Clinical Study of Neuspera's Implantable Sacral Nerve Stimulation (SNS) System in Patients With Symptoms of Urinary Urgency Incontinence (UUI)
Phase: NA
Conditions: Urinary Urgency Incontinence
Sponsor: Neuspera Medical, Inc.

 
 
 
 
 
 
Study Title: Clinical Study of Neuspera’s Implantable Sacral Nerve Stimulation (SNS) System in 
Patients with Symptoms of Urinary Urgency Incontinence (UUI)  
 
Document: Clinical Investigation Plan / Study Protocol  
Protocol No. NSM-004  
Version 21.0  
04 Apr 2025 
 
NCT number: NCT04232696 

 
 
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Neuspera 
 
 
 
Clinical Study of Neuspera’s Implantable 
Sacral Nerve Stimulation (SNS) System in 
Patients with Symptoms of Urinary 
Urgency Incontinence (UUI) 
 
 
 
Clinical Investigation Plan / Study Protocol 
Protocol No. NSM-004 
Version 21.0  
04 Apr 2025  
 
 
Confidentiality Statement: 
The information provided in this document is strictly confidential and may not be disclosed to parties 
other than study personnel, appropriate governmental and regulatory agencies and the Institutional 
Review Board or Ethics Committee directly involved with this study. All parties must understand that 
confidential information may not be disseminated further without prior written permission from 
Neuspera Medical Inc. 
 
 
 
 
 
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Neuspera 
SPONSOR SIGNATURE PAGE 
 
Title: 
Clinical Study of Neuspera’s Implantable Sacral Nerve Stimulation (SNS) 
System in Patients with Symptoms of Urinary Urgency Incontinence  
Protocol ID: 
NSM-004 
 
Sponsor’s statement 
I, the Sponsor, have reviewed this clinical investigation plan describing the design and specific provisions 
of the clinical investigation. I agree with the content of this document.  
 
 
Sponsor representative name (print) 
 
 
Title 
 
 
Signature 
 
 
 
 
 
Date
Docusign Envelope ID: 7B6EEAF4-597D-46D5-8E1E-BDDBEAEEA15D
Director of Clinical Research
2025-Apr-04
Mark Vollmer

 
 
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Neuspera 
 
INVESTIGATOR SIGNATURE PAGE 
 
Title: 
Clinical Study of Neuspera’s Implantable Sacral Nerve Stimulation (SNS) 
System in Patients with Symptoms of Urinary Urgency Incontinence  
 
Protocol ID: 
NSM-004 
 
Investigator’s statement 
I agree to conduct this study in accordance with the design and specific provisions of this protocol; 
modifications to the study are acceptable only with a mutually agreed upon protocol amendment as 
approved by the Sponsor and the Institutional Review Board or the Ethics Committee. I agree to await 
Institutional Review Board or Ethics Committee approval of the protocol and informed consent before 
initiating the study, to obtain consent from subjects prior to their enrollment in the study, to collect and 
record data as required by the protocol and case report forms, and to maintain study documents for the 
period of time required. 
Confidential 
This document contains confidential information belonging to Neuspera Medical Inc. except as may be 
otherwise agreed to in writing, by accepting or reviewing these materials, I agree to hold such 
information in confidence and not to disclose it to others (except where required by applicable law), nor 
use it for unauthorized purposes. 
 
Investigator name (print) 
 
 
Signature 
 
 
 
 
 
Date 
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SYNOPSIS 
Clinical investigation plan 
Title 
Clinical Study of Neuspera’s Implantable Sacral Nerve Stimulation (SNS) 
System in Patients with Symptoms of Urinary Urgency Incontinence  
Short title  
SANS-UUI 
Protocol ID 
NSM-004 
Investigational device  
Name 
Neuspera’s Implantable Sacral Nerve Stimulation (SNS) System 
Description 
Miniature wireless midfield powered implanted neurostimulation device 
for urinary urgency incontinence (UUI). 
Indications statement 
Neuspera’s Implantable SNS System is indicated to treat subjects with UUI 
who have failed or could not tolerate more conservative treatments. 
Sponsor 
Name 
Neuspera Medical Inc.  
Contact details 
Neuspera Medical Inc.  
51 Daggett Drive  
San Jose, CA 95134, USA 
Telephone:  +1 408.612.7570 
Investigation centers  
Number of centers 
The study was designed to be conducted in two Phases.  The enrollment 
period for Phase I has been completed.  Phase I was conducted in 11 
clinical study sites in the US and Europe. 
Phase II of the study will be conducted in up to 35 clinical sites in the US, 
Canada and Europe, inclusive of the Phase I centers who participate in 
Phase II. Phase I sites unable to participate in Phase II will not count 
towards Phase II site limits. It is expected that no more than 5 sites to be 
included from Europe and Canada.  More than 50% of the subjects 
enrolled will be from the United States. 
Location of centers 
United States, Canada, and Europe  
Coordinating Investigator for the SANS-UUI Study 
Contact details 
Osvaldo Padron, MD 
Florida Urology Partners, LLP 
5913 Webb Rd 
Tampa, FL 33615 
Office: (813) 875-8527 x2106 
Clinical investigation design 
Objective 
The trial is designed in two phases: Phase I and Phase II.  
 
The objective of Phase I was to assess the utilization of the system during 
the SNS trial and follow-up periods and to help inform the length of hours 
of daily stimulation to be used in Phase II of the trial.   
 
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The objective of Phase II is to assess the safety and efficacy of the 
Neuspera SNS System at 6-months for the primary efficacy endpoint and 
at 6 and 12 months for secondary safety and efficacy endpoints. As Phase 
II is designed with a Modified Intent-to-Treat analysis (mITT), all implanted 
subjects will be followed to the endpoint determination.  
Design 
Prospective, multi-center, single-arm, seamless phased-pivotal study 
conducted in subjects diagnosed with UUI who have failed or could not 
tolerate more conservative treatment. The trial will be conducted in two 
phases: 
Phase I 
In Phase I, the trial was designed to allow the enrollment of up to 55 
subjects. An enrolled subject is one who signed the informed consent and 
an implant with the Neuspera neurostimulator system (“system”) was 
attempted. A total of 39 subjects were enrolled in Phase I.  As designed 
subjects who failed to achieve an appropriate motor response during 
intra-operative testing were considered enrolled but were not implanted 
and exited from the study. A total of 5 subjects failed to achieve an 
appropriate motor response in Phase I of the trial.  The design of the study 
allowed for the system to be trialed for approximately 21 - 49 days in 
implanted subjects. Subjects had an initial trial period of 21 days with 2-
hours of daily stimulation using the external Wireless Transmitter. At the 
end of a subject’s trial phase, treatment efficacy was assessed. Those 
subjects with acceptable efficacy (≥50% reduction in number of UUI 
episodes) were considered responders and proceeded into the post-trial 
follow-up period with 2-hours of daily stimulation using the Wireless 
Transmitter. Those with less than acceptable efficacy (<50% reduction in 
number of UUI episodes) proceeded for an additional trial period with 4-
hours of daily stimulation with the Wireless Transmitter for 14 days. After 
14 days of 4-hours of daily stimulation those subjects with ≥50% reduction 
in number of UUI episodes were considered responders and proceeded 
into the post-trial follow-up period with 4-hours of daily stimulation. The 
study was designed such that those with <50% reduction in number of 
UUI episodes were to proceed into a third trial period with 8-hours of 
daily stimulation with the Wireless Transmitter for 14 days. After 14 days 
of 8-hours of daily stimulation, those subjects with ≥50% reduction in 
number of UUI episodes were to be considered responders and would 
then proceed into the post-trial follow-up period with 8-hours of daily 
stimulation. For those subjects who did not respond to SNS therapy, 
alternative treatments were to be discussed with the Investigator and the 
Neuspera neurostimulator was to be explanted. Neuspera’s Wireless 
Transmitter(s), Wireless Transmitter Charging Pad, and Patient Controller 
were to be returned to the investigational center and the subject was to 
have a 30-day follow-up visit for safety purposes. The subject would then 
be exited from the study.  
 
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Of the 34 subjects implanted with the neurostimulator, only one subject 
was a non-responder after 2-hours of daily stimulation. This subject was a 
responder after an additional 14-days at 4 hours of daily stimulation and 
continued into the post-trial follow-up phase.  There have been twelve 
device explants in the trial and two subjects exited the trial without device 
explant (one due to lost-to-follow-up, one due to an adverse event of 
dementia). Eleven subjects requested explant due to therapy not 
producing desired effect or unsatisfied with therapy or device 
performance, and one subject was explanted due to non-compliance.  
 
Phase I responders will continue to be followed until US PMA approval. 
European approval, CE Mark, may be achieved earlier or later than PMA 
approval is achieved which may be 36 months or longer post trialing 
period for some subjects; however, all subjects will be followed until US 
PMA approval. If Neuspera determines that regulatory approval will not 
be achieved, the trial will be closed. If regulatory approval is achieved, the 
subjects may be approached to continue participation in a post market 
clinical study and will be provided a separate informed consent at that 
time. 
 
Phase I Sub-Study: There is a sub-study to investigate the effectiveness 
and subject acceptance of half-hour daily stimulation to treat UUI.  The 
details are provided in Appendix A: Phase I Sub-Study. 
 
Phase II 
A group of up to 255 subjects (independent of subjects enrolled in Phase I 
of the trial) will be enrolled. The definition of enrollment for Phase II is 
modified from the definition used in Phase I.  An enrolled subject in Phase 
II is one who signed the informed consent. Subjects who pass all pre-
implant screening criteria will be scheduled for implant. Enrollment will be 
stopped after reaching 120 attempted implants; the implant success rate 
is expected to be 95%.  Subjects who are already enrolled after the last 
attempted implant will be allowed to be implanted.  All subjects who 
successfully complete intraoperative testing will be implanted with the 
neurostimulator. In the first 28 days subjects will receive 2 hours of 
continuous daily stimulation using the external Wireless Transmitter.  At 
the end of 28 days of treatment, efficacy will be assessed. Subjects with 
acceptable efficacy (≥50% reduction in number of UUI episodes) will be 
considered a responder and will continue in the post-implant follow-up 
with 2 hours of daily stimulation using the Wireless Transmitter. Those 
with less than acceptable efficacy (<50% reduction in number of UUI 
episodes) will continue for an additional 14-day period with 4 hours of 
daily stimulation with the Wireless Transmitter. After 14 days of 4 hours 
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of daily stimulation those subjects with ≥50% reduction in number of UUI 
episodes will be considered responders. Those subjects who increased to 
4 hours of daily stimulation, regardless of responder or non-responder 
status at the end of the 42-day period will continue in the post-implant 
follow-up with 4 hours of daily stimulation.  
 
A decision to continue a subject with less than a 50% improvement at the 
end of the 42-day period will be made by the investigator based on what 
they determine is in the best interest of the subject.  
A subject may withdraw their consent from participation at any time 
regardless of responder status. 
 
As commercial sacral neurostimulation therapies report responder rates 
at 1-month post implant or following a trial period with an implanted lead 
connected to an external stimulator, the responder rate at day 28 or day 
42 clinic visit post-implant will be used as a comparison point for SNS trial 
therapy success with current clinical literature.   
 
All implanted subjects will be followed for efficacy and safety with the 
primary endpoint assessed at the 6-month follow-up visit. Subjects will be 
assessed again for safety and efficacy at 12 months post-implant for 
secondary endpoints in the trial. The sponsor intends to file a PMA 
submission at the end of the six-months of follow-up if the primary 
endpoint is achieved. Phase II subjects will continue to be followed 
through 12 months and until US PMA approval. Health Canada approval, 
European approval, CE Mark, may be achieved earlier or later than PMA 
approval. 
Arms and interventions  
Single-arm clinical study 
Follow-up visits 
In Phase I, all subjects will return to the clinic for monthly visits up to 6 
months for post-trial procedures and every three months through the 12-
month post-trial visit, and then every six months thereafter until 
regulatory approval is achieved, estimated to be up to 60 months.  
In Phase II, enrolled subjects will return to the clinic for monthly visits up 
to 6 months for post-implant procedures and every three months through 
the 12-month visit, and then every six months thereafter until regulatory 
approval is achieved, estimated to be up to 36 months.   
Total duration 
The total expected duration of the clinical trial is dependent on the length 
of time to regulatory approval. All implanted subjects in Phase I and Phase 
II will continue to be followed until US PMA approval. Health Canada 
approval, European approval, CE Mark, may be achieved earlier or later 
than PMA approval. If achieved earlier, all Canadian and EU subjects will 
continue to be followed until US PMA approval is achieved which may be 
60 months or longer for some subjects. Subjects enrolled earlier will have 
a longer follow-up than subjects enrolled later. In Phase II, subjects 
enrolled later may be followed for less than 36 months but at least until 
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the 12-month follow-up visit is completed. It is estimated that the first 
subjects implanted in Phase I will be in the study approximately 5 years. If 
Neuspera determines regulatory approval will not be achieved, the study 
will be closed.   
Primary Efficacy Endpoint 
(Phase II) 
The primary efficacy endpoint is defined as the percentage of all 
implanted subjects who experience an improvement in UUI symptoms of 
at least 50% or more (therapy responders). A therapy responder is defined 
as experiencing ≥50% reduction in the number of UUI episodes at 6 
months post-implant, relative to the number of UUI episodes at baseline.  
Statistical evaluation will be based on a comparison of the percentage of 
responders to a performance goal of 50%. 
Calculation of the primary efficacy endpoint will be based on the mITT 
analysis set. 
Safety endpoints (Phase II) 
The primary safety endpoint is defined as the incidence of device-related 
SAEs through the 6-month post-implant visit. The analysis of the endpoint 
is the proportion of subjects experiencing a device-related SAE through 
the 6-month post-implant.  
Secondary Endpoints 
The secondary endpoints include the following, assessed at both the 6 and 
12 months post implant visits unless specified otherwise: 
• 
Change from baseline in quality of life as measured and 
assessed by the total ICIQ-OABqol score.  
• 
Change from baseline in mean number of UUI episodes. 
• 
The percentage of subjects who experience an improvement 
in UUI symptoms (therapy responders) of at least 50% or 
more at 12-month visit post-implant. 
• 
The percentage of subjects who experience an improvement 
in ICIQ-OABqol of at least 10 points. 
• 
Change in urgent voids per day calculated across all diary 
episodes with at least mild urgency.  
• 
Change in average number of daily voids from baseline in 
subjects with at least 8 voids at baseline. 
• 
Change in quality of life measured from baseline as 
measured and assessed by the ICIQ-OABqol subscale scores. 
• 
Comprehensive summary of all adverse events (AEs) for the 
duration of study participation. 
• 
Device parameters including but not limited to voltage, pulse 
width, frequency, and stimulating electrode.   
• 
Physician and subject satisfaction as assessed with the User 
Experience Questionnaire at 6-month visit post-implant. 
• 
Change in Male/Female Lower Urinary Tract Symptoms 
questionnaire.  
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• 
The percentage of subjects with device-related serious 
adverse events reported through 12-month visit post-
implant.  
• 
Change in total urinary output as measured by 72-hour 
bladder diary. 
• 
Change in fecal incontinence as measured by the Wexner 
Scale compared to baseline. Calculated in subjects with fecal 
incontinence. 
• 
Patient Global Impression of Improvement (PGI-I) measured 
after implant during follow-up. 
Secondary Endpoints That May Be 
Used for Labeling Claims (Phase II) 
The following secondary endpoints will be included in a hierarchical 
analysis of study endpoints and may be intended for labeling claims (all at 
6-month visit post-implant follow-up): 
• 
Change from baseline in mean number of UUI episodes 
• 
Change from baseline in ICIQ-OABqol score 
• 
The percentage of subjects who experience an improvement 
in ICIQ-OABqol of at least 10 points 
• 
Change in urgent episodes per day from baseline.  Calculated 
across all diary episodes with at least mild urgency 
• 
Change in average number of daily voids from subjects with 
at least 8 voids at baseline  
• 
Change in fecal incontinence as measured by the Wexner 
Scale compared to baseline. Calculated in subjects with fecal 
incontinence. 
The type I error for the primary efficacy endpoint and for this subset of 
secondary endpoints will be controlled via hierarchical testing.  
Performance goals for each hypothesis and other statistical details are 
provided in the Statistical Analysis Plan (SAP). 
Clinical investigation population 
Sample size 
The study will be conducted in two operationally seamless phases: Phase I 
and Phase II. In Phase I, the trial was designed to allow the enrollment of 
up to 55 subjects and a total of 39 subjects were enrolled. It was 
anticipated that approximately 40 of the enrolled subjects would have an 
appropriate motor response during intra-operative testing and would be 
implanted. A total of 5 subjects failed to achieve an appropriate motor 
response in Phase I of the trial and were exited from the study.  A total of 
34 enrolled subjects were implanted with the Neuspera neurostimulator. 
It was estimated that approximately 33% of the implanted subjects would 
be determined as non-responders or would drop out of Phase I for other 
reasons following the sacral nerve stimulation (SNS) trial period.  Thus, 
approximately 27 subjects were to continue in the post-trial period. A 
total of 34 enrolled subjects were implanted with the Neuspera 
neurostimulator and all 34 subjects continued into the follow-up phase of 
the trial. 
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In Phase II of the trial, the pivotal phase, up to 255 may be enrolled 
(consented). It is anticipated that approximately 43% of subjects may be 
screen failures and that the implant success rate will be approximately 
95%. Enrollment will be stopped after reaching 120 attempted implants, 
resulting in approximately 114 successful implants. Revisions will not 
count towards attempted implants. Subjects who are already enrolled 
after the last attempted implant will be allowed to be implanted.  The 
primary efficacy endpoint will be assessed in all subjects for whom an 
initial implant is attempted. Missing data at 6 months will be imputed.  
Inclusion criteria 
General Inclusion Criteria: 
1. Is willing and able to understand and has voluntarily signed and 
dated the current approved informed consent. 
2. Is male or female 22 years of age or older. 
3. Has a Body Mass Index (BMI) greater than or equal to 18 and less 
than or equal to 40 kg/m2.  
4. Is a good surgical candidate and is capable of participating in all 
testing and follow-up clinic visits associated with this clinical 
study and is capable of independently using the system 
components as described in the Patient Manual. 
5. Is ambulatory and able to use toilet without assistance. 
6. Has a diagnosis of UUI for greater than or equal to 6 months prior 
to the screening baseline visit date. 
7. Has typical residual bladder volume < 150 cc tested within 6 
months prior to the screening baseline visit date or is willing to 
have a test at screening baseline visit.  
8. Has urodynamic testing (uroflowmetry, cystometry, and pressure 
flow) completed within 6 months prior to the screening baseline 
visit date or is willing to have testing at the screening baseline 
visit. 
9. Has cystoscopy testing completed within 6 months prior to the 
screening baseline visit date or is willing to have a test at the 
screening baseline visit.  
10. Has failed or was not a candidate for more conservative 
treatment (e.g, pelvic floor exercise, biofeedback, behavioral 
modification).  
11. Has failed, could not tolerate (stopped taking medication due to 
lack of efficacy or intolerable side effects), or not a good 
candidate for (as determined by treating physician) at least one 
(1) antimuscarinic or β3 adrenoceptor agonist medication.      
12. Is willing and able to washout (at least five half-lives) from OAB 
medications for a period determined appropriate based on type 
of OAB medication prior to the baseline bladder diary and remain 
off OAB medications through the 12-month follow-up visit.   
13. Has appropriate sacral anatomy as determined by sponsor’s and 
investigator’s analysis of radiographic imaging.  (The distance 
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from the surface of the skin in the prone and seated position to 
the bone edge of the S3 foramen must be within the capabilities 
of the system). 
 
