2.0 
Average daily voids associated with urgency ≥ 4 
Average daily incontinence episodes ≥ 1 
Exclusion criteria 
assessed at pre-
screening evaluation, 
and confirmed by 
interview at screening 
visit. No subject may 
meet any. 
Predominant stress incontinence 
For females, pelvic organ prolapse with POP-Q ≥ grade II 
Neurologic disease, e.g. MS, Parkinson’s 
Abnormal upper urinary tract function 
Neurogenic bladder 
Bladder stone or tumor 
BMI > 40 
Chronic pelvic pain 
Urinary fistula 
Peripheral neuropathy 
History of failed neuromodulation for overactive bladder 
Uncontrolled bleeding disorder 
End stage renal failure, GFR < 35, or dialysis  
Untreated diabetes or A1C > 7 
Implanted pacemaker, defibrillator, or neurostimulator 
History of pelvic cancer within the past two years 
Condition requiring magnetic resonance imaging (MRI) 
Condition requiring diathermy 
Metallic implant in planned site of study device  
For females, pregnant 
For females, planning to become pregnant 
For females, given birth in the last 6 months 
For females, of child-bearing potential and not willing to practice a 
medically-approved method of birth control during the study 

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Type of criteria 
List of criteria 
Exclusion criteria 
assessed at physical 
examination and tests 
at screening visit. No 
subject may meet any. 
Anatomical restriction preventing device placement 
Skin lesions or compromised skin at the implant site 
For females, pelvic organ prolapse with POP-Q ≥ grade II 
Post-void residual > 150 cc 
Urinary tract mechanical obstruction due to urethral stricture 
Urinary tract mechanical obstruction due to bladder neck contracture 
In males, urinary tract mechanical obstruction due to BPH 
Vesicoureteral reflux 
Cystoscopic abnormalities that could be malignant 
Current cystitis 
Current urethritis 
Gross hematuria 
In females, positive pregnancy test 
Exclusion criteria 
assessed at pre-
screening evaluation, 
screening visit, and 
pre-implantation 
evaluation. 
Any other medical condition with potential effect on bladder 
function, as assessed by investigator 
Any other medical condition that could compromise the safety of the 
subject, as assessed by investigator 
 
2.2 
Medicare beneficiaries 
Medicare beneficiaries with symptoms of overactive bladder could benefit from the device if it 
performs as intended. Prevalence of overactive bladder is approximately 30 % in the general 
population 65 to 74 years old (Stewart, et al., 2003). Therefore a significant percentage of the 
population eligible for Medicare due to age has symptoms of overactive bladder. The percentage 
of the population eligible for Medicare due to disability, who also have symptoms of overactive 
bladder, is not known. Criteria in §2.1 exclude individuals eligible for Medicare due to ESRD 
but do not exclude those eligible due to ALS. 
2.3 
Endpoints 
A clinical feasibility study is a clinical investigation that is commonly used to capture 
preliminary safety and effectiveness information on a near-final or final device design to 
adequately plan an appropriate pivotal study (FDA, 2013-10-01). A feasibility study does not 
collect definitive evidence; consequently it does not require statistical hypotheses or classifying 
objectives and endpoints as primary or secondary. 
Section 5 on page 15 provides rationales for endpoints. 
Type of endpoints 
List of endpoints 
Safety 
Incidence, severity, and relatedness of all adverse events and device 
deficiencies. 
Stability of neuromodulation pulse amplitude required to evoke 
paresthesia or muscle response (“threshold”). 

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Type of endpoints 
List of endpoints 
Effectiveness, OAB 
symptoms  
Averages per 24 
hours, measured with 
3-day voiding diaries 
Incontinence: Improvement = 50 % reduction from baseline of 
number of episodes. Dryness = 0 episodes. 
Frequency: Improvement = 50 % reduction from baseline of voids 
during waking hours exceeding 7. Cure = number of voids during 
waking hours ≤ 7 (note: FDA uses the term “cure” to describe normal 
frequency). 
Nocturia: Improvement = 50% reduction from baseline of number of 
voids interrupting sleep. 
Urgency: Improvement = 50% reduction from baseline of number of 
voids self-reported with moderate to severe urgency. 
Effectiveness, 
responder criterion 
Subject demonstrating 50 % reduction in at least one relevant OAB 
symptom above and no worsening of their relevant symptoms 
overall.  
Here “relevant” means meeting the inclusion criterion for a symptom 
at baseline, and “overall” means average of percentage changes over 
all relevant symptoms. 
Effectiveness, quality 
of life 
OAB-q, short form symptom bother (Coyne, Matza, & Thompson, 
2005). 
GRA, global response assessment (Propert, et al., 2006). 
3 
Methods for assessing and recording variables 
3.1 
Procedures 
The study will include procedures listed below and will document results with standardized case 
report forms (CRFs). Refer to designated forms for detailed instructions for each procedure, and 
refer to §3.4 for procedure timing requirements. 
Procedure 
Form # 
Purpose 
Pre-
screening 
evaluation 
D-00288 
Preliminary assessment of medical records for inclusion and 
exclusion criteria for potential subject. 
Informed 
consent 
R-00108 
Documentation of potential subject’s informed consent, required 
for enrollment in the study and participation in procedures 
required specifically for the study.  
Screening 
visit 
D-00290 
Record of demographics. Confirmation of inclusion and 
exclusion criteria though subject interview; physical examination; 
urodynamics, cystoscopy, urinalysis, and pregnancy tests 
(subjects without documented urodynamics and cystoscopy 
results prior to screening will be required to undergo these tests 
before completion of the screening visit). 

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Procedure 
Form # 
Purpose 
Pre-therapy 
diary 
D-00291 
3-day voiding diary to assess baseline incontinence, frequency, 
nocturia, and urgency. OAB-q SF for quality of life (QOL). 
Subjects may optionally continue the diary for up to 7 days total. 
Subjects who cannot or will not complete a diary will exit the 
study.  
Pre-
implantation 
evaluation 
D-00292 
Assessment of routine blood chemistry, and OAB symptom 
severity from pre-therapy diary, to qualify or disqualify subject 
for device implantation. 
Implantation 
procedure 
D-00293 
Implantation of ITNS per IFU. Threshold assessment with 
external device and ITNS. ITNS therapy programmed off for a 4-
week healing period. 
4-week 
follow-up 
visit 
D-00294 
Threshold assessment with ITNS for changes since implantation. 
ITNS programmed to threshold amplitude and daily therapy (for 
potentially reducing time to therapy effect). 
6-week 
follow-up 
visit 
D-00295 
Threshold assessment with ITNS for changes after two weeks of 
daily ITNS therapy. ITNS programmed to threshold amplitude 
and weekly therapy (to preserve device longevity). 
Daily 
therapy 
diary 
(optional) 
D-00296 
3-day voiding diary to assess changes from baseline OAB 
symptoms after 2 weeks of daily ITNS therapy. OAB-q and GRA 
to assess QOL changes. Subjects may optionally continue the 
diary for up to 7 days total. 
19-week 
follow-up 
visit 
D-00297 
Threshold assessment with ITNS for changes after 13 weeks of 
weekly ITNS therapy. ITNS programmed to threshold amplitude 
and weekly therapy. 
Weekly 
therapy 
diary 
D-00298 
3-day voiding diary to assess changes from baseline OAB 
symptoms after 13 weeks of weekly ITNS therapy. OAB-q and 
GRA to assess QOL changes. Subjects may optionally complete a 
second weekly therapy diary at 26 weeks after implantation. 
Subjects may optionally continue each diary for up to 7 days 
total. 
26-week 
follow-up 
visit 
D-00299 
Final safety assessment 26 weeks after implantation. Non-
responders (as assessed with the latest weekly therapy diary) 
require device explantation; responders continue with site’s 
standard of care. 
Explantation 
procedure 
D-00300 
Explantation of ITNS for any subject with an unplanned exit 
during the study or for a non-responder after 26 weeks of 
implantation. 
Adverse 
event 
D-00301 
Assessment of nature, onset, actions taken, outcome, relatedness, 
and seriousness for any unfavorable medical occurrence, 
including patient complaints. 

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Procedure 
Form # 
Purpose 
Device 
deficiency 
D-00302 
Record of nature, onset, and actions taken for any device 
malfunction, use error, or inadequate labeling. 
Unplanned 
exit 
D-00303 
Record of any exit from the study due to withdrawal of consent, 
death, or loss to follow-up (including date and type of three 
attempts to contact the subject). Withdrawal of consent for 
dissatisfaction with device or procedure also requires an adverse 
event form. 
Protocol 
deviation  
D-00304 
Description of type and reason for any protocol deviation, where 
a required item was not performed, performed early or late, or 
performed not according to protocol. 
3.2 
Study devices and equipment  
Summary description: The study device is a miniaturized implantable pulse generator with an 
integrated electrode lead. The pulse generator is powered by a primary (non-rechargeable) 
lithium cell. It can be programmed non-invasively by timed applications of an external magnet, 
or it can be programmed and interrogated non-invasively by external programmer model 9C-580. 
Device manufacturer: Nine Continents Medical, Inc., 302 Alden Lane, Livermore, CA 94550 
USA. 
Device identification: Model number 9C-680. 
Device traceability: Each device has a unique serial number. 
Device purpose: The pulse generator automatically provides stimulation at a pulse pattern and 
frequency preset to match those of percutaneous tibial nerve stimulation (PTNS), without 
requiring clinic visits for the patient to receive therapy. 