Baseline Bladder Diary Inclusion Criteria: 
14. Has a diagnosis of UUI with at least 4 UUI episodes on a 72-hour 
diary, and minimum of one (1) UUI episode per 24-hour period. 
Exclusion criteria 
General Exclusion Criteria: 
1. Has a hemoglobin A1c of >8% or has diabetes mellitus with 
glucosuria.    
2. Has diabetic neuropathy. 
3. Has interstitial cystitis or bladder pain syndrome as defined by 
either American Urological Association (AUA) or European 
Association of Urology (EAU) guidelines, chronic pelvic pain, or 
recurrent symptomatic urinary tract infections. 
4. Has skin, orthopedic, neurological, or hematological (bleeding 
disorder) or anatomical limitations that could prevent successful 
placement of the neurostimulator.   
5. Has broken, blistered skin or compromised circulation in the area 
of the neurostimulator implant. 
6. Has neurogenic bladder dysfunction such as traumatic or 
atraumatic myelopathy, multiple sclerosis, Parkinsonism, or 
history of cerebrovascular accident.    
7. Has documented urinary retention within 6 months prior to the 
screening baseline visit date. 
8. Has clinically significant bladder outlet obstruction. 
9. Is currently undergoing or has previously undergone pelvic 
irradiation. 
10. Is a subject with a mechanical obstruction such as benign 
prostatic hypertrophy, urethral stricture, or cancer. 
11. Has current grade 3 or 4 pelvic organ prolapse including 
cystocele, rectocele, enterocele, procidentia or vaginal vault 
prolapse. 
12. Has symptomatic urinary tract infection (UTI); the subject may be 
considered for study enrollment if the subject is symptom-free 
after a full course of treatment prior to beginning the baseline 
bladder diary. If an asymptomatic bacteriuria is detected during 
the urinalysis performed at screening, a subject may be enrolled 
without a waiting period relative to UTI treatment. 
13. Has primary stress incontinence or mixed incontinence where the 
stress component predominates or has been treated surgically 
for stress urinary incontinence within 6 months prior to the 
screening baseline visit date. 
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14. Has received tibial nerve stimulation (TNS) in the past 3 months 
for the treatment of overactive bladder or unwilling to stay off 
TNS therapy for 12-month period following implant. 
15. Has received treatment of urinary symptoms with any botulinum 
neurotoxin type-A (BoNT-A) agent in the past 12 months; (e.g. 
obotulinumtoxinA, Botox,® abobotulinumtoxinA, Dysport®  
IncobotulinumtoxinA, Xeomin®).  
16. Is a woman who is pregnant or planning to become pregnant 
during this clinical study or is a woman of child-bearing potential 
who is not using a medically acceptable method of birth control.  
Women of child-bearing potential must undergo a pregnancy 
test, with clear negative result.   
17. Has active substance abuse, including alcohol. 
18. Has a known hypersensitivity or contraindication to procedural or 
post-procedural medications which cannot be adequately 
managed medically. 
19. Has a known hypersensitivity to Neuspera’s SNS System device 
components.   
20. Has previously failed SNS therapy. 
21. Has active implantable medical devices such as neurostimulators, 
drug pumps, pacemakers, or internal defibrillators since 
compatibility has not been assessed. 
22. Has known needs for diathermy (shortwave, microwave, or 
therapeutic ultrasound) and radiofrequency ablation, in the 
vicinity of the neurostimulator since these procedures have not 
been evaluated.  
23. Has a known need for therapeutic ultrasound in the area of the 
sacral nerve neurostimulator as the device can inadvertently 
concentrate the ultrasound field and cause harm. 
24. Has a known need for therapeutic ionizing radiation as can 
damage the electrical components of the sacral nerve stimulator 
and any damage may not be immediately detectable.  
25. Has plans to enroll or is currently enrolled in another 
investigational device or drug trial during his/her participation in 
this study.   
26. The investigator is unable to elicit an appropriate motor response 
in the subject during the intra-operative testing of the implant 
procedure. 
Statistical analysis  
Statistical design 
 
The study will be conducted in two phases: In Phase I, the trial was 
designed to allow the enrollment of up to 55 subjects and to implant 
approximately 40 of these subjects to assess the utilization of the system 
during the SNS trial period and to help inform the length of hours of daily 
stimulation to be used in the second phase. A total of 34 subjects were 
implanted in Phase I.  
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Phase II will enroll an independent group of up to 255 subjects resulting in 
120 implant attempts, approximately 114 successful implants, to assess 
the safety and efficacy of the Neuspera SNS system at 6 months for the 
primary efficacy endpoint, and again at 6 and 12 months for safety and 
efficacy endpoints. The sponsor intends to file a PMA submission at the 
end of six-months of follow-up if the primary endpoint is achieved. 
 
Phase I analysis may occur at several points during the trial as the sponsor 
wishes to assess compliance and the performance of the system as this 
will be the first chronic use of the system. An interim analysis did occur at 
the completion of the 1-month post-trialing period of Phase I and again 
when the majority of subjects had completed 3 months of follow-up. The 
data from Phase I will not be the basis for formal conclusions; the intent 
was to gain initial data to inform the treatment for Phase II. 
 
Analysis of Phase II will occur when all subjects have completed 6 months 
post-implant (or are exited from the study). An interim analysis will be 
performed when the 60th Phase II subject has completed the 3-month 
post-implant visit.  The study will be completed to the planned sample 
size of 120 attempted implants regardless of the outcome of the interim 
analysis. Revisions will not count towards attempted implants. 
Analysis Populations 
 
Intent-to-Treat (ITT) Analysis Set: The ITT analysis set is defined as all 
Phase II subjects who have signed informed consent. Demographic 
information and study exit details will be reported separately for those 
subjects included in the ITT population where no initial implant was 
attempted. 
 
Modified Intent-to-Treat (mITT) Analysis Set: The mITT analysis set is 
defined as all Phase II subjects for whom an initial implant is attempted.  
Implanted Analysis Set: The Implanted analysis set is defined as all Phase 
II subjects who are implanted with the Neuspera SNS system.   
Responder Analysis Set: The Responder analysis set is defined as subjects 
who are implanted with the system and are defined as responders at the 
Day 28 or Day 42 clinic visit post-implant.   
 
Per Protocol (PP) Analysis Set: The Per Protocol analysis set is defined as 
implanted subjects who have no protocol deviations that may significantly 
affect the primary endpoints. The determination of subjects excluded 
from the Per Protocol analysis set will be made prior to analysis. 
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Primary Safety Analysis 
There is no planned statistical hypothesis test for the primary safety 
endpoint. The proportion of subjects experiencing an event, as well as the 
numerator and denominator, and the associated two-sided exact 95% 
binomial confidence interval will be provided. Values will be expressed as 
percentages.  
 
The primary analysis population for the primary safety endpoint is the 
mITT analysis set.  
 
Any adverse events reported for enrolled subjects who are excluded from 
the mITT analysis set, will be reported separately for the duration of 
participation in the study. 
Primary Efficacy Analysis 
 
Calculation of the primary efficacy endpoint will be based on the mITT 
analysis set. 
 
The statistical hypothesis test for the primary efficacy endpoint will be 
based on comparing the percentage of subjects with at least 50% 
improvement in UUI symptoms (therapy responders) to a null value of 
50%, the same performance goal as in the study by McCrery et al.6. 
Mathematically, the null and alternative hypothesis are stated as: 
 
Ho: p ≤ 0.50 
Ha: p > 0.50 
 
The null hypothesis will be rejected at the one-sided 0.025 alpha level 
based on a one-sided, one-sample exact tests of binomial proportions for 
responders. The proportion of 0.50 for responders corresponds to a value 
of 50%. Study success is defined as successful rejection of the null 
hypothesis.  
 
The 50% reduction in UUI symptoms treats subjects as their own control 
and is based on a clinically meaningful improvement at the subject level in 
the primary efficacy endpoint4-6. Successful rejection of the null 
hypothesis will indicate a clinically meaningful result in the majority of 
subjects by a statistically significant amount.  
Additional Statistical Analysis 
 
 
 
 
 
 
Continuous data will be summarized with mean, standard deviation, 
median, minimum, maximum, and number of evaluable observations. 
Categorical variables will be summarized with frequency counts and 
percentages. Confidence intervals may be presented, where appropriate, 
using the t-distribution for continuous data and Clopper-Pearson Exact 
method for categorical variables. 
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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ................................................................................................................................ 2 
INVESTIGATOR SIGNATURE PAGE ........................................................................................................................ 3 
SYNOPSIS ............................................................................................................................................................ 4 
TABLE OF CONTENTS ......................................................................................................................................... 15 
LIST OF TABLES .................................................................................................................................................. 17 
LIST OF FIGURES ................................................................................................................................................ 18 
ABBREVIATIONS ................................................................................................................................................ 19 
REVISION HISTORY ............................................................................................................................................ 20 
CONTACT INFORMATION ................................................................................................................................... 26 
1. INTRODUCTION .......................................................................................................................................... 27 
1.1 
TREATMENT OF OVERACTIVE BLADDER ................................................................................................................ 27 
2 
INVESTIGATIONAL DEVICE .......................................................................................................................... 29 
2.1 
NEUSPERA IMPLANTABLE SACRAL NERVE STIMULATION SYSTEM ............................................................................... 29 
2.2 
INTENDED USE AND INDICATIONS STATEMENT ....................................................................................................... 42 
2.3 
INTENDED PURPOSE IN THE CLINICAL INVESTIGATION .............................................................................................. 43 
2.4 
MANUFACTURER ............................................................................................................................................. 43 
2.5 
REQUIRED TRAINING AND EXPERIENCE ................................................................................................................. 45 
2.6 
MEDICAL/SURGICAL PROCEDURES ...................................................................................................................... 45 
2.7 
DEVICE TRACEABILITY ....................................................................................................................................... 46 
3 
JUSTIFICATION FOR CLINICAL INVESTIGATION DESIGN ................................................................................ 47 
3.1 
PRIOR CLINICAL INVESTIGATIONS ........................................................................................................................ 47 
3.2 
JUSTIFICATION ................................................................................................................................................. 49 
4 
RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND CLINICAL INVESTIGATION .............................. 51 
4.1 
ANTICIPATED CLINICAL BENEFITS ........................................................................................................................ 51 
4.2 
ANTICIPATED ADVERSE DEVICE EFFECTS ............................................................................................................... 51 
4.3 
RESIDUAL RISKS ............................................................................................................................................... 51 
4.4 
POTENTIAL RISKS THAT MAY BE ASSOCIATED WITH NEUSPERA’S IMPLANTABLE SNS SYSTEM .......................................... 52 
4.5 
CONTRAINDICATIONS ....................................................................................................................................... 57 
4.6 
RISK CONTROL/MITIGATION .............................................................................................................................. 57 
4.7 
RISK-TO-BENEFIT RATIONALE ............................................................................................................................. 59 
5 
OVERALL STUDY DESIGN ............................................................................................................................. 60 
5.1 
STUDY PURPOSE .............................................................................................................................................. 60 
5.2 
STUDY OVERVIEW ............................................................................................................................................ 60 
5.3 
STUDY DURATION ............................................................................................................................................ 64 
5.4 
MINIMIZATION OF BIAS .................................................................................................................................... 64 
6 
STATISTICAL CONSIDERATIONS ................................................................................................................... 65 
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6.1 
OBJECTIVES, ENDPOINTS AND ANALYSIS ............................................................................................................... 65 
6.2 
SAMPLE SIZE DETERMINATION ........................................................................................................................... 69 
6.3 
ANALYSIS OF REPLACEMENTS, EXPLANTS .............................................................................................................. 70 
6.4 
STUDY STOPPING RULES FOR PHASE II ................................................................................................................. 70 
6.5 
DEVIATIONS TO THE STATISTICAL ANALYSIS PLAN ................................................................................................... 72 
7 
DESIGN OF THE CLINICAL INVESTIGATION ................................................................................................... 73 
7.1 
GENERAL ....................................................................................................................................................... 73 
7.2 
INVESTIGATIONAL DEVICE AND COMPARATORS ...................................................................................................... 74 
7.3 
STUDY SITES AND SUBJECT ENROLLMENT LIMITS .................................................................................................... 74 
7.4 
SUBJECTS ....................................................................................................................................................... 75 
7.5 
PROCEDURES .................................................................................................................................................. 78 
8 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES ................................................... 102 
8.1 
DEFINITIONS ................................................................................................................................................. 102 
8.2 
ADVERSE EVENTS CAUSALITY AND SEVERITY RATING ............................................................................................. 104 
8.3 
FORESEEABLE ADVERSE EVENTS AND ANTICIPATED ADVERSE DEVICE EFFECTS ........................................................... 107 
8.4 
REPORTING REQUIREMENTS ............................................................................................................................ 107 
8.5 
SPONSOR RESPONSIBILITIES ............................................................................................................................. 109 
8.6 
INVESTIGATOR RESPONSIBILITIES ....................................................................................................................... 110 
9 
SITE INITIATION ACTIVITIES ....................................................................................................................... 111 
9.1 
INVESTIGATOR AND SITE SELECTION ................................................................................................................... 111 
9.2 
INITIATION REQUIREMENTS ............................................................................................................................. 111 
9.3 
SITE TRAINING .............................................................................................................................................. 111 
10 ETHICS ...................................................................................................................................................... 112 
10.1 
ETHICS REVIEW ............................................................................................................................................. 112 
10.2 
ETHICS CONDUCT OF THE STUDY ....................................................................................................................... 112 
10.3 
WRITTEN INFORMED CONSENT ........................................................................................................................ 112 
10.4 
SUBJECT WITHDRAWAL ................................................................................................................................... 112 
11 DATA MANAGEMENT ............................................................................................................................... 113 
11.1 
CONTRACT SUPPORT GROUPS .......................................................................................................................... 113 
11.2 
SUBJECT IDENTIFICATION ................................................................................................................................. 113 
11.3 
CENTRAL DATABASE ....................................................................................................................................... 113 
11.4 
CASE REPORT FORMS ..................................................................................................................................... 113 
11.5 
PROTOCOL DEVIATIONS .................................................................................................................................. 114 
11.6 
CORRECTIVE AND PREVENTIVE ACTIONS ............................................................................................................. 114 
11.7 
INVESTIGATOR DISQUALIFICATION CRITERIA ........................................................................................................ 114 
11.8 
SITE NONCOMPLIANCE ................................................................................................................................... 114 
11.9 
DATA PROCESSING AND MANAGEMENT ............................................................................................................. 115 
11.10 DATA PROTECTION ........................................................................................................................................ 115 
11.11 CONFIDENTIALITY AND PROTECTION OF STUDY FILES ............................................................................................ 116 
11.12 MONITORING ............................................................................................................................................... 116 
11.13 AUDITS AND INSPECTIONS ............................................................................................................................... 117 
11.14 ACCESS TO STUDY RECORDS ............................................................................................................................ 117 
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11.15 RECORD RETENTION ....................................................................................................................................... 117 
12 RESPONSIBILITIES ..................................................................................................................................... 118 
12.1 
INVESTIGATOR RESPONSIBILITIES ....................................................................................................................... 118 
12.2 
SPONSOR RESPONSIBILITIES ............................................................................................................................. 121 
12.3 
PHYSICIAN REVIEW PANEL ............................................................................................................................... 122 
12.4 
CLINICAL EVENTS COMMITTEE (CEC) ................................................................................................................ 122 
12.5 
DATA SAFETY MONITORING BOARD (DSMB) ..................................................................................................... 122 
12.6 
PUBLICATIONS COMMITTEE ............................................................................................................................. 123 
13 STUDY MATERIAL AND PRODUCT .............................................................................................................. 124 
13.1 
SHIPPING ..................................................................................................................................................... 124 
13.2 
LABELING ..................................................................................................................................................... 124 
13.3 
STORAGE ..................................................................................................................................................... 124 
13.4 
PRODUCT ACCOUNTABILITY ............................................................................................................................. 124 
14 STUDY AMENDMENTS AND CLOSURE ........................................................................................................ 126 
14.1 
AMENDMENTS TO THE PROTOCOL .................................................................................................................... 126 
14.2 
SUSPENSION OR EARLY TERMINATION ................................................................................................................ 126 
14.3 
ROUTINE CLOSEOUT ....................................................................................................................................... 126 
14.4 
FINAL STUDY REPORT ..................................................................................................................................... 126 
15 CLINICAL TRIALS REGISTRY (CLINICALTRIALS.GOV) ..................................................................................... 127 
16 STATEMENTS OF COMPLIANCE ................................................................................................................. 128 
17 VULNERABLE POPULATION ....................................................................................................................... 129 
18 BIBLIOGRAPHY ......................................................................................................................................... 130 
19 APPENDIX A: PHASE I SUB-STUDY ............................................................................................................. 131 
 
LIST OF TABLES 
Table 1: Neuspera SNS System Manufacturers ........................................................................................... 44 
Table 2: Potential Risks Based on Literature Review and Neuspera Clinical Data ...................................... 52 
Table 3. Device and/or Procedure Related Adverse Events - Enrolled Subjects - Phase I .......................... 54 
Table 4. Device and/or Procedure Related Adverse Events – Implant Attempted Subjects - Phase II ....... 56 
Table 5: Comparator Event Probabilities Guiding the Phase II Stopping Rule. Values Shown Are Point 
Estimates (Upper Limits of 95% Confidence Intervals). .............................................................................. 70 
Table 6 : Phase I Follow-Up Schedule .......................................................................................................... 97 
Table 7 : Visit Procedure Schedule – Phase I ............................................................................................... 98 
Table 8 : Phase II Follow-Up Schedule Visit ................................................................................................. 99 
Table 9 : Visit Procedure Schedule – Phase II ............................................................................................ 100 
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LIST OF FIGURES 
Figure 1: Neuspera Implantable SNS system .............................................................................................. 31 
Figure 2: Neuspera’s RF mid-field from the Wireless Transmitter thru the Subject tissue to the 
implantable stimulator ................................................................................................................................ 32 
Figure 3: Neuspera SNS Implantable Neurostimulators ............................................................................. 33 
Figure 4: Implantable Sacral Nerve Stimulation Kit Components ............................................................... 34 
Figure 5: BioStim M7 Digital Tens Unit ........................................................................................................ 35 
Figure 6: Clinician Programmer Interface ................................................................................................... 36 
Figure 7: Wireless Transmitter .................................................................................................................... 37 
Figure 8: Photograph of the Wireless Transmitter Charging Pad ............................................................... 38 
Figure 9:Magnet .......................................................................................................................................... 38 
Figure 10: Patient Controller Running the NEUSPERA Application ............................................................. 39 
Figure 11: Women’s Panty Undergarment ................................................................................................. 40 
Figure 12: Women’s Low Rise Hipster Undergarment With Rear Pocket for the Wireless Transmitter .... 41 
Figure 13: Wearable .................................................................................................................................... 42 
Figure 14: Subject Identification Card ......................................................................................................... 59 
Figure 15:  Phase I Subject Flowchart .......................................................................................................... 61 
Figure 16:Phase II Subject flowchart ........................................................................................................... 63 
Figure 17: Troubleshooting guidance for loss of efficacy or painful stimulation ........................................ 91 
 
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ABBREVIATIONS 
ADE 
 
Adverse Device Effect  
AE 
 
Adverse Event  
AIMDD 
 
Active Implantable Medical Devices Directive  
ASADE 
 
Anticipated Serious Adverse Device Effect  
CIP 
 
Clinical Investigation Protocol 
CRF 
 
Case Report Form  
CRO 
 
Contract Research Organization  
DSMB 
 
Data Safety Monitoring Board 
EC 
 
Ethics Committee 
EDC 
 
Electronic Data Capture 
FI 
 
Fecal Incontinence 
eCRF 
 
Electronic Case Report Forms  
ePRO 
 
Electronic Patient Reported Outcome 
IB 
 
Investigator Brochure  
ICF  
 
Informed Consent Form  
IFU 
 
Instructions for Use  
ISO 14155 
International Standard on the Clinical investigation of medical devices for human subjects – Good clinical 
practice  
MedDRA  
Medical Dictionary for Regulatory Affairs  
MRI 
 
Magnetic Resonance Imaging  
NSM 
 
Neuspera Medical  
OAB 
 
Overactive Bladder 
PI 
 
Principal Investigator  
PGI-I 
 
Patient Global Impression of Improvement 
QA 
 
Quality Assurance  
SAE 
 
Serious Adverse Event 
SADE 
 
Serious Adverse Device Effect  
SNS/SaNS 
Sacral Nerve Stimulation  
SOP 
 
Standard Operating Procedure  
UADE 
 
Unanticipated Adverse Device Effect  
UUF 
 
Urinary Urgency Frequency  
UUI 
 
Urinary Urgency Incontinence  
USADE 
 
Unanticipated Serious Adverse Device Effect  
WT 
 
Wireless Transmitter  
 
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REVISION HISTORY  
Version  
Date 
Summary of Changes/Affected Sections 
1.0 (not 
approved or 
released) 
06 March 2019 
Initial for Regulatory Submission 
2.0 
21 May 2019 
Response to FDA deficiencies 
3.0 (not 
submitted in 
the US or 
released in 
Europe) 
29 July 2019 
Response to EC deficiencies and general updates throughout 
protocol and improving the flow of protocol. 
4.0 (not 
approved or 
released) 
25 September 2019 
Made clarifications and added data collection parameters. 
5.0 
23 October 2019 
Made change to section 10.3 regarding retention of informed 
consent. 
6.0 
05 December 2019 
Clarified the timing of fecal incontinence (FI) diary. Change 
the OAB washout period. Added in data collection 
parameters for device testing and if subject requires MR 
scan. Changed volume of device. Made general updates to 
match Investigator Brochure version 4.0 updates.  
7.0 
28 January 2020 
To increase the number of Phase I clinical sites from 6 to 9 
sites in the US and Europe. Synopsis: Investigation Centers 
and Section 7.1.3: Study Sites and Subject Enrollment Limits 
8.0 
01 May 2020 
To increase the number of Phase I clinical sites from 9 to 14 
sites in the US and Europe. Synopsis: Investigation Centers 
and Section 7.1.3: Study Sites and Subject Enrollment Limits 
9.0 (not 
approved or 
released) 
20 May 2020 
To remove three inclusion criteria (BMI requirement, 
Urodynamics and cystoscopy testing), to clarify the active 
implantable devices exclusion criterion, to add a 
baseline/screening assessment to measure the skin to S3 
foramen distance, to allow final analysis of Phase I data on 1-
month or 3-month follow-up data, and other administrative 
changes. 
 