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Materials in contact with tissues or body fluids: Refer to the drawing below. The study device 
does not contain medicinal products, human or animal tissues or their derivatives, or other 
biologically active substances. 
 
Training and experience needed to use the device: This is a prescription device for implantation 
by a physician. The investigator will complete study and device training before using the device.  
Medical or surgical procedures involved: The miniaturized pulse generator is permanently 
implanted via a percutaneous procedure. The implant site is subcutaneous in the medial lower 
calf, distal to the gastrocnemius muscle. The electrode-lead integrated with the pulse generator is 
advanced distally from the same incision with a marketed implant kit. The study device provides 
electrical pulses to the posterior tibial nerve at a point approximately 5 centimeters proximal to 
the medial malleolus, which is the same location where PTNS is applied. 
Background for study: Refer to sponsor’s report of prior investigations R-00105 for a detailed 
list of verification and validation studies successfully completed for ITNS model 9C-680 and 
programmer model 9C-580. Briefly, ITNS validation studies included sterile packaging, 
sterilization, biocompatibility, and a six-month animal study with eight ITNS implanted in four 
sheep. ITNS verification studies included electromagnetic compatibility; electrical specifications, 
safety, and reliability; mechanical specifications, safety, and reliability; and device longevity and 
lithium cell integrity. Programmer verification studies included electromagnetic compatibility 
and electrical safety. ITNS and programmer software were validated. Risk analysis included 
system-level functions, RF wireless technology, and cybersecurity.  
3.3 
Subjects 
Point of enrollment: The investigator will enroll study subjects at approved investigational sites 
after completing an investigator’s agreement and receiving notification from the sponsor that the 
study has started. 

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Concomitant medication: Medication to be used during the study is at the investigator’s 
discretion, however any change in medication with urinary effects or side effects after the 
screening visit must be recorded as a protocol deviation. 
Replacement of subjects: This study has inclusion and exclusion criteria (§2.1 on page 3) 
intended to ensure that subjects complete the protocol after they receive the study device. 
Consequently this protocol has no provision for replacement of subjects after implantation. 
Efforts to minimize missed visits and drop-outs: The sponsor or sponsor’s designee will monitor 
the investigation as described in its established monitoring procedure and will promptly inform 
the investigator concerning missing data or missed visits. The investigator will remind subjects 
of scheduled visits by telephone or by E mail, and will document at least three (3) efforts to 
contact subjects who miss a visit (e.g. via registered mail, E mail, or telephone). If a patient 
cannot be contacted, this becomes a withdrawal or discontinuation. 
Incentives for subjects: The investigator may provide special incentives to subjects for study 
compliance, but the compensation may not be so large as to unduly encourage the subjects to 
participate. 
Withdrawal or discontinuation: A subject may withdraw from the study at any time, for any 
reason, and without stating a reason. Withdrawal or discontinuation will not prejudice a subject’s 
future medical care by the investigation team or investigation site. Upon withdrawal or 
discontinuation a subject will have their ITNS explanted. An investigator may discontinue a 
subject’s participation for any of the reasons below: 
 Any unanticipated adverse device effect (see adverse event CRF) which is, in the opinion 
of the investigator, related to the treatment and will endanger the well-being of the patient 
if treatment is continued;  
 Development of any concurrent illness, infection, or condition that might interfere with 
the investigation;  
 Non-compliance with the clinical investigation procedures deemed by the investigator to 
be sufficient to cause discontinuation; or 
 Any other problem deemed by the investigator to be sufficient to cause discontinuation.  
Follow-up care: Subjects who do not qualify as responders at the 26-week visit will have their 
ITNS explanted. The investigator will provide medical care for the subjects after the clinical 
investigation has been completed, conforming to their standard practice. 
3.4 
Procedure timing requirements 
Informed consent must be signed before a subject undergoes any test or procedure not required 
for routine care outside the study. For example, the following tests may be performed before 
signed informed consent, provided they are necessary for a patient’s routine care: blood and 
urine analyses, physical examination, urodynamics, cystoscopy, and pre-therapy diary. The study 
device must never be used without prior signed informed consent. The investigator or an 
individual they designate must meet with each prospective subject to explain the study and 
alternatives before requesting consent. 
The pre-therapy diary provides a baseline for calculating symptom improvement after 
implantation of the study device, consequently any improvement of OAB symptoms in the pre-
therapy diary due to prior therapy and medications could mask the effectiveness of the study 
device. Investigational sites may use the study’s pre-therapy diary form for routine care outside 
the study. However, any pre-therapy diary used for the study must start: 

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1. At least 4 weeks after the most recent: 
 Use of any anti-muscarinics, beta-3 adrenergic agonists, or other OAB medications; 
 Dose change of any other medications with urinary side effects (e.g. Flomax, tri-
cyclic antidepressants, diuretics); or 
 TENS use (back, pelvic, or legs).  
2. After sufficient time for symptoms to return to baseline levels of after stopping PTNS or 
Botox for OAB. This time varies from subject to subject. 
When completing the pre-screening, screening, and pre-implantation case report forms, the 
investigator may use results from tests performed for a patient’s routine care outside the study, 
provided that the results are documented in the patient’s medical record, and remain valid for the 
subject’s current medical condition in the investigator’s medical judgment. For example, this 
may include results from blood and urine analyses, physical examination, urodynamics, 
cystoscopy, and a pre-therapy diary as described above. Prior measurements of PTNS current 
required for motor response or sensation may be used.  
The table below provides additional procedure timing requirements: 
From 
To 
Min weeks Max weeks 
Pre-screening evaluation 
Screening visit 
0 
4 
Informed consent 
Screening visit 
0 
4 
Screening visit 
Pre-implantation evaluation 
0 
7 
Pre-implantation evaluation 
Implantation procedure 
0 
4 
Implantation procedure 
4-week follow-up visit 
3 
5 
4-week follow-up visit 
6-week follow-up visit 
2 
3 
6-week follow-up visit 
Daily therapy diary (optional) 
0 
2 
6-week follow-up visit 
19-week follow-up visit 
12 
14 
19-week follow-up visit 
Weekly therapy diary 
0 
2 
Implantation procedure 
26-week follow-up visit 
25 
27 
26-week follow-up visit 
Explantation (if non-responder) 
0 
4 
Unplanned exit 
Explantation (if implanted) 
0 
4 
3.5 
Adverse events and device deficiency definitions 
The investigator will record and classify all adverse events and device deficiencies. They will 
record the onset and resolution times of each adverse event, noting the method of resolution. 
The investigator will record all adverse events and classify them as: 
 Device-related, procedure-related, or non-related. 
 Serious or non-serious. 
 Unanticipated adverse device effects or other. 
An adverse event is any unfavorable medical occurrence, unintended disease or injury, or 
unfavorable clinical signs (including abnormal laboratory findings), in a subject, whether device-
related, procedure-related, or non-related. It is also any such event, in a user or other person, if 
related to the study device. 
A device-related adverse event is caused or contributed to by the study device. This definition 
includes adverse events involving insufficient or inadequate instructions for the study device, 
malfunction of the study device, or use error or intentional misuse of the study device.  

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A procedure-related adverse event is caused or contributed to by a procedure required to use the 
study device.  
Because of the difficulty of determining the root cause of genitourinary events, the investigator 
will categorize events conservatively as either device- or procedure-related unless there is clear 
evidence of other causation. 
A serious adverse event is one that either: 
a) Led to death, or 
b) Led to serious deterioration in the health of the subject, that either resulted in: 
1) A life-threatening illness or injury, or 
2) A permanent impairment of a body structure or a body function, or 
3) In-patient or prolonged hospitalization, or 
4) Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
Planned hospitalization for a pre-existing condition, or a procedure required by the 
investigational plan, without serious deterioration in health, is not considered a serious adverse 
event. 
An unanticipated adverse device effect (UADE) is a serious adverse event that is device- or 
procedure-related, and is not identified in the protocol by its nature, incidence, severity, or 
outcome. The table below identifies potential serious adverse device effects: 
Nature 
Incidence 
Severity 
Outcome 
Implant-procedure related 
complication: infection; damage to 
nerves, tissues, or vessels; 
migration; erosion or extrusion; 
pain at implant site. 
< 40%, based on 
initial clinical 
experience of 
SNS 
Serious 
Surgical revision 
including 
explant; intent-
to-treat failure. 
Increase in the pulse amplitude 
required for neuromodulation, 
beyond the range of the pulse 
generator. 
< 15 % (one event 
maximum in an 
early feasibility 
trial) 
Serious 
Surgical revision 
and/or loss of 
significant 
device function. 
Study device malfunction causing 
or contributing to failure to deliver 
neuromodulation therapy. 
< 15 % (one event 
maximum in an 
early feasibility 
trial) 
Serious 
Surgical revision 
and/or loss of 
significant 
device function. 
Initial clinical experience of SNS: SNS studies reported frequent adverse events, including pain 
at the stimulator site (3.3 to 19.8% of patients), pain at the lead site (4.5 to 19.1% of patients), 
lead migration (2.2 to 8.6% of patients), infection/irritation (2.2 to 14.30% of patients), electric 
shock (5.5 to 10.2 7.9% of patients) and need for surgical revision (6.25 to 39.5% of patients). In 
most studies, the need for surgical revision occurred in greater than 30% of patients (Gormley, et 
al., 2014). 
The investigator will report all device deficiencies involving the study device, whether or not 
they involve adverse events. A device deficiency is an inadequacy of a medical device with 
respect to its identity, quality, durability, reliability, safety or performance. This includes 
malfunctions, use errors, and inadequate labeling. 