 
 
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Version 
Date  
Summary of Changes/Affected Sections 
10.0 
17 July 2020 
To reinsert inclusion criteria requiring urodynamics and 
cystoscopy testing within 6-months of the 
baseline/screening visit or completion of the tests at the 
screening baseline visit (these were removed in version 
9.0 of the protocol). To add an inclusion criterion 
requiring that a subject’s BMI be ≥ 18. To add an 
exclusion criterion that if, during the implant procedure, 
the investigator is unable to elicit an appropriate motor 
response in the subject during the intra-operative 
testing, the subject will be excluded. 
11.0 
06 October 2020 
Updated the number of subjects to be enrolled in Phase 
I to up to 55 subjects to allow for up to 40 subjects to be 
implanted. Clarified definition of enrollment. Updated 
the formatting in Tables 4 and 6 to fit table on one page. 
12.0 
14 January 2021 
Changed title to UUI population. Changed the definition 
of enrollment for Phase II to be consistent with ISO 
14155. Updated number of enrolled subjects in Phase II 
to 255. Added an as treated analysis in Phase II, all 
implanted subjects will be followed. All subjects, 
regardless of responder or non-responder status at day 
28 or 42 post implant will continue in post-implant 
follow-up. Changed post-implant visits to monthly 
though 12-month follow-up and every three months 
thereafter. Added monthly telephone visits mid-way 
between clinical visits through 12 months. Added post 
12-month telephone visits in months where there is not 
a clinic visit. Changed anticipated length of follow-up to 
36 months. Added a new device model, the size 44mm 
neurostimulator for use. Added procedures for device 
replacement. Added statement on limiting physical 
activity for 6 weeks post-implant. Added restrictions on 
device manipulation. Added troubleshooting procedures 
if subject not feeling stimulation. Added analysis plan 
for hierarchical testing of secondary endpoints intended 
for labeling claims. Added null and alternative 
hypotheses for secondary endpoints intended for 
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Version 
Date  
Summary of Changes/Affected Sections 
labeling claims. ISO14155-2020 compliance changes 
made in protocol. 
13.0 (not 
approved or 
released) 
16 March 2021 
Changed the primary endpoint analysis population to an 
Intent-to-Treat Analysis Set. Added a Per Protocol 
Analyses set.  Changed post implant visits to monthly 
through 6-months, quarterly to 12 months and then 
every 6-months thereafter.  Added a physician review 
panel as a final check for trial qualification prior to 
implant attempt. Added another external stimulator 
model (low output) for intraoperative testing. A new 
undergarment and manufacturer have been added. New 
figures added with new undergarment. Added Charging 
Pads to the list of manufacturers for the components of 
the system. Removed the fecal incontinence (FI) diary 
for those subjects with concomitant FI at baseline. 
Justification for Clinician Investigation changed to 
include Phase I results. The model 000197 number was 
changed to SNS-35. Clavien-Dindo Classification System 
for Adverse Events replaced previous Adverse Event 
severity classification system. Other minor modifications 
throughout.  
14.0 (not 
approved or 
released) 
14 July 2021 
Added a monitoring of safety events by the DSMB after 
every 36 subjects are implanted. Added inclusion criteria 
No. 13:  Has appropriate sacral anatomy as determined 
by sponsor’s and investigator’s analysis of radiographic 
imaging.  (The distance from the surface of the skin in 
the prone and seated position to the bone edge of the 
S3 foramen must be within the capabilities of the 
system). Added an assessment of sacral thickness to 
guide selection of implant model (SNS-28 or SNS-35) for 
the implant procedure. Added assessment of distance 
from the surface of the skin to the bone edge of the S3 
Foramen in subjects with a BMI between 30 to 40 kg/m2 
or in subjects with a BMI<30 kg/m2 based on 
investigator discretion. Update the follow-up visit 
windows for months 1 to 12 to be +/- 14 from Implant. 
Updated Figure 6 and 9 with new clinician 
application/patient application interface consistent with 
approved software. Updated protocol throughout with 
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Version 
Date  
Summary of Changes/Affected Sections 
more details associated with ISO 14155-2020 and EU 
MDR requirements/updates.   
15 (not approved 
or released)  
17 November 2021 
Updated Figure 1 to include a picture of the Magnet.  
Added new section 2.19 with the Magnet description.  
Added new Figure 9 with a picture of the Magnet and 
updated Figure numbers throughout document. Added 
study stopping rules.  Added rationale for stopping 
rules. Updated post-operative care section 7.1.5.7.3 
regarding limiting delivery of therapy during certain 
activities such as driving. Updated adverse events 
section to be in compliance with new MDR regulations. 
Removed “Activities by Sponsor Representatives” 
section and combined information with section 12.2.1 
Sponsor Representatives. Updated section 4.4 to include 
a separate table of device and procedure related 
adverse events from Phase I of the trial.  Updated table 
on potential risks. Added primary and secondary 
mitigators for device fracture and dislodgement.  In 
section 8.4.2 added new adverse event reporting 
timeframes for fractures, dislodgements/migrations and 
surgical revisions. Adverse event causality relationship 
definitions were updated. Administrative changes 
throughout. 
16 
08 March 2022 
Updated Phase II stopping rules for continual monitoring 
of device fracture, dislodgement/migration, and surgical 
revisions.  Updated actions taken if a stopping rule is 
met.  Changed reporting time of Sponsor to the FDA on 
lead migration/dislodgment, fracture, and loss of 
therapy to the DSMB and FDA from 15 days to 10 days. 
Added that accounting of all device events or 
malfunctions (i.e. migrations/dislodgements and 
fractures), whether clinically significant (requiring 
revision or resulting in permanent loss of therapy) or 
not, with a further breakdown of how they are dealt 
with (e.g., no action needed, reprogramming, 
permanent loss of therapy and/or surgical 
revision/explantation) will be completed. Changed the 
coordinating investigator from Dr Steven Siegel to Dr 
Osvaldo Padron. Requirement of recording in the 
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Version 
Date  
Summary of Changes/Affected Sections 
stimulation diary changed to recording therapy sessions 
daily, ≤ Month 12 Visit, and weekly, > Month 12 Visit in 
Phase I and Phase II.  Change statistical section 
presentation of secondary endpoints to match synopsis; 
endpoints themselves did not change. Added the 
contact information for the new CROs, NAMSA and 
Axiom.  Added a new Figure 1.  
17 
26 April 2022 
Updated to indicate that an interim analysis will be 
completed when approximately 50% of subjects 
complete the 3-month follow-up visit. Updated 
undergarment wording to indicate low-rise hipster will 
be provided to female subjects who are allergic to 
natural rubber. Clarified the material in the two versions 
of female low-rise hipster. Described the encasement of 
natural rubber in the undergarments. Added in time 
points in which measurements will be taken for 
undergarment. Added a sample subject identification 
card provided to subjects. Added that in the event of 
early termination or at the completion of the 
investigation that the sponsor will notify the FDA, IRBs 
and investigations within 30 days.  Additionally, a final 
report will be submitted to the FDA, IRBs and 
investigators within 6 months of termination or 
completion of the investigation. Added Other Serious 
(Important Medical Events) to the adverse event 
section. Added statement that Phase I data in the 65 
and older population is reflective of the Phase I group as 
a whole. Remove subject pain questionnaire.  
17.1 
23 February 2023 
Added Canada as geographical location for an additional 
clinical site. 
18 
05 April 2023 
The enrollment period for Phase II was extended from 9 
to 12 months. The number of scheduled telephone visits 
in Phase II was decreased. Updated number of explants 
and safety data. Increased estimated time of Phase I 
subject involvement. Removed requirement for 
undergarment measurement and weight. Changed 
exclusion criteria for UTI. Added definition of mITT and 
changed definition of ITT analysis set. Modified activity 
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Version 
Date  
Summary of Changes/Affected Sections 
restrictions post implant. Updated Figure 10, Patient 
Controller running the Neuspera Application software. 
Stimulation sensation verification was changed to 
complete at the end of the therapy session instead of 
during the therapy session. The person(s) who may 
perform the Sacral Anatomy reading was updated. 
Scheduled device parameter/downloads was revised to 
be periodically recorded. Added information on what 
should not be considered an AE. Updated quantitative 
endpoints for OAB. 
19 
12 June 2023 
Increased number of clinical sites from 25 to 35. 
Lowered the number of attempted implants from 145 to 
120.  Lowered the approximate number of successful 
implants from 138 to 114.  Lower the power for a one-
sided 0.025 exact binomial test from 90 to 85%. 
Updated the “worst case” scenario results that would 
still meet the statistical threshold for this performance 
goal, changed to 72 out of 120 (60%).  Added a ICIQ-
OABqol responder rate secondary endpoint to be 
potentially used for labeling claims.  Added statistical 
information per FDA feedback. Updated details on 
interim analysis. 
20 
16 March 2024 
Updated safety information based on 2023 FDA annual 
report.  Incorporated Neuspera Wearable into the study.  
Refined secondary endpoints that will be included for 
labeling claims.  Removed the 12-month time point 
assessment for all secondary endpoints that may be 
used for labeling claims.  Noted that performance goals 
for all secondary endpoints are included in the Statistical 
Analysis Plan (SAP).  Added that subjects who take OAB 
medications prior to the six-month visit will be 
considered device failures.  Added Phase II weight 
assessment at 12, 24, and 36 month visits (and 42 and 
60 month visits for Phase I subjects).  Added bladder 
diary assessments to every clinical visit in Table 8.  
Added that a delegated implanting sub-investigator can 
complete the Physician User Experience Questionnaire.  
Noted that stimulation settings were recorded, but not 
downloaded.  Noted that if a subject is symptomatic 
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Version 
Date  
Summary of Changes/Affected Sections 
with a urinary tract infection (UTI) prior to beginning or 
in the middle of a 72-hour bladder diary, it is 
recommended to the subject start the diary after the 
subject is asymptomatic after standard-of-care 
treatment.  Updated Statistician to Fortrea.  Formatting 
changes. 
21 
4 April 2025 
Removed the specific brand name (Apple) reference on 
the Clinician Programmer and Patient Controller and 
described Neuspera Application software with off-the-
self equipment. Added new Patient Controller picture. 
Updated Table 1 (Neuspera SNS System Manufacturers), 
the Neuspera App for the Clinician Programmer and 
Patient Controller added. Removed duplicate sciatica 
reference in Table 2 (Potential Risks Based on Literature 
Review and Neuspera Clinical Data). Updated Figure 17 
(Troubleshooting guidance for loss of efficacy or painful 
stimulation) to include Wearable.  
Added a sub-study available for Phase I subjects only in 
Appendix A: Phase I Sub-Study 
CONTACT INFORMATION 
Study Sponsor 
Neuspera Medical Inc.  
51 Daggett Drive  
San Jose, CA 95134, USA 
Telephone:  +1 408.612.7570 
Sponsor’s Funding Source: Neuspera Medical Inc. 
Courtney Lane, PhD, Vice President of Clinical, Quality, and Regulatory Affairs 
Telephone: +1 805.856.8141
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1. INTRODUCTION 
Millions of patients worldwide are diagnosed annually with overactive bladder (OAB) including urinary 
urgency, frequency, nocturia and urinary urgency incontinence (UUI). An estimated 546 million patients 
will be affected by OAB of which 423 million patients will be affected by UI.1 Many in this patient 
population are not well controlled by conventional medical management. 
The International Continence Society (ICS) defines UUI as a “Complaint of involuntary loss of urine 
associated with urgency.” Patients with UUI often experience urinary urgency at inconvenient or 
unpredictable times and often experience leakage and voiding in advance of reaching a toilet. As a result, 
these symptoms interfere with normal daily activities such as work, intimacy, and sexual function. This 
disruption to the patient’s normal daily activity leads to embarrassment, depression, diminished self-
esteem, and reduced quality of life.2 
The clinical diagnosis of OAB is based on a history and physical examination of the patient, as well as 
urinalysis. In some patients, additional procedures and measures may be necessary to validate an OAB 
diagnosis or exclude other disorders. A urine culture and/or post-void residual assessment may be 
performed and details from bladder diaries and/or symptom questionnaires may be obtained. 
1.1 
Treatment of Overactive Bladder 
Multiple options are available to patients who are diagnosed with overactive bladder (OAB). Physicians 
typically take a guideline-based phased approach to the treatment of symptoms with OAB.3   
1.1.1 First-Line Treatment 
First-line treatment for UUI as a consequence of OAB includes behavioral therapies such as bladder 
training, bladder control strategies, pelvic floor exercise, and fluid management. Behavior therapies may 
be combined with pharmacologic management. 
1.1.2 Second-Line Treatment 
When symptoms are not adequately improved with first-line treatment, second-line treatment includes 
oral anti-muscarinics, and β3-adrenoceptor agonists. If a patient continues to experience inadequate 
symptom control and/or unacceptable adverse events with one anti-muscarinic medication, then a dose 
modification or different choice of anti-muscarinic or β3-adrenoceptor agonists may be tried. 
1.1.3 Third-Line Treatment 
Third-line treatments include neuromodulation and bladder chemo denervation with Onabotulinumtoxin 
A injection. These third-line options bridge the treatment gap between conservative therapies for UUI as 
a consequence of OAB and irreversible surgical procedures such as enterocystoplasty.  
Neuromodulation targets the sacral nerve plexus which regulates control of the bladder and pelvic floor 
muscles. Neuromodulation treatments currently available for OAB are Sacral Nerve Stimulation (SNS) 
and Posterior Percutaneous Tibial Nerve Stimulation (PTNS).  
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For SNS therapy, two systems are commercially approved: Medtronic InterStim and Axonics 
Neuromodulation System. The Medtronic InterStim® Therapy and Axonics systems are indicated for the 
treatment of urinary retention and the symptoms of OAB, including UUI and significant symptoms of 
urgency-frequency, alone or in combination in patients who have failed or could not tolerate more 
conservative treatments. Sacral Nerve Stimulation using the InterStim® Therapy system has been shown 
in an as treated analysis to have a therapeutic success of 76% (93% were female) versus 49% for 
standard medical therapy (P = 0.002).4 Device related complications associated with the InterStim® 
Therapy system include the following: lead migration and fracture, pocket infection, lead infection, 
pocket pain, cosmetic issues including a bulge above the buttocks and requirement for frequent 
reprogramming. Device related adverse events occurred in 31% of patients with InterStim system versus 
27% of adverse events in patients with standard medical therapy. A 5-year prospective, multicenter, non-
randomized study of 272 subjects implanted with InterStim for treatment of OAB demonstrated 
successful long-term outcomes using sacral neuromodulation. The InSite Study showed that of the 272 
subjects with OAB there was a therapeutic success rate of 67% (95% CI 60-74) using a modified 
completers analysis and 82% (95% CI 76-88) using a completers analysis.5 
The Axonics system, in an as treated analysis, at 6 months, showed a therapeutic success rate of 90% 
(116/129 subjects). The average number of UUI episodes was reduced from 5.6 ± 0.3 at baseline to 1.3 ± 
0.2 at 6 months (p<0.0001) representing a 79% reduction in UUI episodes. The most frequent adverse 
events (AEs) were discomfort due to stimulation, pain at the neurostimulator site, and lead migration.6 
The 1-year, as treated, outcomes data demonstrated that 89% of study participants (115/129) were 
therapy responders (i.e., had ≥50% reduction in UUI symptoms as compared to baseline). A consistent 
responder rate was seen from 1-month to 1-year. The UUI episodes reduced from 5.6 ± 0.3 at baseline to 
1.4 ± 0.2 at 1-year (p <0.0001) which is a 75% reduction in UUI episodes. The most frequent AEs were 
discomfort due to stimulation, discomfort/heating near the charging area, pain at the neurostimulator 
site, and lead revision.7 
 
 
 
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2 
INVESTIGATIONAL DEVICE 
2.1 
Neuspera Implantable Sacral Nerve Stimulation System 
The Neuspera Implantable Sacral Nerve Stimulation System (herein referred to as Neuspera SNS system) 
is a sacral nerve stimulation system consisting of a miniaturized implantable neurostimulator system 
combining a receiver antenna, hermetically sealed electronic package, and tined stimulation electrode 
array with four programmable electrodes. The neurostimulator’s antenna receives energy from an 
externally worn powering unit (Wireless Transmitter, see below). The hermetically sealed electronic 
package (0.03 cc) consists of a highly integrated electronic circuit with a custom ASIC (application specific 
integrated circuit) and flex circuit interconnect. This package harvests the received energy, manages 
power and communication, and generates stimulation, analogous to the InterStim® implantable pulse 
generator (IPG). The programmable electrode array is similar in geometry and functionality to the 
electrode array at the distal end of the InterStim lead. The electrode array delivers stimulation to the 
sacral nerve.  
The Neuspera SNS system is provided in two sizes: 44 mm length (Model SNS-28) and 51 mm length 
(Model SNS-35). 
There is no implantable battery in the Neuspera SNS system. The absence of the implantable battery and 
the miniaturized electronic package reduces the total implanted volume of the Neuspera SNS system to 
approximately 0.12 cc. As noted above, the volume of the Neuspera pulse generator (hermetically sealed 
electronic package) is 0.03 cc vs the InterStim II implantable pulse generator volume of approximately 14 
cc or the InterStim Micro implantable pulse generator volume of approximately 2.8 cc. The Neuspera 
SNS system is powered by an externally worn Wireless Transmitter which contains a rechargeable 
battery. Power is delivered to the implanted neurostimulator using Neuspera’s proprietary mid-field 
powering technology. The Wireless Transmitter is worn over the subject’s sacrum, directly over the 
implanted neurostimulator, and held in position by custom designed undergarments or Wearable. The 
Wireless Transmitter is controlled by custom Neuspera software Application  (referred to as the Clinician 
Programmer and the Patient Controller) running on off-the-shelf equipment. The rechargeable battery of 
the Wireless Transmitter is charged by an off-the-shelf charging pad.  
The tools provided in the Neuspera Implantable SNS Kit are used to introduce and implant the 
neurostimulator. Additionally, the Neuspera Intraoperative Test Kit and an off-the-shelf Intraoperative 
External Stimulator are used to identify the location of the sacral nerve by observing motor responses 
(bellows response and great toe/toe flexion) to stimulation.   
The Neuspera Implantable SNS System consists of: 
• 
Implantable Sacral Nerve Stimulation Kit 
o Foramen Needle and Stylet Set 
o Guidewire 
o Dilator/Introducer Sheath Set 
o Implant/Push Rod Assembly 
• 
Intraoperative External Stimulator 
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• 
Intraoperative Test Kit 
o Intraoperative Stimulator Lead (cable) 
o Alligator Clip 
o Surface Electrode 
• 
Wireless Transmitter  
• 
Magnet 
• 
Neuspera Undergarments 
• 
Neuspera Wearable 
• 
Clinician Programmer 
• 
Patient Controller 
• 
Wireless Transmitter Charging Pad  
Figure 1 displays the Neuspera SNS System. A detailed description of each relevant component is 
provided in the sections that follow.   
The following components will have contact with subject tissue or bodily fluids: 
• 
Implantable Sacral Nerve Stimulation Kit 
o Foramen Needle and Stylet Set 
o Guidewire 
o Dilator/Introducer Sheath Set 
o Implant/Push Rod Assembly 
• 
Intraoperative Test Kit 
o Surface Electrode (short-term skin contact only) 
• 
Neuspera Undergarments (skin contact only) 
• 
Neuspera Wearable (skin contact only) 
Additionally, the following components are intended to be handled (held and/or touched) by subjects: 
• 
Wireless Transmitter 
• 
Magnet 
• 
Patient Controller 
• 
Wireless Transmitter Charging Pad  
• 
Neuspera Undergarments 
• 
Neuspera Wearable 
 
 
 
 
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Figure 1: Neuspera Implantable SNS system 
2.1.1 Principle of Operation 
Neuspera’s SNS System relies on a radio frequency signal that is sent from the Wireless Transmitter to 
power a miniature neurostimulator implanted in the S3 Foramen in close proximity to the sacral nerve.  
The Neuspera’s SNS System uses a midfield radio frequency (RF) signal within the FCC ISM (industrial, 
scientific, and medical) radio band between 902 and 928 MHz as the default band. The RFID 
(radiofrequency identification) band between 865 and 868 MHz is available as an alternate band in 
regions where the ISM band cannot be used. The neurostimulator has an antenna at its proximal end 
that receives the signal. The received signal passes from the antenna through the proximal bipolar 
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feedthrough to the circuit assembly within the sealed circuitry housing. The controller integrated circuit 
(IC) with circuit assembly rectifies the antenna signal and uses the harvested energy to power the 
internal implant circuitry. The incident signal is also modulated by the wireless transmitter to encode 
information that is used by the implant to set parameters of the therapeutic pulse output. The pulses are 
conducted through the distal quadripolar feedthrough to the distal electrodes used for stimulation of the 
subject’s sacral nerve. 
This midfield powering technique efficiently couples the RF signal through the subject’s tissue to the 
implanted device. The dielectric properties of the tissue between Wireless Transmitter and the 
Implantable Neurostimulator are factored into the transmitter design and transmission frequency. This 
enables a much higher energy transfer efficiency relative to comparable near field or far field-based 
implantable device systems. In the simulation generated field density plot, the Neuspera Medical radio 
frequency (RF) Mid-Field signal emanating from the Wireless Transmitter (top in Figure 2) is shown 
propagating through the subject’s tissue to the Implantable Neurostimulator (bottom in Figure 2). The 
energy from this RF field is received in the antenna at the proximal end of the Implantable 
Neurostimulator. Circuitry within the sealed circuit assembly decodes telemetry data, rectifies energy 
from the field, and generates programmed neural stimulation pulses at the distal end of the device when 
instructed by the Wireless Transmitter. 
 