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Timing: The investigator will report serious adverse events to the sponsor and IRB within 24 
hours. They will report other adverse events and device deficiencies to the sponsor within 30 
days. 
3.6 
Activities performed by sponsor 
The investigator will perform or supervise all required study procedures. The sponsor’s 
personnel may assist at study device implant, assessment of adverse events and device 
deficiencies, and measurement of response threshold.  
3.7 
Investigator selection and training 
The sponsor will select a study site and investigator capable of recruiting sufficient numbers of 
eligible subjects, representative of the target population for the study device. 
To help ensure the safe, proper, and consistent use of the investigational device, the sponsor will 
conduct a training program to educate investigators and their staff on the use of the study device. 
This training will consist of didactic instruction, covering the device functions and principles of 
operation. Additionally, the training will highlight the important or unique aspects of the clinical 
study, such as screening, obtaining informed consent, the follow-up schedule, data collection 
methods, and adverse event reporting. Finally, the training will include a cadaver study. 
4 
Data management 
4.1 
Case report forms (CRFs) 
Refer to §3.1 on page 6.  
4.2 
Procedures used for data review, database cleaning, and issuing and resolving data 
queries 
The sponsor will enter all CRF data into a central database. The sponsor will review all incoming 
data to identify inconsistent or missing data as well as any adverse events. The sponsor will 
promptly address any data issues with the investigator.  
4.3 
Procedures for verification, validation and securing of electronic clinical data 
systems, if applicable. 
This clinical investigation will use paper CRFs rather than an electronic clinical data system. 
4.4 
Procedures for data retention and specified retention period 
The sponsor and investigator will maintain the clinical investigation documents for a minimal 
period of five (5) years after the clinical investigation is completed, or longer depending on 
national requirements. They will take measures to prevent accidental or premature destruction of 
these documents and ensure these are filed in a secure place. Investigator or sponsor may transfer 
custody of records to another person or party and document the transfer at the investigation site, 
or at the sponsor's facility. 
The investigator will maintain all source documents required by the protocol, including 
laboratory results, supporting medical records, and signed informed consent forms. 
4.5 
Other aspects of clinical quality assurance, as appropriate 
The measures described in §4.1 through §4.4 provide appropriate clinical quality assurance for 
an early feasibility study. 

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4.6 
Study report 
The sponsor will provide a study report with tables listed below. Each table will provides data 
organized by subject unless otherwise noted. 
Table 
Information provided 
Study summary 
Investigational plan title and version; IDE number and approval date; 
clinical investigation suspension and/or completion dates. 
Sites 
Site number, name, and address; investigator names; IRB name and 
approval date; number of subjects consented and number of subjects 
implanted at the site. 
Subject 
demographics 
Age, sex, race, and ethnicity. (NIH recommends collecting race and 
ethnicity). 
Subject 
accountability 
Date completed for each procedure required by the protocol, with total 
number of subjects that complete each procedure (CONSORT diagram 
data). 
Medications 
Type, dose, and dose interval for any medications with urinary effects or 
side effects. 
Procedure timing 
Compliance with protocol requirements for minimum and maximum time 
between procedures.  
Unplanned exits 
Any exits for withdrawal of consent, death, or loss to follow-up. 
Protocol 
deviations 
Type of deviation, reason for deviation, description of deviation, and 
effect of deviation (management of potential adverse effects on rights, 
safety, or welfare of subject and/or scientific soundness of the study). 
Adverse events 
Dates of onset and resolution, seriousness, relatedness, and description of 
adverse event. 
Device 
deficiencies 
Date of onset, type and description of device deficiency. 
Thresholds 
Lowest amplitudes at which paresthesia or motor response occurred, at 
screening visit; implantation; and 4-, 6-, 19-, and 26-week follow-up 
visits. 
Durations 
Time from implantation procedure start to end, and time from 
implantation procedure end to discharge. 
Pre-therapy diary 
Average events per 24 hours: incontinence, frequency, nocturia, and 
urgency. Whether or not subject met each of the 4 inclusion criteria. 
First therapy 
diary 
Average events per 24 hours: incontinence, frequency, nocturia, and 
urgency. Improvement or worsening from baseline after 2 weeks of daily 
therapy.  

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Table 
Information provided 
Second therapy 
diary 
Average events per 24 hours: incontinence, frequency, nocturia, and 
urgency. Improvement or worsening from baseline after 13 weeks of 
weekly therapy. 
Quality of life 
From pre-therapy, first therapy, and second therapy diaries: OAB-q Part A 
and Part B scores and GRA scores, with changes from baseline. 
Device 
accountability 
For each ITNS released for investigational use: delivery site and date; 
implant attempt subject #, date, and outcome; explantation reason and 
date; return reason and date; and returned product analysis result and date. 
The report will include descriptive statistics (average and standard deviation) for all effectiveness 
endpoints, and will employ graphical displays such as spaghetti plots to represent individual 
changes. 
5 
Rationales for endpoints 
Safety endpoints: The adverse event endpoint in this study comes from FDA guidance (FDA, 
2011-03-08) and is often used in medical-device studies. The neuromodulation pulse amplitude 
endpoint comes from the sponsor and is intended to detect functional changes in the interface 
between the stimulation electrode and the biological substrate it stimulates, analogous to pacing 
thresholds measured in studies of cardiac electrode-leads. 
Effectiveness endpoints: OAB is a symptom complex with four factors: incontinence, frequency, 
nocturia, and urgency. For incontinence, objective endpoints for improvement and cure come 
from FDA guidance (FDA, 2011-03-08). For the other OAB factors, objective endpoints for 
improvement are similarly defined as a 50 % reduction in pathological episodes: frequency 
(voids during waking hours exceeding 7), nocturia (voids awakening from sleep), and urgency 
(voids with moderate to severe urgency). Subjective endpoints (quality of life) are a 
questionnaire selected for OAB symptoms including urinary incontinence and a global response 
assessment (Peters, et al., 2010). 
5.1 
Rationale for the criterion for improvement in frequency 
Frequency improvement is defined as a 50 % reduction from baseline of the number of voids 
during waking hours exceeding 7. This criterion takes into account that traditionally up to 7 
micturition episodes during waking hours has been considered normal (Fitzgerald & Brubaker, 
2003). This criterion is analogous to the criteria for improvement for the other three OAB 
components (incontinence, nocturia, and urgency), all of which require a 50 % improvement in 
the number of pathological events. Seven or fewer daytime voids are not pathological. A 50 % 
improvement in daytime voids exceeding 7 is a 50 % improvement in pathological events. This 
same endpoint (50 % improvement in frequency exceeding normal) is currently used in an IDE 
trial for another OAB device, NCT02873312 on clinicaltrials.gov. 
5.2 
Rationale for the criterion for worsening 
Background:  
 In pre-IDE Q161967 the sponsor proposed defining a responder as a subject with significant 
improvement of at least one OAB symptom (e.g. 50 % better). FDA provided feedback: 
“Patients would be considered ‘responders’ if they improve significantly by one of those 
criteria but are overall worse in terms of their overactive bladder (OAB) symptoms. Criteria 