FIGURE 2: NEUSPERA’S RF MID-FIELD FROM THE WIRELESS TRANSMITTER THRU THE SUBJECT TISSUE TO THE 
IMPLANTABLE STIMULATOR 
2.1.2 Implantable Neurostimulator 
The sterile Implantable Neurostimulator (neurostimulator) is constructed of commonly used materials 
and available in two lengths measuring approximately 51 mm long and 44 mm long and 2.3 mm in 
diameter at its widest point. Figure 3 shows the device differences in device length from the proximal 
end to the first electrode for the two implant models. The distal portion of the implant is pre-formed 
with a curvature intended to mimic to the physiologic curvature of the sacral nerve sheath; an 
incorporated keying feature mates with the Push Rod to prevent accidental rotation of the pre-formed 
curve during the implant procedure. 
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The tined neurostimulator electrode has an internal circuit assembly that is connected, welded, and 
sealed within a housing. On its distal end, it has four 3mm electrodes, spaced at 3mm intervals that 
create a bipolar stimulation field. On the proximal end, it has an encapsulated antenna to receive the 
propagated midfield signal from the Wireless Transmitter; the implant does not contain a battery. The 
radial tines maintain the axial position of the implant. The suture on the proximal end of the implant (not 
shown) is designed to remain tethered to the stimulator during the trial period to simplify removal of the 
device in the event of an unsuccessful trial period. Due to the duration of the trialing period in the 
clinical trial, the suture is trimmed and tucked under the skin at the time of implant.  
One implantable neurostimulator will be implanted per subject. Subjects receiving the Neuspera SNS 
System will have the system in place for the duration of their participation in the study. After study 
completion, subjects may choose to leave the system in place. 
Please refer to Neuspera’s Implantable Sacral Nerve Stimulator Kit Instructions for Use.   
 
 
FIGURE 3: NEUSPERA SNS IMPLANTABLE NEUROSTIMULATORS  
 
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2.1.3 Implantable Sacral Nerve Stimulation Kit    
The Implantable Sacral Nerve Stimulation Kit contains the Implantable Stimulator (described above) pre-
loaded on the Push Rod (Implant/Push Rod Assembly) in addition to tools needed to introduce and 
implant the neurostimulator. The Implantable Sacral Nerve Stimulation Kit is shown in Figure 4.   
 
 
1. Foramen Needle and Stylet Sets 
(shown with protective cover; n=2) 
2. Guidewires (n=2) 
3. Pre-dilator 
4. 7F Dilator 
5. Introducer Sheath 
6. Implant/Push Rod Assembly 
FIGURE 4: IMPLANTABLE SACRAL NERVE STIMULATION KIT COMPONENTS 
 
The Implantable SNS Kit contains:  
• 
Foramen Needle and Stylet Sets (n=2) 
• 
Guidewire (n=2) 
• 
Dilator/Introducer Sheath Sets  
o Pre-dilator 
o 7F Dilator 
• 
Implant/Push Rod Assembly  
Each item noted above is described in the remainder of this section.   
Foramen Needle and Stylet: The sterile, custom stainless steel 20-gauge foramen needle (with stylet) is 
inserted under fluoroscopy into the S3 foramen, and the needle is used with the components of the 
Intraoperative Test Kit (i.e., electrical clips, cable, and surface electrode) and the Intraoperative External 
test stimulator to conduct an initial assessment of the subject to determine their responsiveness to 
stimulation therapy prior to implanting the neurostimulator.   
Guidewire: The guidewire is a 0.6 mm diameter stainless steel wire measuring 305 mm long to place the 
Pre-dilator and 7F Dilator/Introducer Sheath Assembly. During the implant procedure, the guidewire is 
placed through the lumen of the foramen needle. The foramen needle is then removed.   
Dilator/Introducer Sheath Set: Custom dilators and an introducer sheath are used to introduce the 
Implant/Push Rod Assembly to the implant location. The Pre-Dilator is inserted over the guidewire and 
then removed, keeping the guidewire in place.  The 7F Dilator/Introducer Sheath Assembly is then 
inserted over the guidewire. Once the 7F Dilator/Introducer Sheath Assembly is in place, the guidewire 
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and then the 7F Dilator are removed. The Pre-Dilator and 7F Dilator each have a distal radiopaque 
marker.   
Implant/Push Rod Assembly: The Implantable Neurostimulator is supplied pre-loaded on a Push Rod to 
form the Implant/Push Rod Assembly. The Assembly is inserted through the introducer sheath to 
properly place the neurostimulator in the correct implant location. Once the neurostimulator is in the 
correct position, the push rod is detached from the neurostimulator and removed.    
2.1.4 Intraoperative Test Kit 
The single-use Intraoperative Test Kit is used in conjunction with the Intraoperative External Stimulator 
and the Implantable SNS Kit to aid in finding the correct implant site for the Implantable 
Neurostimulator. The following accessories are packaged in the Intraoperative Stimulator Test Kit: 
• 
Stimulator Lead (cable)  
• 
Alligator Clip 
• 
Surface Electrode (Ground pad)  
The Intraoperative Test Kit components are commercially available products and are packaged and 
labeled by Neuspera Medical.  
2.1.5 Intraoperative External Stimulator  
The Intraoperative External Stimulator is used with the foramen needle and the Intraoperative 
Stimulator Test Kit to identify the location of the sacral nerve by observing motor responses (bellows 
response and great toe/toe flexion) to stimulation using the foramen needle. This is done to identify the 
best implant location for the neurostimulator.   
As part of the clinical study, participating centers will be provided with the BioStim M7 Digital TENS unit 
from Biomedical Life Sciences, shown below in Figure 5.  An additional low output BioStim model will be 
added for use in Phase II of the clinical trial.   
 
FIGURE 5: BIOSTIM M7 DIGITAL TENS UNIT 
 
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2.1.6 Clinician Programmer 
The Clinician Programmer (Programmer) enables management of the Wireless Transmitter associated 
with the subject’s implant, programming a subject’s stimulation therapy, review of subject’s therapy 
statistics, and connection of a Patient Controller to a Wireless Transmitter. The Clinician Programmer 
runs Neuspera’s software Application (“Neuspera App”) on off-the-shelf equipment. Software updates 
may be provided throughout the study when approved for use by the FDA, Health Canada and the 
European regulatory authorities.  
Clinicians will primarily navigate among four views on the programmer software application: Home 
Screen; Patient Information and Settings; Wireless Transmitter Management; and Therapy Configuration 
(Figure 6).  
 
 
 
FIGURE 6: CLINICIAN PROGRAMMER INTERFACE 
2.1.7 Wireless Transmitter  
The Wireless Transmitter measures approximately 8 cm in diameter and is approximately 1.5 cm in 
thickness with a weight of 103g (Figure 7). The Wireless Transmitter can be turned on/off using the 
Patient Controller and Clinician Programmer and is designed to last 2 hours before recharging is 
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required. Depending on the prescribed stimulation session, multiple Wireless Transmitters may be 
provided to each subject to allow therapy delivery using one Wireless Transmitter while charging 
another Wireless Transmitter.   
The Wireless Transmitter is placed in the pocket of the undergarment or Wearable (discussed below), 
which positions the Wireless Transmitter directly above the implanted neurostimulator. The Wireless 
Transmitter must be worn in the provided undergarment or Wearable.   
The Wireless Transmitter contains an implant antenna and a programming antenna. The implant 
antenna transmits power and communicates with the implanted neurostimulator. The battery charging 
antenna recharges the Wireless Transmitter using common Qi charging. Additionally, there is a 
Bluetooth® antenna mounted on the printed circuit board (PCB) to communicate with the Clinician 
Programmer and the Patient Controller, allowing the user to adjust settings and activate or cease 
therapy. The internal components in the Wireless Transmitter are constructed of conventional surface 
mount electronics components and conventional circuit board substrate materials. The white outer shell 
is polycarbonate.   
The Wireless Transmitter is water resistant and able to withstand daily cleaning. The Wireless 
Transmitter is internally powered (with a lithium-ion battery) and wirelessly recharged. The Wireless 
Transmitter can switch its operating frequency for international traveling.  
 
 
FIGURE 7: WIRELESS TRANSMITTER 
 
 
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2.1.8 Wireless Transmitter Charging Pad 
The Wireless Transmitter charging pad shown in Figure 8 below is an off-the-shelf wireless charging pad 
which can be plugged into a wall or USB outlet. The Wireless Transmitter is placed white side facing up 
and the logo/label side facing down (i.e. device is “upside-down”) on the charging pad to charge (Figure 
8). A light can be seen on the charging pad when the Wireless Transmitter is charging.   
 
FIGURE 8: PHOTOGRAPH OF THE WIRELESS TRANSMITTER CHARGING PAD 
2.1.9 Magnet 
The Wireless Transmitter will be provided with a Magnet (Figure 9). The Magnet may be used to reset 
the Wireless Transmitter when the Wireless Transmitter is not charging appropriately or becomes 
inoperative.  When the Wireless Transmitter needs to be reset, the subject will place the Wireless 
Transmitter correctly on the charging pad (dotted side face up as in Figure 8).  The label side of the 
Magnet (bottom of Magnet) is placed against the dotted side of the Wireless Transmitter to perform the 
reset. The teardrop point of the Magnet should be aligned with the teardrop point of the Wireless 
Transmitter. After 5-10 seconds, remove Magnet from the Wireless Transmitter. The subject will confirm 
the reset was successful by 1) confirming the green light on the Wireless Transmitter is blinking and 2) 
waiting 30 seconds and observing that the status light of the charging pad has initiated. The magnet 
should not be left on the Wireless Transmitter when it is being charged between therapy sessions.  
 
FIGURE 9:MAGNET 
 
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2.1.10 Patient Controller 
The Patient Controller (Figure 10) runs Neuspera’s software Application on off-the-shelf equipment. The 
Patient Controller comes with its own USB charging cord. The Patient Controller is used by the subject to 
turn their Wireless Transmitter on/off, adjust stimulation amplitude (within limits set by the physician) 
and select which of the physician’s pre-programmed stimulation programs to use. The user can also 
monitor the Wireless Transmitter battery level, view his/her program use history and adjust the Wireless 
Transmitter for airplane and international travel.   
 
FIGURE 10: PATIENT CONTROLLER RUNNING THE NEUSPERA APPLICATION 
 
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2.1.11 Custom Undergarment  
The custom designed Neuspera Undergarment is a pair of underwear with a rear pocket that 
comfortably positions the Wireless Transmitter in the correct position directly over the sacrum; see 
Figure 11 and Figure 12. The specially designed pocket in the undergarment includes a layer of foam to 
pad and insulate the Wireless Transmitter against the body to improve comfort and provide the optimal 
distance from the skin. During use, the Wireless Transmitter is inserted into the pocket such that the 
white (dotted) side faces the body, and the logo/label rim faces away from the body. The undergarment 
may be worn by itself or over pads or diaper.  The custom undergarments are provided by two different 
manufacturers (see section 2.4). The pictures of the women’s designs for both manufactures are 
provided in Figure 11 (Women’s Panty) and Figure 12 (Women’s Low Rise Hipster).  There is also a Men’s 
Brief that will be used for male subjects (as pictured in Figure 1 with the full system). The Men’s Brief has 
the same rear pocket design as the Women’s Panty design. 
 
 
FIGURE 11: WOMEN’S PANTY UNDERGARMENT 
 
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FIGURE 12: WOMEN’S LOW RISE HIPSTER UNDERGARMENT WITH REAR POCKET FOR THE WIRELESS TRANSMITTER 
The undergarments are available with the pocket on either the right or left side, corresponding to the 
side in which the neurostimulator is implanted and come in men’s and women’s sized extra-small (XS) to 
extra-extra-extra-large (XXXL). The undergarments are made from standard garment material. The 
Women’s Panty contains: spandex, nylon, polyester, cotton, and polyurethane. The Men’s brief contains: 
spandex, nylon, polyester, cotton, natural rubber and polyurethane.  The Women’s Low Rise Hipster is 
provided in two versions that differ in materials only. One version contains: spandex, nylon, polyester, 
cotton, natural rubber, and polyurethane, and one version contains: spandex, nylon, polyester, cotton 
and polyurethane.  All undergarment versions are worn the same way as standard undergarments.   
All female subjects initially implanted in Phase II will be provided with Women’s Low Rise Hipster 
garments containing natural rubber.  Those subjects allergic to the natural rubber will be provided with 
the Low Rise hipster that does not contain natural rubber.  All male subjects will receive the Men’s brief 
containing natural rubber. Male subjects allergic to the natural rubber should discuss study participation 
with the clinical investigator. In the Women’s Low Rise Hipster and Men’s briefs containing natural 
rubber, the natural rubber is encased in two layers of polyester (Women’s Low Rise Hipster) and 
polyester and cotton (Men’s Brief). The two layers prevent the natural rubber from having direct skin 
contact. The first layer is within the elastic trim itself where the trim is made of natural rubber tubes 
wrapped in polyester. This elastic trim is incorporated into the waistband of the women’s low rise hipster 
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garment where the main fabric (polyester/spandex) is wrapped around the elastic trim. In the Men’s 
Brief, the elastic trim is incorporated into the leg opening of the men’s brief undergarment where the 
main fabric (cotton/spandex) is wrapped around the elastic trim. Two layers of polyester between the 
skin (women’s undergarment) and polyester/cotton (men’s undergarment) and the natural rubber 
serves as a protective layer.  The natural rubber is not intended to contact the skin and is unlikely to 
contact the skin of the subject during use; however, the undergarment will be labeled “Caution: This 
Product Contains Natural Rubber Latex Which May Cause Allergic Reactions.”  This information will be 
provided in the Subject Informed Consent, Patient Manual and Clinician Manual for the clinical trial. 
2.1.12 Wearable 
The Neuspera Wearable (Wearable) is designed to hold and maintain the Wireless Transmitter (WT) 
above the implanted neurostimulator for delivery of therapy. The specially designed pocket will also pad 
and insulate the Wireless Transmitter against the body to improve comfort. An optional leg loop strap is 
provided to offer additional support for maintaining vertical positioning. The Wearable is intended to be 
worn under general clothing (i.e. pants, shirts, and jackets) and over undergarments. It is also compatible 
with pads and diapers. The Wearable is available in four sizes from Small to Extra Large. 
 
FIGURE 13: WEARABLE 
2.2 
Intended Use and Indications Statement 
2.2.1 Intended Use 
The Neuspera Implantable Sacral Nerve Stimulation System is intended for stimulation of the sacral 
nerve to treat urinary urgency incontinence (UUI) symptoms.    
2.2.2 Indications Statement 
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Neuspera's Implantable SNS System is indicated to treat subjects with UUI who have failed or could not 
tolerate more conservative treatments.  
2.3 
Intended Purpose in the Clinical Investigation 
The Neuspera’s Implantable SNS System is intended for stimulation of the sacral nerve to treat UUI 
symptoms. This study will collect data on the efficacy and safety of the Neuspera SNS system in subjects 
who have UUI.   
2.4 
Manufacturer 
The Neuspera SNS System is a combination of a number of different devices. The devices of the 
Neuspera SNS system are manufactured at a mix of in-house and off-site contract manufacturers within 
the United States. Neuspera executes quality agreements and relies on supplier quality systems for 
adequate controls of documentation records.  
Neuspera is the manufacturer of record / legal manufacturer and maintains control over all product 
released for clinical use. 
 
 
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The Table 1 below identifies the manufacturing facilities associated with the Neuspera SNS System: 
TABLE 1: NEUSPERA SNS SYSTEM MANUFACTURERS  
Description 
Manufacturer 
Wireless Transmitter 
Neuspera 
Implantable SNS Kit 
(implanted stimulator & implant 
tools) 
Oscor, Inc. 
3816 DeSoto Blvd 
Palm Harbor, FL 34683 
(USA) 
Neuspera App for the Clinician 
Programmer 
Velentium 
22322 Grand Corner 
Drive, Suite 140 
Katy, TX 77494 (USA) 
Neuspera App for the Patient 
Controller 
Intraoperative Test Kit 
Pro-Tech 
14561 Marquardt Ave 
Santa Fe Springs, CA 
90670 (USA)  
Undergarment 
Clothier Design Source 
2408 W Territorial Rd 
St Paul, MN 55114 (USA) 
Jennifer Loel Designs 
460 Aaron St, Suite B 
Cotati, CA 94931 (USA) 
Wearable 
TPI Custom Solutions 
13828 Lincoln Street NE 
Ham Lake, MN 55304 
Intraoperative (External) 
Stimulator 
Biomedical Life Sciences 
1954 Kellogg Avenue 
Carlsbad, CA 92008-6581 
Charging Pad, Black 
Samsung 
Charging Pad, White 
Samsung 
Charging Pad, White 
Belkin 
Magnet 
Neuspera 
 