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for ‘responder’ should depend upon the underlying diagnosis/diagnoses and require that the 
patient meet the elements for all relevant diagnosis.” The sponsor was concerned that this 
required a subject to demonstrate significant improvement for every relevant symptom to 
qualify as a responder, even though improvement in a single symptom could have clinical 
significance. 
 Therefore in Q161967/S001 the sponsor proposed defining a responder as a subject with 
significant improvement of at least one symptom and no significant worsening of any other 
symptom (e.g. 50 % worse). FDA provided feedback again: “Worsening of incontinence 
episodes and the number of voids would be any increase over the respective baseline number. 
A threshold of a 50% increase in order to be counted as worsening is arbitrary and lacks 
clinical meaning.”  The sponsor was concerned that with this definition, a vanishingly small 
worsening of one symptom could classify a subject as a non-responder, despite a significant 
improvement of one or more other symptoms. 
To address FDA’s and sponsor’s concerns, this protocol defines a responder as a subject 
demonstrating significant improvement of at least one relevant OAB symptom (e.g. 50 % better), 
and no worsening of their relevant symptoms overall (worsening would be any increase overall). 
Here “relevant” means meeting the inclusion criterion for a symptom at baseline, and “overall” 
means average of changes over all relevant symptoms.  
For example, a subject with a baseline diary showing daily averages of 9 voids during waking 
hours, 3 interrupting sleep, 5 with urgency, and 0.3 with incontinence would meet the study’s 
inclusion criteria in §2.1 for nocturia and urgency (i.e. the subject would have two relevant 
symptoms). If their therapy diary showed daily averages of 1 void interrupting sleep and 6 with 
urgency, that would correspond to a -67 % change (improvement) in nocturia but a +20 % 
change (worsening) in urgency, or an overall change of -44% (improvement). That subject would 
qualify as a responder. 
5.3 
Dichotomous and continuous criteria 
This study requires a dichotomous “responder” criterion for an individual subject, to inform a 
decision about allowing the subject to keep the study device after the 26-week follow-up visit. 
As discussed above, FDA guidance also recommends dichotomous “improvement” criteria for 
individual subjects, e.g. 50 % symptom improvement. 
As a feasibility study, this protocol does not establish prospective criteria for effectiveness for all 
subjects as a group. A pivotal study would establish hypothesis testing for statistics such as 
percentages of subjects meeting a dichotomous criterion, and averages over subjects of a 
continuous parameter. To inform the design of the pivotal study, this feasibility study will report 
descriptive statistics (including average, median, minimum, maximum, and standard deviation) 
for all effectiveness endpoints, and will employ graphical displays such as spaghetti plots to 
represent individual changes. 
5.4 
Effectiveness data from prior studies 
Many prior studies of PTNS have presented mean or median improvements, or responder 
percentages for subjective endpoints, but only a limited number have provided responder 
percentages for objective endpoints. The available studies show positive responses to PTNS, 
which are perhaps comparable to responses to SNS, although inclusion criteria and responder 
definitions varied across studies: 

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 In a study of subjects with urge incontinence, 18 were treated with 12 PTNS sessions, and 17 
were treated with stimulation sessions in the medial part of the gastrocnemius muscle as 
controls (Finazzi-Agro, et al., 2010). A responder was defined as a subject showing > 50 % 
reduction in urge incontinence episodes. There were 71 % responders in the PTNS group and 
0 % in the control group (p < 0.001). 
 In a study of subjects with OAB (defined as clinical complaints of urinary frequency, 
nocturia, and/or urgency incontinence), 8 were treated for 12 weeks with PTNS (Souto, Reis, 
Palma, Palma, & Denardi, 2013). The percentage with urinary incontinence (any involuntary 
leakage of urine) decreased from 94 % to 11 %. The percentage with nocturia (waking one or 
more times at night to void) also decreased from 94 % to 11 %.  
 In a study of subjects with OAB (defined as > 7 voids or > 2 urge incontinence episodes per 
24 hours) who had previously demonstrated a reduction of more than 50 % in incontinence 
episodes or voids with PTNS, 8 had their PTNS treatment stopped for at least 3 months and 
then were treated for 12 months with an implanted PTNS device (van der Pal, van Balken, 
Heesakkers, F.M.J., & Bemelmans, 2006). Defining a responder as a subject with > 50 % 
improvement in an endpoint and no increase in the other two endpoints, the table below 
shows percentages of responders (from 24-hour voiding diaries): 
Responders 
Baseline to month 3 
Baseline to month 6 
Baseline to month 12 
Voids 
13% 
25% 
25% 
Nocturia 
38% 
50% 
25% 
Incontinence 
88% 
63% 
50% 
 In a study of subjects with OAB (defined as > 8 voids per 24 h, or > 3 urge urinary 
incontinence episodes per week, or nocturia; and phasic detrusor contractions in the filling 
phase of saline cystometry), 43 were treated for 6 weeks with PTNS (Yoong, Ridout, 
Damodaram, & Dadswell, 2010). A positive response was defined as: (i) OAB symptoms no 
longer being bothersome; (ii) reduction by half in frequency episodes and (iii) reduction by 
25% in IIQ-7 outcomes. A positive response rate of 69.7 % was found. Yoong, et al., did not 
specify whether “frequency episodes” meant episodes per 24 hours or episodes exceeding 8 
per 24 hours. 
SNS studies showed comparable results (Medtronic, Inc., 2011): 
 For subjects with urge incontinence, 61 % of those undergoing SNS test procedures (naïve to 
SNS) experienced > 50 % improvement in leaking episodes. Of those who went on to a 
permanent implant, 75 % remained improved at six months.  
 For subjects with urgency-frequency, 36 % of those undergoing SNS test procedures 
experienced > 50 % improvement in urgency-frequency parameters (decrease in voids/day or 
increase in volume/void). Of those who went on to a permanent implant, 34 % remained 
improved with a > 50 % decrease in voids/day, and 54 % remained improved with > 50 % 
increase in volume/void. 
6 
Rationale for type of design 
This clinical feasibility study has a single-arm longitudinal design with no implanted comparator.  
The study’s small sample size, selected to limit exposure to unforeseen risks during this first 
human use of the study device, does not provide sufficient power to test effectiveness changes 
versus a concurrent control group. 