During Phase I of the trial, all undergarments were manufactured by Jennifer Loel Designs.  This 
manufacturer is no longer providing undergarments for the clinical trial. A new manufacturer, Clothier 
Design Source, has developed a new women’s undergarment design.  Male subjects in the trial will be 
provided undergarments previously purchased and designed by Jennifer Loel Designs.  Female subjects 
enrolled in Phase I of the trial received undergarments designed by Jennifer Loel Designs and could 
receive replacement undergarments manufactured by Jennifer Loel Designs or Clothier Design Source. 
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Female subjects in Phase II may receive undergarments from either Jennifer Loel Design or Clothier 
Design Source.  All subjects may receive the Wearable as well as the undergarment. 
2.5 
Required Training and Experience 
Clinicians who are trained by education in urology or urogynecology, have experience in treatment in 
OAB, urinary surgery, clinical studies, and Good Clinical Practice for Medical Devices (ISO 14155), ICH-
GCP, applicable FDA Code of Federal Regulations (CFR), and are able to read and understand English 
qualify for the investigation. Sites will be selected based on completing a site qualification visit. Prior to 
the beginning of the clinical investigation, on-site initiation visits will be organized, in which full training 
will be given to all appropriate staff members participating in the clinical investigation. This training will 
include at least the following: instructions on the functions and use of the investigational device, 
procedures outlined in the clinical investigation plan, main principles of ICH-GCP and ISO 14155, 
overview of all investigational device units (including storage requirements and accountability 
instructions), instructions on completion of the case report forms, content of the investigator site file, 
and management of adverse events and serious adverse events. 
Subjects will be trained on the use of the Neuspera SNS system by the clinical study staff and will be 
provided with the Patient Manual on operating the system.   
2.6 
Medical/Surgical Procedures  
The Neuspera SNS neurostimulator implant procedure will be performed in accordance with approved 
Neuspera Intraoperative Kit Instructions for Use and Neuspera Implantable Sacral Nerve Stimulator Kit 
Instructions for Use for Model SNS-35 or Model SNS-28. Selection of the model number will be made at 
the time of the implant. 
The subject will be prepped and will undergo local anesthesia, intravenous conscious sedation, or 
general anesthesia. The S3 foramen will be located per Neuspera’s Implantable Sacral Nerve Stimulator 
Kit Instructions for Use. Following appropriate identification of the sacral nerve location, the 
neurostimulator will be implanted and stimulation parameters will be confirmed by observing motor 
responses of anal bellows with or without twitching of the big toe or movement in other toes.  If motor 
responses are not confirmed at S3, the S4 foramen may be located, and motor response confirmed at 
this location. After confirming the functionality of all electrodes and optimal stimulation parameters, the 
tethering suture will be clipped, and the incision closed in accordance with approved Neuspera’s 
Implantable Sacral Nerve Stimulator Kit Instructions for Use. A bandage will be placed over the implant 
site. 
If appropriate physiological response cannot be achieved during the implant procedure, the 
neurostimulator will be removed and the subject will be followed for 30 days post procedure and exited 
from the study.    
In Phase I, subjects determined to be SNS responders after the trial period had lateral and  
anterior/posterior radiographic images taken to confirm position of the neurostimulator at the final trial 
visit (day 21, 35 or 49). 
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In Phase II, all subjects will have lateral and anterior/posterior radiographic images taken to confirm 
position of the neurostimulator at Day 28 clinic visit (if determined a responder) or Day 42 clinic visit 
(responder or non-responder) post-implant.  
2.7 
Device Traceability 
The Neuspera SNS System components will be identified and labeled by lot and/or serial number and will 
be traced for the duration of the clinical study. Each subject will be provided a Wireless Transmitter, 
Wireless Transmitter Charging Pad, Magnet, Patient Controller, and custom undergarments or Wearable. 
Additional Wireless Transmitters will be provided during the study should the subject have 4 hours of 
daily stimulation.  See Section 13 for shipping, labeling, storage, and product accountability. 
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3 
JUSTIFICATION FOR CLINICAL INVESTIGATION DESIGN 
3.1 
Prior Clinical Investigations 
3.1.1 Acute Clinical Investigation 
A prospective, acute, single center clinical study was conducted in six (6) subjects at the Maastricht 
University Medical Center in the Netherlands. The study was designed to evaluate Neuspera’s 
Implantable SNS System in an acute setting. The study was approved by Maastricht University Medical 
Center Regional Ethics Committee.   
The first primary objective of the study was to verify that energy could be transmitted from an external 
unit to the Neuspera Implantable SNS System, through a wireless connection, resulting in stimulation of 
the S3 sacral nerve. The second primary objective was to confirm that Neuspera’s Implantable SNS 
System could be correctly placed and inserted in close proximity of the sacral nerve, in the S3 foramina. 
The secondary objective was to characterize the explant of the device after the intraoperative 
stimulation procedure. The safety objective was to assess the safety of the device during implantation, 
stimulation and explantation. 
A total of 6 subjects signed an informed consent and were enrolled in the trial. All subjects were 
indicated for the Medtronic InterStim® procedure to treat their overactive bladder and passed all 
screening criteria for participation in the trial. One subject withdrew consent prior to the procedure and 
all remaining 5 subjects underwent the study procedure.   
The Neuspera Implantable SNS System could be correctly placed in all subjects and a fluoroscopy image 
of the optimal position was obtained. 
An obvious motor response was seen in 4 of the 5 subjects treated. The subject not showing a motor 
response to the stimulation had a high minimal threshold (5V) during stimulation with a foramen needle, 
exceeding the 2.4V stimulation voltage in Neuspera’s Acute Human Study Implantable SNS System. This 
individual ultimately also proved to be a non-responder to the InterStim® device. 
All 5 explant procedures were characterized as being performed successfully. The elapsed time in 
minutes between the end of the stimulation protocol and the moment the device was explanted from 
the body was on average 0.2 minutes with a maximum explant duration of 1 minute. 
No device related, or procedure related adverse events, nor any device deficiencies, occurred during the 
course of the study. 
The results of the clinical investigation demonstrate the feasibility of stimulating the S3 sacral nerve with 
a 2-part system using an external powering unit placed above an ultra-miniature implantable stimulator. 
The implant and explant procedures were performed successfully, and the safety results did not show 
any device related adverse events. 
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3.1.2 Phase I Clinical Results 
The Phase I Clinical interim trial safety and efficacy results are summarized below. The safety results are 
from the 2023 FDA annual report with a data snapshot on 23 August 2023.  The efficacy results are from 
an interim report based on a data cutoff date of 21 June 2021. 
Of the 89 consented subjects, 39 were enrolled, and 34 of these were successfully implanted; five 
enrolled subjects had unsuccessful implant attempts. All 34 subjects implanted with the System 
completed the Trial Period and moved on into the Post Trial Period.    
3.1.2.1 
Efficacy 
The mean number of UUIs per day was 4.1 ± 2.0 at baseline and decreased to 0.8 ± 0.9 at the Final Trial 
Visit, a mean decrease of 3.3 ± 1.7 UUIs per day from baseline.  Of all implanted subjects, 88.2% (30/34) 
were responders (≥ 50% reduction in UUIs from baseline) at Day 21. Four subjects were not trial 
responders at Day 21. Of these, three subjects continued the trial period through Day 35, and 100% (3/3) 
were responders at Day 35. At the Final Trial Visit (Day 21 for n = 31, Day 35 for n = 3), 97.1% (33/34) of 
subjects were responders.  One subject, initially thought to be a responder at Day 21, continued into the 
follow-up period at two hours per day of stimulation. The subject was later determined to be a non-
responder at Day 21 and continued in the trial through 6-months of follow-up and was subsequently 
explanted as the subject was not satisfied with the therapy outcome. 
The proportion of responders has continued to be statistically significantly greater than 50% during the 
follow-up period. The responder rates were 85.3% (P<0.0001) at Month 1, 90.0% (P<0.0001) at Month 2, 
96.9% (P< 0.0001) at Month 3, 97% (P<0.0001) at Month 4, 78.6% (P= 0.0037) at Month 5, 88.5% 
(P<0.0001) at Month 6 and 100% (P=0.0002) at Month 9.   
3.1.2.2 
Safety 
The safety results are from the 2023 FDA annual report with a data snapshot on 23 August 2023.  Safety 
information is reported separately for Phase I and Phase II cohorts.  
3.1.2.2.1 
Phase I  
There has been a total of 214 adverse events in 92.3% (36/39) of enrolled subjects; of these, there have 
been eight serious adverse events; all eight events were not related to the study device or study 
procedure. The majority of adverse events were mild or moderate in severity and were unrelated to the 
implant procedure or study device.  A total of 32 adverse events reported in 15 subjects were related to 
the device and/or procedure. There were seven successful surgical revisions related to three device 
dislodgements and four device fractures.  All subjects with device dislodgment and fractures remain in 
the study and are responding to the therapy post revisions.   There have been twelve device explants. 
Three explants occurred after the database snapshot on 23 August 2023. Eleven subjects requested 
explant due to therapy not producing desired effect or unsatisfied with therapy or device performance, 
and one subject was explanted due to non-compliance.   
 
To date, no serious adverse device effects (SADEs), unanticipated adverse device effects (UADEs), or 
deaths have been reported. 
 
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3.1.2.2.2 Phase II 
There has been a total of 57 adverse events in 47.1% (33/70) of Implant Attempted subjects; of these, 
there was one serious adverse event (SAE), classified as respiratory failure, which was adjudicated as 
possibly related to the implant procedure and not related to the study device.  The majority of adverse 
events were mild or moderate in severity (Clavien Dindo Classification I or II) and were unrelated to the 
implant procedure or study device.  A total of 13 adverse events reported in 15.7% (11/70) Implant 
Attempted subjects were related to the device and/or procedure. Since the 23 August 2023 data 
snapshot, there have been 130 implant attempted subjects.  In this group, there have been two device 
fractures in two subjects (1.5%), five clinically significant dislodgments in four subjects (3.9%), one 
dislodgement that was not clinically significant (0.77%), and four surgical revisions in four subjects 
(3.1%).  There have been twelve (12) device explants.  Overall, the number of fractures, migrations, and 
revisions observed are similar or below the rates seen for commercially available devices. 
To date, no serious adverse device effects (SADEs), unanticipated adverse device effects (UADEs), or 
deaths have been reported. 
 
3.1.2.2.3 Conclusion 
Phase I of the study has demonstrated the preliminary effectiveness of 2 hours of daily stimulation 
duration with the Neuspera Implantable Sacral Nerve Stimulation System for the treatment of subjects 
with UUI who have failed or could not tolerate more conservative treatments.  The type and rate of 
occurrence of adverse events are within the rates reported within the protocol and informed consents. 
The DSMB has reviewed all safety data included in the interim Phase I report, has provided 
recommendations on the daily stimulation duration that are consistent with the Phase II trial design, and 
supports the trial expansion to the pivotal Phase II.   
Additionally, learning from Phase I of the trial has resulted in improvements of design and instructions 
for use that further mitigate risks of unsuccessful implants, implant movement and implant fracture.  The 
undergarments for use in the trial have been redesigned, and programming parameters are well 
understood and standardized for use.  The protocol has been modified to incorporate the intent-to-treat 
analysis for the primary efficacy endpoint, and processes are in place to maximize patient safety.  
Collectively all trial results and process improvements support expansion of the study to initiate the 
pivotal Phase II at 2 hours of daily stimulation with the option to increase to 4 hours of daily stimulation 
as needed. 
3.2 
Justification 
The acute clinical investigation demonstrated the feasibility of implantation and stimulation of the S3 
sacral nerve with a 2-part system using a wireless transmitting unit. Phase I of the clinical trial 
demonstrated the initial feasibility of the system in chronic use. 
Phase I of the study characterized the human interaction with the wearable external Wireless 
Transmitter and associated system accessories.  Phase I also demonstrated that short daily stimulation (2 
hours per day) delivers appropriate urinary urgency incontinence symptom relief. 
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The purpose of Phase II, pivotal phase of this chronic study in human beings, is to evaluate the safety and 
efficacy of Neuspera’s Implantable SNS System in the treatment of overactive bladder symptoms, 
specifically urinary urgency incontinence in patients who have failed or could not tolerate more 
conservative treatment. Based on the learning from Phase I of the trial, Phase II will be designed so that 
all subjects are trialed with 2-hours daily stimulation for 28 days, those subjects who are treatment 
responders (≥50% reduction in symptoms) will continue in the follow-up phase of the trial.  As one 
subject in Phase I required 4-hours of daily stimulation to achieve response, Phase II of the trial will allow 
subjects with <50% reduction of symptoms to have the stimulation duration increased to 4-hours per day 
for an additional 14 days.  This increase in duration of stimulation for subjects with less than 50% 
improvement in symptoms was also supported by the DSMB. All subjects regardless of response 
following 4-hours of stimulation duration will continue in the follow-up phase of the trial. Data from the 
Axonics ARTISAN-SNM trial as reported by McCrery,6 indicates that some subjects who are non-
responders at 1-month have demonstrated response at 6-months.  Continuation of subjects who are 
non-responders after 4-hours of stimulation is based on subject informed consent. Non-responders, and 
any subject regardless of response, may withdraw consent to continue to participate in the study at any 
time.  
The primary endpoint, defined as the percentage of all implanted subjects who experience an 
improvement in UUI symptoms of 50% or more (therapy responders) compared with baseline, will be 
assessed at 6-months of follow-up.  The primary safety endpoint is defined as the incidence of device-
related SAEs through the 6-month post-implant follow-up visit.  Secondary endpoints will be assessed at 
both 6 and 12 months of follow-up.  The sponsor intends to file a PMA submission at the end of the six-
months of follow-up if the null hypothesis associated with the primary efficacy endpoint is rejected.  
 
 
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4 
RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND CLINICAL 
INVESTIGATION 
The study protocol has been designed to provide the greatest benefits while assuring the safety of the 
participating subjects by mitigating the occurrence, limiting the severity and ameliorating the effects of 
any possible adverse events. The following describes the benefits subjects may receive as well as 
possible adverse events which have been identified as risks and for which subjects will be carefully 
monitored. 
4.1 
Anticipated Clinical Benefits 
4.1.1 Direct Benefit 
Subjects may potentially benefit from this study if they show improvement in overall medical condition, 
such as improvements in overactive bladder symptoms, and associated improvements in quality of life. 
Potential benefits that may be associated with the investigational device that differ from current 
commercial products include: 
A smaller implantable device with no pocket formation, no tunneling of the lead, or blunt dissection 
required, which may avoid complications associated with the other treatment options such as infection 
and pain. These complications are typically associated with creation of a pocket and battery presence 
and positioning for an implantable neurostimulator can and lead technology. 
No implanted battery needing replacement which may result in fewer surgeries and complications 
associated with surgery. 
4.1.2 Indirect Benefit 
Subjects may indirectly benefit as a result of their participation in this study by helping researchers 
improve their understanding of the Neuspera Implantable SNS System. This research study allows the 
Sponsor and the Investigators to eventually help other subjects indicated for the same procedure. 
4.2 
Anticipated Adverse Device Effects 
An anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, severity 
or outcome has been identified in the risk analysis report. Anticipated risks that may be associated with 
Neuspera’s Implantable SNS System are noted in Section 4.4. 
4.3 
Residual Risks 
In conducting the risk analysis, the concepts of risk estimation, risk acceptability, risk control and overall 
risk evaluation were applied in accordance with ISO 14971:2007. Based on an evaluation of residual risk 
acceptability, it was concluded that the overall residual risk did not exceed the criteria for acceptable 
risk. 
 
 
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4.4 
Potential Risks that may be Associated with Neuspera’s Implantable SNS System  
Potential risks associated with the Neuspera Implantable SNS System based on a review of the literature 
and manuals for similar systems, the Neuspera Acute Human Study adverse events, and interim results 
from the SANS-UUI trial are listed in Table 2 below. Risks associated specifically identified in the Phase I 
Trial are noted in Table 3 and for Phase II in Table 4. 
TABLE 2: POTENTIAL RISKS BASED ON LITERATURE REVIEW AND NEUSPERA CLINICAL DATA 
Reported Adverse Events 
Estimated Percent of 
Patients Reporting Event 
Gastro-Intestinal Symptoms (abdominal pain, diarrhea, constipation, nausea, vomiting)  
≥10% 
Implant site infection 
≥10% 
Implant site pain 
≥10% 
Lead fibrosis 
≥10% 
Neurostimulator malfunction 
≥10% 
Neurostimulator migration 
≥10% 
Paresthesia 
≥10% 
Therapeutic product ineffective 
≥10% 
Undesirable change in stimulation  
≥10% 
Undesirable stimulation or sensations, including jolting or shock sensations 
≥10% 
Urinary tract infection  
≥10% 
Adverse change in bowel or voiding function 
3% to <10% 
Musculoskeletal discomforts including Muscle Tightness, Muscle Twitching, Muscle 
Contracture, Muscle Spasms, Musculoskeletal Pain, and Arthralgia 
3% to <10% 
Back pain 
3% to <10% 
Leg pain  
3% to <10% 
Falls 
3% to <10% 
Neurostimulator breakage or fracture 
3% to <10% 
Retained lead fragments 
3% to <10% 
Pain 
3% to <10% 
Pain in extremity 
3% to <10% 
Pollakiuria 
3% to <10% 
Seroma 
3% to <10% 
Dysuria, Urinary complications 
1% to <3% 
Genitourinary symptoms 
1% to <3% 
Granuloma 
1% to <3% 
Implant site hematoma, medical device site bruise 
1% to <3% 
Incision site complication 
1% to <3% 
Numbness 
1% to <3% 
Pelvic pain, Abdominal Pain 
1% to <3% 
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Reported Adverse Events 
Estimated Percent of 
Patients Reporting Event 
Skin discomfort, irritation, redness, or a burn associated with use of an external 
charging/powering system 
1% to <3% 
Stroke  
1% to <3% 
Sciatica 
1% to <3% 
Urinary incontinence 
1% to <3% 
Accidental puncture  
<1% 
Allergic reaction to system components 
<1% 
Anal discomfort 
<1% 
Asthenia 
<1% 
Cellulitis 
<1% 
Change in sensation of Stimulation 
<1% 
Dermatitis contact, Skin Reaction 
<1% 
Discomfort 
<1% 
Dyskinesia 
<1% 
Fecal incontinence 
<1% 
Flank pain 
<1% 
Hypersensitivity 
<1% 
Implant site discharge 
<1% 
Implant site effusion 
<1% 
Implant site erosion 
<1% 
Implant site erythema 
<1% 
Implant site hematoma 
<1% 
Implant site irritation 
<1% 
Implant site pruritus 
<1% 
Implant site rash 
<1% 
Implant site reaction 
<1% 
Implant site scar 
<1% 
Implant site warmth 
<1% 
Incision site hemorrhage 
<1% 
Incisional hernia 
<1% 
Kidney Infection 
<1% 
Medical device complication 
<1% 
Micturition urgency 
<1% 
Nerve damage   
<1% 
Nocturia 
<1% 
Perineal pain 
<1% 
Post procedural complication 
<1% 
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Reported Adverse Events 
Estimated Percent of 
Patients Reporting Event 
Post procedural pain 
<1% 
Pyrexia (fever) 
<1% 
Radiculopathy 
<1% 
Sacral pain 
<1% 
Sensory disturbance 
<1% 
Skin discoloration 
<1% 
Skin reaction 
<1% 
Therapeutic response decreased 
<1% 
Urinary incontinence 
<1% 
Vaginal pain 
<1% 
Wound dehiscence 
<1% 
 
The safety results are from the 2023 FDA annual report with a data snapshot on 23 August 2023.  Safety 
information is reported separately for Phase I and Phase II cohorts.  
 
Phase I enrolled subjects:  
There has been a total of 214 adverse events in 92.3% (36/39) of enrolled subjects; of these, there have 
been eight serious adverse events; all eight events were not related to the study device or study 
procedure. The majority of adverse events were mild or moderate in severity and were unrelated to the 
implant procedure or study device.  A total of 32 adverse events reported in 15 subjects were related to 
the device and/or procedure (see Table 3). There were seven successful surgical revisions related to 
three device dislodgements and four device fractures.  All subjects with device dislodgment and fractures 
remain in the study and are responding to the therapy post revisions.   There have been twelve device 
explants. Three explants occurred after the database snapshot on 23 August 2023. Eleven subjects 
requested explant due to therapy not producing desired effect or unsatisfied with therapy or device 
performance, and one subject was explanted due to non-compliance.   
 
To date, no serious adverse device effects (SADEs), unanticipated adverse device effects (UADEs), or 
deaths have been reported. 
 
TABLE 3. DEVICE AND/OR PROCEDURE RELATED ADVERSE EVENTS - ENROLLED SUBJECTS - PHASE I 
Body System / Preferred Term1 
Events 
n 
Subjects 
n/N (%) 
Total Device- or Procedure-Related Adverse Events 
32 
15/39 (38.5%) 
Gastrointestinal disorders 
2 
2/39 (5.1%) 
Abdominal pain 
1 
1/39 (2.6%) 
Anal incontinence 
1 
1/39 (2.6%) 
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Body System / Preferred Term1 
Events 
n 
Subjects 
n/N (%) 
General disorders and administration site conditions 
10 
7/39 (17.9%) 
Implant site nodule 
1 
1/39 (2.6%) 
Implant site pain 
7 
5/39 (12.8%) 
Medical device site bruise 
1 
1/39 (2.6%) 
Pain 
1 
1/39 (2.6%) 
Musculoskeletal and connective tissue disorders 
9 
5/39 (12.8%) 
Back pain 
2 
2/39 (5.1%) 
Bursitis 
1 
1/39 (2.6%) 
Muscle tightness 
2 
2/39 (5.1%) 
Muscle twitching 
1 
1/39 (2.6%) 
Musculoskeletal pain 
1 
1/39 (2.6%) 
Pain in extremity 
2 
2/39 (5.1%) 
Nervous system disorders 
4 
2/39 (5.1%) 
Paraesthesia 
1 
1/39 (2.6%) 
Sensory disturbance 
3 
1/39 (2.6%) 
Product issues 
3 
3/39 (7.7%) 
Device dislocation 
2 
2/39 (5.1%) 
Device stimulation issue 
1 
1/39 (2.6%) 
Renal and urinary disorders 
1 
1/39 (2.6%) 
Urinary incontinence 
1 
1/39 (2.6%) 
Skin and subcutaneous tissue disorders 
1 
1/39 (2.6%) 
Erythema 
1 
1/39 (2.6%) 
Surgical and medical procedures 
1 
1/39 (2.6%) 
Therapy cessation 
1 
1/39 (2.6%) 
Vascular disorders 
1 
1/39 (2.6%) 
Hypotension 
1 
1/39 (2.6%) 
1As coded by the CEC chairperson. 
 
Phase II Implant Attempted subjects:  
There has been a total of 57 adverse events in 47.1% (33/70) of Implant Attempted subjects; of these, 
there was one serious adverse event (SAE), classified as respiratory failure, which was adjudicated as 
possibly related to the implant procedure and not related to the study device.  The majority of adverse 
events were mild or moderate in severity (Clavien Dindo Classification I or II) and were unrelated to the 
implant procedure or study device (see Table 4).  A total of 13 adverse events reported in 15.7% (11/70) 
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Implant Attempted subjects were related to the device and/or procedure. Since the 23 August 2023 data 
cut-off, there have been 130 implant attempted subjects.  In this group, there have been two device 
fractures in two subjects (1.5%), five clinically significant dislodgments in four subjects (3.9%), one 
dislodgement that was not clinically significant (0.77%), and four surgical revisions in four subjects (3.1%) 
There have been twelve (12) device explants.  Overall, the number of fractures, migrations, and revisions 
observed are similar or below the rates seen for commercially available devices. 
To date, no serious adverse device effects (SADEs), unanticipated adverse device effects (UADEs), or 
deaths have been reported. 
 
TABLE 4. DEVICE AND/OR PROCEDURE RELATED ADVERSE EVENTS – IMPLANT ATTEMPTED SUBJECTS - PHASE II 
Body System / Preferred Term1 
Events 
 n 
Subjects 
 n/N (%) 
Total Device- or Procedure-Related Adverse Events 
13 
11/70 (15.7%) 
Gastrointestinal disorders 
4 
3/70 (4.3%) 
Dysphagia 
1 
1/70 (1.4%) 
Frequent bowel movements 
1 
1/70 (1.4%) 
Haematemesis 
1 
1/70 (1.4%) 
Vomiting 
1 
1/70 (1.4%) 
General disorders and administration site conditions 
2 
2/70 (2.9%) 
Implant site pain 
1 
1/70 (1.4%) 
Medical device pain 
1 
1/70 (1.4%) 
Musculoskeletal and connective tissue disorders 
2 
2/70 (2.9%) 
Back pain 
1 
1/70 (1.4%) 
Pain in extremity 
1 
1/70 (1.4%) 
Nervous system disorders 
1 
1/70 (1.4%) 
Radicular pain 
1 
1/70 (1.4%) 
Product issues 
2 
2/70 (2.9%) 
Device stimulation issue 
2 
2/70 (2.9%) 
Renal and urinary disorders 
1 
1/70 (1.4%) 
Micturition urgency 
1 
1/70 (1.4%) 
Respiratory, thoracic and mediastinal disorders 
1 
1/70 (1.4%) 
Respiratory failure 
1 
1/70 (1.4%) 
1As coded by the CEC chairperson. 
 