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This feasibility study has effectiveness endpoints for two other reasons: (a) to gain experience 
with the effectiveness assessments planned for a pivotal study; and (b) to assess an individual 
subject’s symptom improvement with device use, to inform a decision about continued use after 
26 weeks. 
7 
Future pivotal study 
If there is a successful completion of this clinical feasibility study, the sponsor will propose a 
pivotal study to demonstrate safety and effectiveness for regulatory approval. If the feasibility 
study proceeds as planned, the pivotal study will be based on the same procedures and endpoints, 
together with the additional information gained about effectively conducting a study in the target 
population. 
8 
Deviations from clinical protocol 
Prior approval: The investigator will obtain prior written approval of a request for deviation 
from the protocol, from the investigator’s IRB, if the deviation affects subject’s rights, safety, 
and well-being, or the scientific integrity of the clinical investigation.  
Emergency: Under emergency circumstances, deviations from the protocol to protect the rights, 
safety and well-being of human subjects may proceed without prior approval of the sponsor and 
the IRB. Such deviations shall be documented and reported to the sponsor and the IRB as soon as 
possible. 
Records: The investigator will use the protocol deviation CRF listed in §3.1 on page 6 for 
recording and reporting protocol deviations to the sponsor, and to the IRB or EC if required 
above.  
Corrective and preventive actions: The sponsor will review all reported deviations, and will 
cooperate with the investigator to implement corrective and preventive actions where 
appropriate. If necessary the sponsor may take additional action including terminating the 
investigator’s participation in the investigation.  
9 
Suspension or premature termination of the clinical investigation 
Criteria: In response to a concern about the rights, safety, or well-being of subjects, or about the 
scientific soundness of the study, which cannot be resolved by other means: 
 An investigator may suspend or prematurely terminate the study at his or her 
investigational site, after consultation with the sponsor.  
 The sponsor may suspend or prematurely terminate the study at one, several, or all 
investigational sites, after consultation with the investigator(s) concerned. 
Follow-up: During suspension the investigator will continue scheduled follow-up, provided this 
does not adversely affect the rights, safety, or well-being of subjects. After premature or 
scheduled termination of the clinical study, the investigator will provide medical care for the 
subjects after the clinical investigation has been completed, conforming to their standard 
practice. 
10 Amendments 
The sponsor and investigator will record approval and justification for any amendment to an 
approved protocol. If changes affect the scientific soundness of the clinical investigation, or 
affect the health, welfare, safety and rights of patients, the investigator and/or sponsor will obtain 

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written approval by the investigator’s institutional review board (IRB) and FDA before 
implementing changes. If changes are merely administrative in nature, the investigator will 
notify their site’s IRB.  
11 Device accountability 
The sponsor will ship or convey investigational devices only to a qualified investigators 
participating in this clinical investigation. The sponsor will not ship or convey investigational 
devices to any site until evidence of IRB approval has been provided to the sponsor or sponsor’s 
designee.  
Investigators will control access to investigational devices, and will only use investigational 
devices in the clinical investigation and according to the protocol.  
The sponsor will keep records to document the physical location of each investigational device. 
Record(s) will include information documenting devices shipped or conveyed, devices at 
investigation sites, devices disposed of, and devices returned.  
The investigator will keep records documenting the receipt, use, return and disposal of the 
investigational devices, which will include:  
 Date of receipt,  
 Identification of each investigational device (serial number or unique code),  
 Use-before date, if applicable,  
 Date or dates of use,  
 Subject identification,  
 Date on which the investigational device was returned, or explanted from subject, if 
applicable, and  
 Date of return of unused, expired or malfunctioning investigational devices, if applicable.  
12 Statements of compliance 
The investigator will conduct the clinical investigation in accordance with this protocol and an 
investigator agreement executed before beginning the study.  
The sponsor will provide clinical investigation insurance for subjects. This will continue to cover 
direct costs associated with any device deficiencies after the subject exits from the study. 
The clinical investigation will be conducted in compliance with Title 21 of the Code of Federal 
Regulations (“21 CFR”), Parts: 
 50, Protection of Human Subjects. 
 54, Financial Disclosure by Clinical Investigators. 
 56, Institutional Review Boards. 
 812, Investigational Device Exemptions. 
13 Publication policy 
For this clinical feasibility study, the investigator agrees to maintain confidentiality and refrain 
from publication without the sponsor’s prior written approval.