    
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Wireless Transmitter - Surface Skin Heating 
The Wireless Transmitter must be worn in the pocket of the Neuspera undergarment or Wearable. This is 
to protect the subject from the heat of the Wireless Transmitter and to position it correctly to power the 
neurostimulator. Wearing the Wireless Transmitter directly against skin may result in discomfort, 
irritation, or a burn. Instruct the subject to not lie on the Wireless Transmitter or wear it while sleeping. 
 
It is normal for the Wireless Transmitter to become warm during use as it is delivering power to the 
neurostimulator. If it becomes uncomfortably hot, the subject will be instructed to turn it off. If it is too 
hot to keep wearing the device, the subject will be instructed to take off the undergarment or Wearable 
and contact the investigator/clinic.  
Lack of Stimulation 
The subject may be a non-responder to SNS therapy, or the study device may fail to adequately induce 
therapeutic response. 
Procedural Risks 
Standard risks associated with minor surgery, including side effects from anesthesia, post-procedural 
pain or discomfort, and complications at the incision/injection site such as infection, bleeding, bruising, 
or swelling, may occur due to the neurostimulator implantation procedure. 
Unknown Risks 
There may also be risks that are unanticipated at this time. 
Concomitant Medication 
There are no identified risks associated with concomitant medication and the Neuspera SNS System. 
4.5 
Contraindications 
Electrical treatments where the conducted current is induced into the body from an external source into 
the area of the implant (this may permanently damage the implant). 
Medical treatments or procedures utilizing effects caused by electric fields (such as diathermy) unless 
the treatment or procedure is identified as acceptable. 
4.6 
Risk Control/Mitigation  
Risk management methods will be followed for the study. The manners in which risks will be minimized 
include the following: 
• 
In response to the device dislodgements and fractures noted in Section 4.4, Neuspera 
implemented three mitigations. These improvements are expected to reduce the risks of 
device dislodgement and fracture in Phase II of the clinical trial. 
o A shorter version of the implantable device was created for subjects with thinner sacra.  
o The implant instructions for use were revised to instruct implanters to place the devices 
deeper within sacral foramen to ensure that the proximal tines of the device are 
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implanted in more anchorable tissue.  The shorter device and deeper placement of 
implants are primary mitigators to prevent device movement and to keep the 
neurostimulator within the sacral foramen along the sacral nerve.  The epoxy strain relief 
joint, which was subject to fracture, will then remain within the protection of the 
foramen. 
o As a secondary mitigation, the length of overlap of epoxy in the strain relief joint was 
increased to improve the mechanical integrity of the epoxy / array interface. The 
increase in overlap improves the resistance to shear and bending loads if the implant 
moves outwards and exposes the epoxy strain relief joint.  
• 
The Investigator and clinical site staff were chosen because of their expertise in the 
management of OAB and use of sacral nerve stimulation for the treatment of OAB. 
• 
The physicians performing device-related procedures have received the appropriate training 
in the use of the device. 
• 
Subjects are being monitored/observed throughout the study by multiple-disciplinary site 
staff, trained in the management of subjects with OAB. 
• 
Investigators will discuss the signs and symptoms that each subject should be made aware of 
with respect to a potential adverse event. Additionally, each subject will be sent home with a 
copy of the informed consent which provides details regarding the signs and symptoms to be 
aware of with respect to a potential adverse event.  These signs and symptoms will be 
reviewed with the subject at the time the informed consent is signed. Subjects will be 
encouraged to notify the site if they have concerns about signs and symptoms they are 
experiencing.  They may be instructed to come to the clinic/hospital for further evaluation 
and/or treatment if further assessment is needed. 
• 
Pre-clinical testing has been performed in order to optimize the device safety and function. 
• 
Field Clinical Engineers may be present during implants in order to provide training and 
support. 
• 
Experienced Clinical Monitors will perform on-site and remote monitoring throughout the 
study to ensure protocol compliance and compliance with GCP, ISO 14155, FDA regulations, 
IRB/EC requirements and other regional regulations. 
• 
Ongoing monitoring of study data and results, including the use of an independent Clinical 
Events Committee, comprised of physicians knowledgeable in the procedure and treatment 
of subjects with OAB. 
• 
An independent Data Safety Monitoring Board (DSMB) will serve as an advisory group to the 
Sponsor/CRO and will review aggregate Phase I and Phase II data.  The DSMB will assure the 
safety and welfare of the study subjects and ongoing validity and scientific merit of the 
study.   
• 
Study stopping rules have been put in place to be followed by the DSMB.  These stopping 
rules have been added to Section 6.4 of the protocol.  
• 
All subjects will be provided with an identification card (ID) indicating they have an 
investigational device implant and phone number to call in case of emergency. Figure 14 
presents a sample ID card.  
 
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FIGURE 14: SUBJECT IDENTIFICATION CARD 
 
Furthermore, potential risks associated with participation in this investigation will be minimized and 
managed in accordance with applicable regulations, and requirements of the approving Institutional 
Review Board(s)/Ethics Committee(s). 
4.7 
Risk-to-Benefit Rationale 
Any potential risk presented by this clinical investigation has been minimized and adequate testing, 
safeguards, and safety monitoring have been incorporated into the clinical investigation to further 
minimize and mitigate the risks. The benefits of Neuspera’s Implantable SNS System outweigh the 
potential risks posed to participating subjects.   
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5 
OVERALL STUDY DESIGN 
5.1 
Study Purpose 
The purpose of this seamless phased study is to test the overall safety and efficacy of the Neuspera 
Implantable SNS System in the treatment of overactive bladder symptoms, specifically UUI in subjects 
who have failed or could not tolerate more conservative treatment. 
5.2 
Study Overview 
This is a prospective, multi-center, single-arm, seamless phased pivotal clinical study using the Neuspera 
Implantable SNS System for treatment of UUI in subjects who have failed or could not tolerate more 
conservative treatment. 
The study will be conducted in two phases.  Phase I has been used to understand the initial usability of 
the system and to determine the daily stimulation parameters for Phase II.  Enrollment in Phase I has 
been completed and all implanted subjects are in the follow-up phase. All enrolled subjects did undergo 
a SNS trial period to test their clinical response to sacral nerve stimulation.  Stimulation started with 2 
hours of stimulation per day, and in 1/34 enrolled subjects, stimulation was extended to 4 hours per day.  
The trial was designed to allow up to 8 hours of stimulation if 4 hours was not successful, but no subject 
required 8 hours of stimulation to achieve a therapeutic response (≥50% reduction of symptoms when 
compared to baseline).  
 
Phase I 
All Phase I subjects will continue to be followed until regulatory approval, estimated to be up to 60 
months post-trial period.  Figure 15 below details subject flow for Phase I of the study based on the 
initial trial design. As noted, no subjects received 8-hours of stimulation in Phase I of the trial.  
 
 
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FIGURE 15:  PHASE I SUBJECT FLOWCHART 
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Phase I Sub-Study: There is a sub-study to investigate the effectiveness and subject acceptance of half-
hour daily stimulation to treat UUI.  The details are provided in Appendix A: Phase I Sub-Study. 
 
Phase II 
Figure 16 below details subject flow for Phase II of the study.  Results of Phase I were used to determine 
the number of hours of daily stimulation per day in Phase II. In Phase II, during the first 28 days, subjects 
will receive 2 hours of continuous daily stimulation using the external Wireless Transmitter.  At the end 
of 28 days treatment efficacy will be assessed.  Subjects with acceptable efficacy (≥50% reduction in 
number of UUI episodes) will be considered a responder and will continue in the post-implant follow-up 
with 2 hours of daily stimulation using the Wireless Transmitter.  Those with less than acceptable efficacy 
(<50% reduction in number of UUI episodes) will continue for an additional 14-day period with 4 hours of 
daily stimulation with the Wireless Transmitter.  After 14 days of 4 hours of daily stimulation those 
subjects with ≥50% reduction in number of UUI episodes will be considered a responder.  As the primary 
efficacy endpoint is based on intent-to-treat analysis, all implanted subjects, regardless of responder or 
non-responder status at the end of the 42-day period will continue in the post-implant follow-up with 4 
hours of daily stimulation. A decision to continue a subject with less than a 50% improvement at the end 
of the 42-day period will be made by the investigator based on what they determine is in the best 
interest of the subject. All implanted subjects will be followed until regulatory approval is achieved, 
estimated to be up to 36 months.  When stimulation is not sufficient, subjects may leave the trial at any 
time.  At such time, device explant procedures will be followed (Section 7.5.8.10).  
 
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FIGURE 16:PHASE II SUBJECT FLOWCHART  
 
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5.3 
Study Duration 
The enrollment period is expected to take approximately 12 months for Phase II.  The total expected 
duration of the clinical trial is dependent on the length of time to regulatory approval.  Implanted 
subjects from Phase I and Phase II will continue to be followed until US PMA approval.  Health Canada 
approval, European approval, CE Mark, may be achieved earlier or later than PMA approval.  If achieved 
earlier, all Canadian and EU subjects will continue to be followed in the trial until US PMA approval is 
achieved which is estimated to be up to 36 months or longer for some subjects.  Subjects enrolled earlier 
will have a longer follow-up than subjects enrolled later. In Phase II, subjects enrolled later may be 
followed for less than 36 months but at least until the 12-month follow-up visit is completed. It is 
estimated that the first subjects enrolled in Phase II will be in the study approximately 3 years.  If 
Neuspera determines regulatory approval will not be achieved, the study will be closed.   
5.4 
Minimization of Bias 
The potential for bias during this study has been minimized by the clinical study design that is expected 
to be conducted under the terms of the approved study protocol. The following methods have been 
incorporated into the study protocol to minimize potential bias: 
• 
Subjects will be screened to confirm eligibility for implant with defined inclusion/exclusion 
criteria prior to procedure. 
• 
All sites will use the same version of the protocol and data collection materials. 
• 
The study contains pre-defined endpoints, analyses, and success criteria.    
• 
All study and Sponsor personnel will be trained on their respective responsibilities for the 
study using standardized training materials. 
• 
All study personnel will be trained on and are required to follow the protocol. 
• 
All study investigators will be required to comply with 21 CFR Part 54 and Financial 
Disclosure by Clinical Investigators. 
• 
Experienced Clinical Monitors will perform on-site and remote monitoring throughout the 
study to ensure protocol compliance and compliance with GCP, ISO 14155, FDA and IRB/REC 
regulations. 
• 
Ongoing monitoring of adverse events, including the use of an independent Clinical Events 
Committee, comprised of physicians knowledgeable in the procedure and treatment of 
subjects with OAB. 
• 
A Data Safety Monitoring Board will serve as an independent advisory group to the 
Sponsor/CRO managing Neuspera’s Implantable Sacral Nerve Stimulation System clinical 
study to assure the safety and welfare of the study subjects and ongoing validity and 
scientific merit of this study.  
• 
Study stopping rules have been put in place to be followed by the DSMB.  These stopping 
rules have been added to Section 6.4 of the protocol.  
 
 
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6 
STATISTICAL CONSIDERATIONS 
6.1 
Objectives, Endpoints and Analysis  
The overall objective of the study is to assess the safety and efficacy of the Neuspera Implantable SNS 
System based on Phase II results, following the determination of daily stimulation settings as informed 
by Phase I. Accordingly, hypotheses and formal endpoints are primarily based on results of Phase II. 
Unless otherwise specified, all analyses described in this section refer to the analysis of data gathered 
only under Phase II. Analyses for Phase I will consist of descriptive statistics since stand-alone definitive 
conclusions regarding safety or efficacy from this phase are not desired, and the purpose of Phase I is 
simply to inform stimulation settings for Phase II.  The Statistical Analysis Plan (SAP) for this study 
provides additional details.   
6.1.1 Analysis Populations 
Intent-to-Treat (ITT) Analysis Set: The ITT analysis set is defined as all Phase II subjects who have signed 
informed consent.  Demographic information and study exit details will be reported separately for those 
subjects included in the ITT population where no initial implant was attempted. 
Modified Intent-to-Treat (mITT) Analysis Set: The mITT analysis set is defined as all Phase II subjects for 
whom an initial implant is attempted. The mITT analysis set is the primary analysis set for assessment of 
primary endpoints. 
Implanted Analysis Set: The Implanted analysis set is defined as all Phase II subjects who are implanted 
with the Neuspera SNS system. 
Responder Analysis Set: The Responder analysis set is defined as subjects who are implanted with the 
system and are defined as responders at Day 28 or Day 42 clinic visit post-implant. 
Per Protocol (PP) Analysis Set: The Per Protocol analysis set is defined as implanted subjects who have no 
protocol deviations that may significantly affect the primary endpoints. The determination of subjects 
excluded from Per Protocol analysis set will be made prior to analysis. 
6.1.2 Primary Efficacy Objective, Endpoints, and Analysis 
6.1.2.1 
Primary Efficacy Objective 
To test the efficacy of the Neuspera Implantable SNS System for treatment of UUI. 
6.1.2.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the percentage of subjects who experience an improvement 
in UUI symptoms of 50% or more (therapy responders). A therapy responder is defined as experiencing 
≥50% reduction in the number of UUI episodes at 6-months post-implant, relative to the number of UUI 
episodes at baseline. 
Calculation of the primary efficacy endpoint will be based on the mITT analysis set. 
6.1.2.3 
Primary Efficacy Analysis  
The statistical hypothesis test for the primary efficacy endpoint will be based on comparing the 
percentage of subjects with at least 50% improvement in UUI symptoms (therapy responders) to a null 
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value of 50%, the same performance goal as in the study by McCrery et. al.6 Mathematically, the null and 
alternative hypothesis are stated as:   
Ho: p ≤ 0.50  
Ha: p > 0.50  
The null hypothesis will be rejected at the 0.025 alpha level based on a one-sided, one sample exact tests 
of binomial proportions for responders. The proportion of 0.50 for responders corresponds to a value of 
50%. Study success is defined as successful rejection of the null hypothesis.  
The 50% reduction in UUI symptoms treats subjects as their own control and is based on a clinically 
meaningful improvement at the subject level in the primary efficacy endpoint.4-6 Successful rejection of 
the null hypotheses will indicate a clinically meaningful result in the majority of subjects by a statistically 
significant amount.  Success for the statistical test will require that the lower confidence bound for the 
percentage of subjects with at least 50% improvement in UUI symptoms (therapy responders) will 
exceed 50%. This means practically, that the percentage of subjects with at least a 50% improvement 
must be substantially greater than 50% in order for the lower confidence bound to exceed 50%. For 
example, with an evaluable sample size of implanted subjects, the “worst case” results that would still 
meet the statistical threshold for this performance goal would be 72 out of 120 (60%).  Additionally, the 
study is powered around an assumed population responder rate of 63.5% or higher.  
 
The primary analysis population for the primary efficacy endpoint is the mITT Analysis Set. The primary 
efficacy endpoint will also be evaluated in the Implanted analysis set, the Responder analysis set, and the 
Per Protocol analysis set (without imputation for missing data) to assess the robustness of results. If 
there are no differences between analyses sets (e.g., Implanted and Responder analysis sets include all 
the same subjects), separate analyses will not be presented. Analyses of the primary efficacy endpoint 
for all analysis populations will be conducted after 6-month post-implant follow-up is completed for all 
subjects.  
For the primary efficacy endpoint, subjects withdrawing for reasons related to a lack of efficacy or due to 
an adverse event (including death) will be counted as failures. Also, those subjects who take OAB 
medications (after the first two weeks following implant) and prior to the six-month visit should be 
adjudicated as device failures. For subjects with missing primary efficacy endpoint results for other 
reasons (missing diary, subject loss-to-follow-up, etc.), multiple imputation will be used to impute the 
outcome and results from the imputed data sets combined appropriately to preserve valid inference. 
Details of the multiple imputation are provided in the Statistical Analysis Plan.  
The primary efficacy endpoint will be presented by study visit with descriptive statistics and nominal 95% 
confidence intervals.  
6.1.3 Primary Safety Objective, Endpoint and Analysis 
6.1.3.1 
Primary Safety Objective 
The primary safety objective of the study is to assess the safety of the Neuspera Implantable SNS System 
for treatment of UUI. 
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6.1.3.2 
Primary Safety Endpoint 
The primary safety endpoint is defined as the incidence of device-related SAEs through the 6-month 
post-implant visit.  The analysis of the endpoint is the proportion of subjects experiencing device-related 
SAEs through the 6-month post-implant visit.  
6.1.3.3 
Primary Safety Analysis 
There is no planned statistical hypothesis test for the primary safety endpoint. The proportion of 
subjects experiencing an event, as well as the numerator and denominator, and the associated two-sided 
exact 95% binomial confidence interval will be provided. Values will be expressed as percentages.  
The primary analysis population for the primary safety endpoint is the mITT analysis set as defined in 
Section 6.1.1.  Subjects who exit the study prior to reaching the 6-month post-implant follow-up visit 
without experiencing a device-related SAE will be assumed free of such an event. 
Any adverse events reported for enrolled subjects who are excluded from the mITT analysis set will be 
reported separately for the duration of the study.  
6.1.4 Interim Analyses 
The Sponsor will use Phase I, feasibility phase, of the trial to assess system performance, subject 
compliance, and determination of the daily stimulation duration for Phase II. Phase I data will also be 
examined as needed to determine if modifications need to be made to training of the centers on implant 
technique, subject instructions, duration of stimulation, etc.  Formal statistical conclusion from Phase I 
will not be made so there are no type I error concerns.  
For Phase II, there are no planned interim analyses for the purpose of adaptive study modifications or 
early stopping for success.  An interim analysis will be performed when the 60th Phase II subject has 
completed the 3-month post implant visit. For this interim analysis, the primary and secondary safety 
and effectiveness endpoints will be assessed, but at the three-month timepoint.  This interim analysis 
will be used for business purposes only, no modifications to the study will be made based on this 
analysis, and outcomes will not be published or shared with investigators, patients, or Neuspera 
employees with direct subject access.  The study will be completed to the planned sample size of 120 
attempted implants regardless of the outcome of the interim analysis.  Operational bias will be 
minimized by having a third party, independent statistician separate from study operational personnel 
and study statistician, who will perform the interim analysis.  
6.1.5 Secondary Endpoints  
The secondary endpoints include the following, assessed at both 6- and 12-months post-implant visits 
unless specified otherwise: 
• 
Change from baseline in quality of life as measured and assessed by the total ICIQ-OABqol 
score.  
• 
Change from baseline in mean number of UUI episodes. 
• 
The percentage of subjects who experience an improvement in UUI symptoms (therapy 
responders) of at least 50% or more at 12 months visit post implant. 
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• 
The percentage of subjects who experience an improvement in ICIQ-OABqol of at least 10 
points.8 
• 
Change in urgent voids per day calculated across all diary episodes with at least mild 
urgency.  
• 
Change in average number of daily voids from baseline in subjects with at least 8 voids at 
baseline. 
• 
Change in quality of life measured from baseline as measured and assessed by the ICIQ-
OABqol subscale scores. 
• 
Comprehensive summary of all adverse events (AEs) for the duration of study participation. 
• 
Device parameters including but not limited to voltage, pulse width, frequency, and 
stimulating electrode.   
• 
Physician and subject satisfaction as assessed with the User Experience Questionnaire at 6-
month visit post implant. 
• 
Change in Male/Female Lower Urinary Tract Symptoms questionnaire.  
• 
The percentage of subjects with device-related serious adverse events reported through 12-
month visit post-implant.  
• 
Change in total urinary output as measured by 72-hour bladder diary. 
• 
Change in fecal incontinence as measured by the Wexner Scale compared to baseline. 
Calculated in subjects with fecal incontinence. 
• 
Patient Global Impression of Improvement (PGI-I) measured after implant during follow-up. 
 
Secondary endpoints will be summarized across study visits.  Type I error control for testing of secondary 
endpoints intended for labeling claims is described in section 6.1.6.2. 
6.1.6 Phase II Analysis of Secondary Endpoints 
6.1.6.1 
Analysis of Secondary Efficacy Endpoints That May Be Used for Labeling Claims 
The type I error for the primary efficacy endpoint and for a subset of secondary endpoints will be 
controlled via hierarchical testing.  The following secondary endpoints will be included in a hierarchical 
analysis of study endpoints and may be intended for labeling claims (all at 6-month visit post-implant 
follow-up): 
• 
Change from baseline in mean number of UUI episodes 
• 
Change from baseline in ICIQ-OABqol score 
• 
The percentage of subjects who experience an improvement in ICIQ-OABqol of at least 10 
points 
• 
Change in urgent episodes per day from baseline.  Calculated across all diary episodes with 
at least mild urgency 
• 
Change in average number of daily voids in subjects with at least 8 voids at baseline  
• 
Change in fecal incontinence as measured by the Wexner Scale compared to baseline. 
Calculated in subjects with fecal incontinence. 
 
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The primary efficacy endpoint will be analyzed with a one-sided test at the α = 0.025 level. To maintain 
the overall type I error rate, testing of these secondary hypotheses will only proceed if the analysis for 
the primary efficacy endpoint is statistically significant (one-sided 𝑝𝑝< 0.025). If the primary efficacy 
analysis is not statistically significant (one-sided 𝑝𝑝≥0.025), these secondary endpoints will not be 
formally tested, and analysis of these endpoints will be considered exploratory. 
Provided that the primary endpoint analysis is statistically significant, testing will proceed to the 
secondary endpoints included in the hierarchical analysis. Performance goals for each secondary 
endpoint that may be used for labeling claim are included in the statistical analysis plan (SAP).  Testing 
will proceed in the order specified above with each endpoint tested sequentially. If the analysis of the 
secondary endpoint under consideration is statistically significant (one-sided 𝑝𝑝< 0.025), the result for 
that endpoint is declared statistically significant, and testing proceeds to the secondary endpoint next in 
the order. As soon as an analysis is not statistically significant (one-sided 𝑝𝑝≥0.025), that endpoint is 
declared statistically non-significant, further testing of these secondary endpoints is terminated, and no 
formal statistical conclusion is reached on the remaining endpoints, irrespective of their observed 𝑝𝑝-
values. 
The sponsor intends to file a PMA submission at the end of the six-months of follow-up if the null 
hypothesis associated with the primary efficacy endpoint is rejected. This will include analysis of the 
primary endpoint and the first secondary endpoint in the hierarchical sequence. If the analysis of the first 
secondary endpoint is statistically significant, the remaining secondary endpoints in the sequence will be 
analysed in order when the data are available. 
6.1.6.2 
Analysis of Secondary Efficacy Endpoints Not Intended for Labeling Claims 
Analysis of secondary endpoints not intended for labeling claims, (i.e., those not included in the 
hierarchical testing) will be considered exploratory in nature. Each of these endpoints will be tested at 
the α = 0.05 level using a two-sided test with no adjustment for multiplicity. Any p-values from these 
analyses will not be reported in the labeling.  
6.2 
Sample Size Determination 
Sample size for Phase II is based on power requirements for the primary efficacy endpoint.  A total of 120 
attempted implants will provide over 85% power for a one-sided 0.025 exact binomial test against the 
null hypothesis assuming that 1) the implant success rate is 95%, 2) subjects in whom an implant is 
attempted but is not successful are counted as failures, and 3) the overall responder rate, including 
failed implant attempts, is 63.5%.  Calculations are based on a one-sample, one-sided exact test of 
binomial proportions with a normal approximation and were performed with PASS 2019.  To account for 
potential attrition prior to implant of up to approximately 43% including screen failures, up to 255 
subjects will be enrolled/consented in Phase II. Revisions will not count towards attempted implants. 
Sample size at any one investigational site will be restricted to no more than 25 subjects implanted for 
Phase II.  Consideration will be given to lifting the 25 subject implanted cap in Phase II if the investigator 
makes a request of the sponsor.  
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6.3 
Analysis of Replacements, Explants  
During the course of the study, it may be necessary for the investigational device to be replaced or 
permanently explanted from the subject. Revision rates in the literature range from 4% in the InSite 
study4 to 33% in the Herbison9 study.  Depending on the timing of replacements, it may be necessary for 
the subject’s response rate to be reassessed in the first 28 to 42-days post-implant. 
During Phase I of the study, if a subject receives a neurostimulator replacement prior to Month 3 clinic 
visit, the subject will restart their follow-up schedule, and repeat the trialing period and any of the 
follow-up visits completed prior to replacement.  If a subject receives a device replacement prior to the 
assessment of the primary efficacy endpoint in Phase II (Month 6 clinic visit), the subject will restart their 
entire follow-up schedule post-implant, including the responder rate assessments at Day 28 and Day 42, 
if not a responder at Day 28.  The date of replacement will be considered the new Device Implant date 
for analysis and follow-up purposes.  If a device replacement is required after the follow-up periods 
indicated above, subjects will continue on their original follow-up schedule and will not repeat any of the 
assessments or follow-up visits already completed. 
If assessment of the response rate is repeated in the first 28 to 42-days post-implant, data collected after 
the most recent implant will be used in the analysis.  Similarly, if the subject is required to repeat any 
portion of the post-implant follow-up visits after a replacement (replacement occurred before Month 6 
clinic visit), the data from the replacement visit(s) will be used in analysis.  The date of replacement will 
be considered the Device Implant date for analysis and follow-up purposes.  A subject is only allowed to 
repeat any portion of the post-implant period once. 
If the device is permanently explanted prior to the assessment of the primary efficacy endpoint for any 
reason, the subject will be considered a failure for the primary efficacy analysis. 
6.4 
Study Stopping Rules for Phase II 
Phase II will use stopping rules designed to suspend enrollment and trigger a series of events if at any 
time there is sufficient statistical evidence to conclude that any of the Phase II probabilities of device 
fracture, device dislodgement/migration, or surgical revision exceed comparator probabilities from an 
approved device. The comparator probabilities are shown in Table 5.  
TABLE 5: COMPARATOR EVENT PROBABILITIES GUIDING THE PHASE II STOPPING RULE. VALUES SHOWN ARE POINT 
ESTIMATES (UPPER LIMITS OF 95% CONFIDENCE INTERVALS). 
Event Type 
Proportion of Subjects with Event 
Fractures 
0.014 (0.022)1 
Dislodgements/Migrations 
0.026 (0.036)2 
 
1 Based on Medtronic’s 2020 Product Performance Report showing 19 subjects experienced lead fractures out of 
1,314 subjects followed (page 167). 
2 Based on Medtronic’s 2020 Performance Report showing 34 subject experienced lead dislodgements/migrations 
out of 1,314 subjects followed (page 167).  
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Surgical Revisions 
0.118 (0.239)3 
 
Phase II will use the following stopping rule. At each occurrence of device fracture, 
dislodgement/migration, or surgical revision, form an exact one-sided binomial confidence interval for 
the event probability. Determine whether any of the following conditions is met: 
• 
The lower limit of the interval for device fractures exceeds 0.014.  
• 
The lower limit of the interval for device dislodgements/migrations exceeds 0.026.  
• 
The lower limit of the interval for surgical revisions exceeds 0.118.  
The numerator for each event is the number of subjects who have experienced the event up to that 
time. The denominator will be the number of subjects implanted up to that time. For device fractures 
and migrations/dislodgements, the confidence level of the interval will be 95%. For surgical revisions, the 
confidence level will be 80% if 50 or fewer subjects have been implanted; if more than 50 subjects have 
been implanted, the confidence level will be 95%. If any of the above conditions is met, the following 
actions will be taken: 
• 
Both enrollment and implants will be suspended, and FDA will be notified within 7 days 
• 
Neuspera will conduct a root cause analysis to determine the cause of the safety events that 
triggered the stopping rule  
• 
Neuspera will prepare a safety report for submission to the DSMB  
• 
The DSMB will convene, review the safety report and root cause analysis, and make a 
recommendation on study continuance (continue enrollment post FDA review and approval, 
continue enrollment suspension pending FDA decision and/or further investigation by the 
sponsor, etc.)  
• 
Neuspera will submit to FDA the safety report, the root cause analysis, and the DSMB’s 
recommendation  
• 
FDA will make final determination on study continuance 
The stopping rules will take effect only when more than 15 subjects have been implanted. After more 
than 15 subjects have been implanted, all events, including any events within the first 15 subjects will be 
counted in assessing the criteria for stopping. However, if there are 4 or more surgical revisions when 15 
or fewer subjects have been implanted, the stopping rule is triggered once the 4th surgical revision 
occurs. Additional subjects will not be implanted in the scenario that the stopping rules will 
automatically be triggered at subject 16 (i.e., 4 surgical revisions occur in the first 15 subjects). 
 
3 Based on Medtronic Clinical Summary Report stating 6 out of 51 subjects had “surgical procedures to resolve 
adverse events or technical observations, or due to lack of efficacy from the time of test lead implant to 6-month 
follow-up after full system implant” (page 16). 
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The use of an 80% confidence level as compared to 95% early in the study for surgical revisions makes it 
more, not less, likely that enrollment would stop due to surgical revisions in the event that revision rates 
are unacceptably high.  
6.5 
Deviations to the Statistical Analysis Plan 
If there are any deviations to the Statistical Analysis Plan, this will be noted in any interim and final 
reports for the trial. 
 
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7 
DESIGN OF THE CLINICAL INVESTIGATION 
7.1 
General 
The study is a prospective, multi-center, seamless, single-arm, pivotal clinical study assessing the safety 
and efficacy of Neuspera’s Implantable SNS System in subjects with symptoms of UUI. The Neuspera 
Implantable Sacral Nerve Stimulation System Investigator’s Brochure is available upon request from the 
Sponsor. 
The seamless, single-arm study is designed in two phases: Phase I, feasibility phase and Phase II, pivotal 
phase. The feasibility phase was to assess the utilization and performance of the system during the SNS 
trial and follow-up periods and to help plan and inform the pivotal trial design, including the length of 
hours of daily stimulation to be used in Phase II of the trial. The Phase II, pivotal phase, is a confirmatory 
investigation to collect safety and efficacy data on the performance of the overall system.   
As this is a clinical trial evaluating an investigational sacral nerve stimulation system, there are baseline 
screening criteria, sacral nerve stimulation trialing procedures, implant procedures and follow-up 
procedures that deviate from screening criteria and procedures for commercially available systems.  
Commercially available sacral nerve stimulation devices require subjects to have failed or be intolerable 
to more conservative treatments.  Eligible subjects receive a peripheral nerve evaluation implant, 
typically 7 days, or a staged trial with a tined lead, typically 2-3 weeks, to evaluate the subject’s response 
to sacral nerve modulation.  Post implant follow-up consultation in the first year typically occurs at 1, 6 
and 12 months.11  In the clinical trial design, the inclusion and exclusion criteria requires some clinical 
testing or therapy restrictions that may not be required in general clinical practice.  Likewise, the 
additional follow-up visits post implant are required by the study design and are outlined in the 
remainder of this section.  The additional testing and follow-up visits deviate from general clinical 
practice SNS therapy due to the investigational nature of the system under study.  
Enrollment in Phase I is closed. Should an enrolled subject require a replacement before the 3-month 
clinic visit, the subject will undergo a repeat SNS trial period testing their clinical response for 
approximately 21 days. During the first SNS trial period, subjects will have 2 hours of continuous 
stimulation with Neuspera’s SNS System. Subjects who are responders (≥50% reduction in UUI episodes 
compared to baseline) will continue to the post-trial phase with 2 hours of daily therapy. Subjects who 
have <50% reduction in UUI episodes will continue in the trial period with 4 hours of continuous daily 
therapy for 14 days. Following the additional 14 days of trial, response rate will be determined. Subjects 
who have ≥50% reduction in UUI episodes compared to baseline will proceed to the post-trial period 
with 4 hours of continuous daily therapy. Subjects who have <50% reduction in UUI episode will continue 
in the trial period with 8 hours of continuous daily therapy for 14 days. Following the additional 14 days 
of trial, response rate will be determined. Subjects who have ≥50% reduction in UUI episodes will 
proceed to the post-trial period with 8 hours of continuous daily therapy. Subjects who have <50% 
reduction in UUI episodes are deemed non-responders.  The subject may discuss alternative therapy 
options with the investigator to determine if the neurostimulator will be removed.  Subjects may remain 
in the trial at 8 hours of continuous stimulation. If the subject and the investigator determine that it will 
be in the subject’s best interest the neurostimulator may be removed.  The Neuspera Wireless 
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Transmitter(s), Wireless Transmitter Charging Pad, Magnet and Patient Controller will be returned to the 
clinic. Subjects may dispose of used custom undergarments or Wearable at their discretion. These 
subjects will return to the clinic approximately 30 days for a safety evaluation and will then be exited 
from the study and no further data or information will be collected on these subjects.   
In Phase I, subjects will return to the clinic for monthly visits up to 6 months for post-trial procedures and 
every three months through the 12-month post-trial visit, and then every six months thereafter until 
regulatory approval is achieved, estimated to be up to 60 months.   
In the first 28 days of Phase II, subjects will receive 2 hours of continuous daily stimulation using the 
external Wireless Transmitter. At the end of 28 days treatment efficacy will be assessed. Subjects with 
acceptable efficacy (≥50% reduction in number of UUI episodes) will be considered responders and will 
continue in post-implant follow-up with 2 hours of daily stimulation using the Wireless Transmitter. 
Those with less than acceptable efficacy (<50% reduction in number of UUI episodes) will continue for an 
additional 14-day period with 4 hours of daily stimulation with the Wireless Transmitter. After 14 days of 
4 hours of daily stimulation those subjects with ≥50% reduction in number of UUI episodes will be 
considered a responder. Those subjects who increased to 4 hours of daily stimulation, regardless of 
responder or non-responder status at the end of the 42-day period will continue in the post-implant 
follow-up with 4 hours of daily stimulation. A decision to continue a subject with less than a 50% 
improvement at the end of the 42-day period will be made by the investigator based on what they 
determine is in the best interest of the subject.  
 
A subject may withdraw their consent from participation at any time regardless of responder status.  
 
Subjects will continue to be followed post-implant for monthly visits up to 6 months and every three 
months through the 12-month visit, and then every six months thereafter until regulatory approval is 
achieved, estimated to be up to 36 months.   
7.2 
Investigational Device and Comparators 
This is a single-arm study where subject’s baseline assessment is the base comparator. There are no 
comparator devices.   
7.3 
Study Sites and Subject Enrollment Limits 
The pivotal phase (Phase II) of the study will have up to 35 participating clinical sites in the US, Canada 
and Europe. Up to 255 subjects will be enrolled across 35 clinical sites. The point of study subject 
enrollment is when the subject signs the informed consent. The number of implants will be limited to 25 
subjects at any one clinical site.  Consideration will be given to lifting the 25 subject implanted cap if the 
investigator makes a request of the sponsor.  We expect no more than 5 sites to be included from 
Europe and Canada.  More than 50% of the subjects enrolled will be from the United States.  
Clinical sites included in the study will have met study qualification requirements, received necessary 
institutional review board/ethics committee and/or other approvals, be in countries in which the study is 
approved as required by law, and be approved by the Sponsor to participate. 
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Geographies being considered for the study include United States, Canada, and Europe. Additional 
countries may be considered for participation.     
7.4 
Subjects 
7.4.1 Inclusion Criteria 
Subjects must meet all of the following criteria:  
General inclusion criteria: 
1. Is willing and able to understand and has voluntarily signed and dated the current approved 
informed consent. 
2. Is male or female 22 years of age or older. 
3. Has a Body Mass Index (BMI) greater than or equal to 18 and less than or equal to 40 kg/m2.  
4. Is a good surgical candidate and is capable of participating in all testing and follow-up clinic visits 
associated with this clinical study and is capable of independently using the system components 
as described in the Patient Manual. 
5. Is ambulatory and able to use toilet without assistance. 
6. Has a diagnosis of UUI for greater than or equal to 6 months prior to the screening baseline visit 
date.  
7. Has typical residual bladder volume <150 cc tested within 6 months prior to the screening 
baseline visit date or is willing to have a test at screening baseline visit.  
8. Has urodynamic testing (uroflowmetry, cystometry, and pressure flow) completed within 6 
months prior to the screening baseline visit date or is willing to have testing at the screening 
baseline visit. 
9. Has cystoscopy testing completed within 6 months prior to the screening baseline visit date or is 
willing to have a test at the screening baseline visit. 
10. Has failed or was not a candidate for more conservative treatment (e.g., pelvic floor exercise, 
biofeedback, behavioral modification) 
11. Has failed, could not tolerate (stopped taking medication due to lack of efficacy or intolerable 
side effects), or not a good candidate for (as determined by treating physician) at least one (1) 
antimuscarinic or β3 adrenoceptor agonist medication. 
12. Is willing and able to washout (at least five half-lives) from OAB medications for a period 
determined appropriate based on type of OAB medication prior to the baseline bladder diary 
and remain off OAB medications through the 12-month follow-up visit.   
13. Has appropriate sacral anatomy as determined by sponsor’s and investigator’s analysis of 
radiographic imaging.  (The distance from the surface of the skin in the prone and seated 
position to the bone edge of the S3 foramen must be within the capabilities of the system). 
 
Baseline Bladder Diary Inclusion Criteria: 
14. Has a diagnosis of UUI with at least 4 UUI episodes on a 72 - hour diary, and minimum of one (1) 
UUI episode per 24-hour period. 
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7.4.2 Exclusion Criteria 
Subjects will be excluded if any of the following criteria are met:  
General exclusion criteria: 
1. 
Has a hemoglobin A1c of >8%, or has diabetes mellitus with glucosuria.   
2. 
Has diabetic neuropathy.  
3. 
Has interstitial cystitis or bladder pain syndrome as defined by either American Urological 
Association (AUA) or European Association of Urology (EAU) guidelines, chronic pelvic pain, 
or recurrent symptomatic urinary tract infections.   
4. 
Has skin, orthopedic, neurological, or hematological (bleeding disorder) or anatomical 
limitations that could prevent successful placement of the neurostimulator. 
5. 
Has broken, blistered skin or compromised circulation in the area of the neurostimulator 
implant.  
6. 
Has neurogenic bladder dysfunction such as traumatic or atraumatic myelopathy, multiple 
sclerosis, Parkinsonism, or history of cerebrovascular accident.   
7. 
Has documented urinary retention within 6 months prior to the screening baseline visit date.  
8. 
Has clinically significant bladder outlet obstruction. 
9. 
Is currently undergoing or has previously undergone pelvic irradiation. 
10. 
Is a subject with a mechanical obstruction such as benign prostatic hypertrophy, urethral 
stricture, or cancer. 
11. 
Has current grade 3 or 4 pelvic organ prolapse including cystocele, rectocele, enterocele, 
procidentia, or vaginal vault prolapse. 
12. 
Has symptomatic urinary tract infection (UTI); the subject may be considered for study 
enrollment if the subject is symptom-free after a full course of treatment prior to beginning 
the baseline bladder diary.  If an asymptomatic bacteriuria is detected during the urinalysis 
performed at screening, a subject may be enrolled without a waiting period relative to UTI 
treatment.  
13. 
Has primary stress incontinence or mixed incontinence where the stress component 
predominates or has been treated surgically for stress urinary incontinence within 6 months 
prior to the screening baseline visit date.  
14. 
Has received tibial nerve stimulation (TNS) in the past 3 months for the treatment of 
overactive bladder or unwilling to stay off TNS therapy for 12-month period following 
implant. 
15. 
Has received treatment of urinary symptoms with any botulinum neurotoxin type-A (BoNT-
A) agent in the past 12 months; (e.g. obotulinumtoxinA, Botox®, abobotulinumtoxinA, 
Dysport®, IncobotulinumtoxinA, Xeomin®). 
16. 
Is a woman who is pregnant or planning to become pregnant during this clinical study or is a 
woman of child-bearing potential who is not using a medically acceptable method of birth 
control. Women of child-bearing potential must undergo a pregnancy test, with clear 
negative result. 
17. 
Has active substance abuse, including alcohol. 
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18. 
Has a known hypersensitivity or contraindication to procedural or post-procedural 
medications which cannot be adequately managed medically. 
19. 
Has a known hypersensitivity to Neuspera’s SNS System device components.   
20. 
Has previously failed SNS therapy.  
21. 
Has active implantable medical devices such as neurostimulators, drug pumps, pacemakers, 
or internal defibrillators since compatibility has not been assessed.    
22. 
Has known needs for diathermy (shortwave, microwave, or therapeutic ultrasound), and 
radiofrequency ablation in the vicinity of the neurostimulator since these procedures have 
not been evaluated.  
23. 
Has a known need for therapeutic ultrasound in the area of the sacral nerve neurostimulator 
as the device can inadvertently concentrate the ultrasound field and cause harm. 
24. 
Has a known need for therapeutic ionizing radiation as can damage the electrical 
components of the sacral nerve stimulator and any damage may not be immediately 
detectable.  
25. 
Has plans to enroll or is currently enrolled in another investigational device or drug trial 
during his/her participation in this study. 
26. 
The investigator is unable to elicit an appropriate motor response in the subject during the 
intra-operative testing of the implant procedure. 
 
7.4.3 Definition of Enrollment 
Phase I: Subjects were considered enrolled in the study after signing the informed consent form and 
after an implant was attempted. The principal investigator ensured that the subject had met all pre-
operative eligibility criteria prior to enrollment in the study. The intraoperative eligibility criterion of an 
appropriate motor response was confirmed during the implant procedure. Subjects in whom an implant 
was attempted but the appropriate motor response was not observed, were considered enrolled in the 
study but did not go on to receive the neurostimulator implant.  
 
Phase II: In compliance with ISO 14155, subjects will be considered enrolled at the time the subject signs 
and dates the study specific informed consent form. Subjects who do not meet all eligibility criteria are 
considered enrolled in the study but will not receive an implant. Subjects in whom an implant is 
attempted but the appropriate motor response is not observed, will be considered enrolled in the study 
but will not go on to receive the neurostimulator implant.  
 
7.4.4 Subject Withdrawal, Discontinuation, and Study End 
Phase I study subjects who were implanted with the Neuspera Implantable SNS System and were 
determined to be responders during the SNS trial period are being followed in the post-trial period.  
Phase II study subjects who are implanted with the Neuspera Implantable SNS System will be followed in 
the post-implant period. 
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Subjects who become pregnant during the study will have stimulation stopped for the duration of the 
pregnancy and will return for follow-up visits. 
A subject’s participation in the study is voluntary and subjects may choose to exit the clinical trial at any 
time. Subjects who do not have any part of the Neuspera Implantable SNS System introduced into the 
body, may be exited from the study immediately. Subjects who have been implanted with the Neuspera 
SNS System, will have the implanted neurostimulator explanted and complete a 30-day post-explant 
follow-up prior to study exit. These subjects must return the Patient Controller, Wireless Transmitter(s) 
and Wireless Transmitter Charging Pad and Magnet to the investigational center. Subject may dispose of 
used custom undergarments or Wearable at their discretion. 
The investigator will document the reason for subject study exit and record the reason, if known, on a 
study exit form. This information will be recorded for subjects who exit after enrollment and subjects 
who complete the study. After exit from the study, subjects will be followed per standard of care.  
For those subjects who miss a scheduled study visit, the site shall make all attempts at contacting the 
subject and at a minimum contact must be made three times, with at least one attempt being a certified 
letter, prior to considering the subject lost to follow-up (LTF). 
For subjects who withdraw from the study early, all attempts will be made to collect the primary and 
secondary endpoint data, including safety data. 
A subject’s continued participation in the study may be terminated for the following reasons: 
• 
Serious or severe adverse event or unanticipated adverse device effect. 
• 
Termination of study by the Sponsor. 
• 
Investigator determines that continued participation is not in the best interest of the subject. 
• 
Pregnancy 
• 
Subject withdrawal of consent at any time. 
 
Enrollment will stop when 120 subjects have had attempted implants. At that time, if there are subjects 
enrolled, but not yet implanted, they may continue in the study and receive an implant.  
7.4.5 Subject Replacement 
Subjects will be enrolled once into the study and cannot be enrolled again. The sample size calculations 
have accounted for subject lost to follow-up, thus subjects who exit after enrollment will not be 
replaced. Additionally, subjects who fail screening, will not be re-screened at a later time.  
7.5 
Procedures 
7.5.1 Screening/Baseline  
Potential study subjects will be identified and informed of the study. Subjects who provide informed 
consent for study participation will undergo baseline screening evaluations to determine their eligibility 
for study participation. These evaluations will be done at the Screening/Baseline visit and include: 
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• 
Inclusion/Exclusion review 
• 
Demographics 
• 
Medical history 
• 
OAB history 
• 
Medication Use (includes OAB medications and therapies) 
• 
Physical examination 
• 
Vital Signs 
• 
Hemoglobin A1c collection 
• 
Urinalysis 
• 
Pregnancy test (as applicable) 
• 
A radiographic image (X-ray or fluoroscopy) to determine sacral thickness to provide the 
recommended model (SNS-28 or SNS-35) for implant.  For sacral thickness of 16.5 mm or less 
the SNS-28 neurostimulator is recommended for implant and for sacral thickness >16.5 mm, 
the SNS-35 is recommended for implant. The final device model implanted will be based on 
the investigator’s assessment at the time of implant.  
• 
A radiographic image (X-ray or fluoroscopy) assessment of the distance from the skin surface 
to the bone edge of the S3 foramen on all subjects. The X-ray image can be the same image 
as the image taken to determine sacral thickness. 
• 
Urodynamics (uroflowmetry, cystometry, and pressure flow).  Completed within 6 months of 
screening/baseline visit or test at the screening/baseline visit. 
• 
Cystoscopy completed within 6 months of screening baseline visit or at screening/baseline 
visit. 
 
7.5.2 Informed Consent 
Prior to any study related procedures, the investigator or delegated staff must explain the study, answer 
any questions the subject may have, and provide the subject with the approved consent form to read. 
The informed consent form must be approved by the reviewing IRB/EC. 
In order to participate in the study, the subject must sign and date the informed consent form. 
All applicable laws, regulations, and IRB/EC requirements must be followed during the consent process. 
7.5.3 OAB Medication Washout and Therapy Discontinuation 
Standard medications and therapies used for OAB should be stopped before the scheduled Neuspera 
Implantable SNS System procedure. These medications, and therapies, must be stopped for a period of 
at least five half-lives before the baseline bladder diary is completed. For a given subject, the drug they 
are on with the longest half-life (X5) will determine the length of the washout period. Subjects will 
remain off these OAB medications through the 12-month post-trial period for Phase I and Phase II.  
7.5.4 Custom Undergarments 
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Subject’s normally worn undergarment size will be recorded. Custom undergarments will be provided to 
the subject in the same size that they normally wear.  Subject will be asked to wear the custom 
undergarments and to inform the research staff if an alternate size (smaller or larger) will be required.  
The subject will be provided with the size that best fits them prior to or at the implant visit.  New 
undergarments will be provided if needed if body size changes over time. 
7.5.5 Wearable 
Subjects can elect to use the Wearable or the custom undergarment to hold the WT in place.  At any 
time during the study, the subject can use either the custom undergarment or the Wearable.  
7.5.6 Baseline Assessments  
It is acceptable to complete OAB washout and subsequent Baseline Assessments prior to Urodynamic, 
Cystoscopy procedures, and Assessment of Sacral Anatomy. This would ensure subjects meet the 
primary criteria for UUI before undergoing invasive procedures. 
7.5.6.1 
Assessment of Sacral Anatomy 
A radiographic image (x-ray or fluoroscopy) must be completed to determine sacral thickness and the 
distance from the skin surface to the bone edge of the S3 foramen on all subjects. 
7.5.6.2 
Bladder Diary  
Subjects must complete a baseline 72-hour bladder diary to confirm inclusion and exclusion criteria.  The 
baseline 72-hour bladder diary must be completed when the potential subject has been off OAB 
medications for a period determined appropriate based on type of OAB medication (at least five half-
lives). The following inclusion criterion must be confirmed prior to the Neuspera implant procedure: 
• 
Has a diagnosis of UUI with at least 4 UUI episodes on a 72-hour diary, and minimum of one 
(1) UUI episode per 24-hour period. 
• 
Subjects must remain off OAB medications through the 12-month post-trial period for Phase 
I and post-implant for Phase II.   
7.5.6.3 
Wexner Scale (Fecal Incontinence Assessment) 
Subject must complete the Wexner Scale after they have been off OAB medications for a period 
determined appropriate based on type of OAB medication (at least five half-lives). The Wexner scale will 
only be completed by subjects who have FI concomitant with UUI at baseline as documented in the 
baseline medical history. 
7.5.6.4 
Quality of Life Measures  
Subject must complete the health-related quality of life questionnaires (ICIQ-OABqol and MLUTS/FLUTS) 
after they have been off OAB medications for a period determined appropriate based on type of OAB 
medication.   
7.5.6.5 
Physician Review Panel 
A member of the physician review panel, experienced in the implant of sacral neuromodulation devices, 
will review all inclusion / exclusion criteria and associated medical history for subjects prior to approving 
subjects for implant in the trial.   
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7.5.6.6 
Sacral Nerve Stimulation (SNS) Pre-Implant Assessments 
Pre-implant assessments include:   
• 
Inclusion/Exclusion review 
• 
Vital Signs 
• 
Adverse Events 
• 
Changes to medication (including OAB medications) and OAB therapies 
7.5.7 Implant Procedure  
The implant procedure will be scheduled with the goal to be completed within six weeks following the 
date of subject informed consent. If additional time is required to accommodate participants and 
surgical schedules, procedures can occur after six weeks from informed consent but no later than 12 
weeks following the completion of the baseline 72-hour bladder diary. If scheduled beyond 12 weeks, 
the 72-hour baseline bladder diary will need to be repeated following washout of any OAB medications 
that may have been restarted. Prior to proceeding with the implant procedure, the investigator will 
review and confirm inclusion and exclusion criteria. One exception is the exclusion criterion related to 
the failure to elicit an appropriate motor response during the intra-operative testing of the implant 
procedure as this cannot be confirmed until the implant procedure is attempted. 
The implant procedure will be performed in accordance with approved Neuspera Implantable Sacral 
Nerve Stimulator Kit Instructions for Use and Neuspera Intraoperative Kit Instructions for Use.      
The subject will be prepped and will undergo local anesthesia, intravenous conscious sedation or general 
anesthesia. The S3 foramen will be located per Neuspera’s Implantable Sacral Nerve Stimulator Kit 
Instructions for Use.  Following appropriate identification of the sacral nerve, the neurostimulator will be 
implanted and a stimulation threshold will be confirmed by noting motor responses of anal bellows 
and/or flexion of the big toe or movement in other toes. If motor responses are not observed in the S3 
foramen or if the physician assesses that better motor response may be achieved in the contralateral S3 
foramen or the S4 foramen, then the placement may be attempted at these locations, following a similar 
procedure used to identify the sacral nerve location in the S3 foramen.  Following implantation of the 
neurostimulator, motor responses will be observed for each of three electrode pairs. The goal is to have 
motor response for all three electrode pairs. If motor responses are not observed for each electrode 
pair, the physician may remove the device, re-thread it, and re-implant, and retest for motor responses 
in a new location.  This can be done up to two more times with a specific neurostimulator. If more 
attempts are needed, a new neurostimulator must be used.  If after multiple attempts to position a 
device in the same, contralateral, or S4 foramen are unable to yield three electrode pairs with motor 
responses, two out of three electrode pairs is acceptable.  If the physician determines suitable motor 
response cannot be achieved, the device should not be implanted. After confirming the stimulation 
thresholds for all electrode pairs, a neurostimulator position confirmation radiographic image will be 
completed, and the tethering suture will be clipped, and the incision closed in accordance with approved 
Neuspera’s Implantable Sacral Nerve Stimulator Kit Instructions for Use. A bandage will be placed over 
the incision site. 
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If the device is a replacement device, the device may be replaced at the time it is determined a 
replacement is necessary. As the subject has already been enrolled in the study, the inclusion and 
exclusion criteria list will not be reviewed again prior to a device replacement.   
7.5.7.1 
SNS Post-operative Care  
The subject’s post-operative care will be per the institution’s standard medical practice.  In addition, 
subjects will be instructed to follow guidelines on activities for six weeks following the implant 
procedure. Subjects will be informed to avoid sexual activity during the first week following the implant 
of the neurostimulator. Subjects will be instructed to limit physical activities that may put stress on the 
implanted device. Activities that include sudden, excessive, or repetitive bending, twisting, bouncing, or 
stretching can cause component fracture or dislodgement.  Component fracture or dislodgement may 
result in loss of stimulation, intermittent stimulation, stimulation at the fracture site, and additional 
surgery to replace or reposition the component.  Examples of such activities include gymnastics, 
mountain biking, and other sports or equipment that involve the movements described above. 
Strenuous physical activity may cause implant fracture or dislodgement which may result in loss of 
stimulation, intermittent stimulation, or pain at the implant site.  Postural changes, and other activities 
may result in the subject perceiving an increase in stimulation which may be uncomfortable.  Some 
subjects have described this as a jolting or shocking sensation.  Subjects should be instructed to not wear 
the Wireless Transmitter to deliver therapy during activities that could be unsafe for themselves or 
others (e.g, driving or the use of dangerous equipment) if they were to receive an unexpected jolt or 
shock. Instruct subjects to consider movements involved in any planned activity and take precaution to 
avoid putting undue stress on the implanted system. For example, in activities such as skydiving, when 
the parachute opens, there can be a sudden jerking motion that occurs. This may cause a 
neurostimulator dislodgement or fracture. A surgical procedure may be required to reposition or replace 
the neurostimulator. 
Subjects will be asked to inform the investigator about the activities in which they participate to 
determine if there should be any additional restrictions.  
Subjects will also be instructed for the duration of study participation to refrain from receiving any form 
of spinal or pelvic manipulation in the area of the neurostimulator by chiropractors as this may damage 
the implant. This may result in implant fracture or dislodgement which may result in loss of stimulation, 
intermittent stimulation, or pain at the implant site.  Subjects will also be asked to refrain from 
manipulating the implant. Pushing on or rubbing the implant site may cause implant damage, 
dislodgement, uncomfortable stimulation, or pain at the implant site. 
 
Pre-discharge data collection will be completed and include the following assessments:  
• 
Vital Signs 
• 
Adverse Events 
• 
Wound Check 
• 
Wireless Transmitter positional testing 
• 
Record Device Parameters 
 
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Follow the ‘Post-Operative Patient Training and Follow-up Instructions’ provided in the Clinician Manual 
for training the subject on system use and programming stimulation settings. The Neuspera system will 
be programmed in accordance with the Clinician Manual. During the study, sensory threshold responses 
with different electrode configurations and RF Power level adjustment of the Wireless Transmitter will 
be made.  
Subjects will follow instructions provided by the investigator and study staff, along with the Patient 
Manual.  Subjects will wear the Wireless Transmitter to receive therapy delivery per the Investigator’s 
directions (2 hours continuously per day) during the SNS trial period in Phase I and post-implant period in 
Phase II.  Subjects will be encouraged to wear the Wireless Transmitter during a consistent time each 
day, e.g., 6 am to 8 am, or 7 pm to 9 pm, etc. 
7.5.8 SNS Follow-up Visits  
The research coordinator will call the subject 1-3 days post implant to ensure the subject understands all 
post implant training requirements on the use of the system including:   
• 
Proper charging of the Wireless Transmitter on the Charging Pad 
• 
Proper use of the Magnet with the Wireless Transmitter 
• 
Placement of the Wireless Transmitter in the undergarment or Wearable for 2 hours of 
continuous stimulation per day 
• 
Proper use of the stimulation diary 
• 
Proper use of the Patient Controller to adjust stimulation amplitude or programs. 
 
The research coordinator will provide re-training as appropriate. 
7.5.8.1 
Phase I 
The enrollment and trialing phase has been completed for Phase I of the trial. The trialing phase visit 
schedule will remain in the protocol until all subjects complete 3-months of follow-up.   
Subjects are required to return to the clinic 7-days, 14-days and 21-days post procedure during the Phase 
I SNS trial period. Just prior to each of these clinic visits, subjects will complete a 72-hour bladder diary 
documenting the number of voids, voided volume (specified times), leaks, urgency episodes (leaks and 
voids), and pad use. During the Therapy Session, when the subject is wearing the Wireless Transmitter 
and receiving stimulation therapy, the subject must also complete a Stimulation Diary noting stimulation 
sensation approximately every 30 minutes. If the subjects do not feel the stimulation during the 
stimulation sensation checks, they are instructed to adjust the undergarment or Wearable, increase the 
stimulation amplitude, or change programs until they feel a comfortable level of stimulation. Subjects 
should repeat this process every 30 minutes, each hour or every 2 hours depending on what duration of 
daily stimulation is being used. At the end of the therapy session subjects will be asked to answer 
questions on the diary about that session regarding the consistency of stimulation. The overall goal is 
that subjects feel a comfortable level of stimulation throughout the stimulation period.   
The following will be completed and documented during the SNS trial period follow-up visits:   
• 
Review of subject therapy and usage history  
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• 
Device data will be periodically recorded. 
• 
Adjustments of device stimulation parameters on Clinician Programmer  
• 
Vital Signs 
• 
Changes to medication (including OAB medications) and OAB therapies 
• 
Adverse event assessment  
• 
Wound check  
• 
72-hour bladder diary (reviewed)  
• 
Stimulation Diary (reviewed)  
• 
Pain Questionnaire (Day 7 only) 
• 
Wexner Scale (reviewed, only in subjects with FI at baseline) 
 
Subject’s completed 72-hour bladder diary will be reviewed and SNS therapy response will be 
determined.  A responder is defined as a subject who experiences at least a 50% improvement in the 
number of UUI episodes from baseline.   
If the investigator determines that SNS therapy is a treatment option for the subject, the subject will 
continue to participate in the post-trial follow-up period of the clinical study and will have the post-trial 
procedures. 
If the investigator determines that the subject did not respond to SNS therapy with 2 hours of daily 
stimulation, the subject will continue with an additional 14 days of trial with 4 hours of continuous daily 
stimulation.  During the Therapy Session, when the subject is wearing the Wireless Transmitter and 
receiving stimulation therapy, the subject must also complete a Stimulation Diary noting stimulation 
sensation approximately every hour during the 4-hour therapy session. If the subjects do not feel the 
stimulation during the stimulation sensation checks, they are instructed to adjust the undergarment or 
Wearable, increase the stimulation amplitude or to change programs until they feel a comfortable level 
of stimulation. Subjects should repeat this process every hour, if needed, to feel a comfortable level of 
stimulation. The overall goal is that subjects feel a comfortable level of stimulation throughout the 4-
hour stimulation period.   
The subject will return to the clinic at approximately 28- and 35-days post-implant procedure. At the 35-
day visit the physician will determine if the subject is a responder, i.e., has ≥50% reduction in the number 
of UUI episodes from baseline. If the subject is determined a responder, the subject will continue to 
participate in the post-trial period and will have the post-trial procedures. The subject will continue in 
the post-trial period with 4 hours of daily stimulation therapy.   
If the investigator determines the subject has <50% reduction in the number of UUI episodes from 
baseline, the subject will continue in the trial period for an additional 14 days with 8 hours of continuous 
daily therapy stimulation. During the Therapy Session, when the subject is wearing the Wireless 
Transmitter and receiving stimulation therapy, the subject must also complete a Stimulation Diary noting 
stimulation sensation approximately every 2 hours during the 8-hour therapy session. If the subjects do 
not feel the stimulation during the stimulation sensation checks, they are instructed to adjust the 
undergarment or Wearable, increase the stimulation amplitude, or change programs until they feel a 
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comfortable level of stimulation. Subjects should repeat this process every 2-hours, if needed, to feel a 
comfortable level of stimulation. The overall goal is that subjects feel a comfortable level of stimulation 
throughout the 8-hour stimulation period.   
The subject will return to the clinic at approximately 42- and 49-days post-implant procedure. The 
investigator will determine at approximately 49 days if the subject is a responder. If the subject is 
determined to be a responder with ≥50% reduction in the number of UUI episodes from baseline, the 
subject will continue to participate in the post-trial period and will have the post-trial period procedures 
completed. The subject will continue in the post-trial period with 8 hours of daily stimulation therapy.   
At the end of the trial period, if 8 hours of daily stimulation therapy did not provide a ≥50% reduction in 
the number of UUI episodes, the subject is considered a non-responder to SNS therapy. The subject may 
discuss alternative therapy options with the investigator to determine if the neurostimulator will be 
removed. Subjects may remain in the trial at 8 hours of continuous stimulation. If the subject and the 
investigator determine that it will be in the subject’s best interest the neurostimulator may be removed. 
The neurostimulator will be explanted and alternative therapy options will be discussed with the subject 
by the investigator. The Wireless Transmitter(s), Wireless Transmitter Charging Pad, Magnet and Patient 
Controller will be returned to the investigational center.  Subjects may dispose of used custom 
undergarments or Wearable at their discretion.  These subjects will be followed for 30-days for safety 
following the post-trial period and will then be exited from the study and no further data or information 
will be collected on these subjects.   
7.5.8.2 
Phase II 
The implant procedure and post procedure care in Phase II is consistent with that performed in Phase I.  
In the first 28 days post implant, subjects will receive 2 hours of continuous daily stimulation using the 
external Wireless Transmitter.  At the end of 28 days treatment efficacy will be assessed. Subjects with 
acceptable efficacy (≥50% reduction in number of UUI episodes) will be considered a responder and will 
continue in the post-implant follow-up with 2 hours of daily stimulation using the Wireless Transmitter. 
Those with less than acceptable efficacy (<50% reduction in number of UUI episodes) will continue for an 
additional 14-day period with 4 hours of daily stimulation with the Wireless Transmitter.  After 14 days 
of 4 hours of daily stimulation those subjects with ≥50% reduction in number of UUI episodes will be 
considered a responder.  Those subjects who increased to 4 hours of daily stimulation, regardless of 
responder or non-responder status at the end of the 42-day period will continue in the post-implant 
follow-up with 4 hours of daily stimulation.  A decision to continue a subject with less than a 50% 
improvement at the end of the 42-day period will be made by the investigator based on what they 
determine is in the best interest of the subject.  
The following will be completed and documented using the appropriate CRFs during the post-implant 
follow-up visits:  
• 
Review of subject therapy and usage history 
• 
Device data will be periodically recorded 
• 
Adjustments of device stimulation parameters on Clinician Programmer  
• 
Vital Signs 
• 
Changes to medication (including OAB medications) and OAB therapies 
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• 
Adverse event assessment  
• 
Wound check 
• 
72- hour bladder diary (reviewed)  
• 
Stimulation Diary (reviewed)  
• 
Wexner Scale (reviewed, only in subjects with FI at baseline) 
 
During the post-implant period, subjects will complete a 72-hour bladder diary documenting the number 
of voids, voided volume (specified times), leaks, urgency episodes (leaks and voids), and pad use prior to 
each clinic visit.  
During the Therapy Session, when the subject is wearing the Wireless Transmitter and receiving 
stimulation therapy, the overall goal is to feel a comfortable level of stimulation.  Subjects must 
complete a Stimulation Dairy to document daily therapy use. 
Subject’s completed 72-hour bladder diary will be reviewed and SNS therapy response will be 
determined.  A responder is defined as a subject who experiences a ≥50% reduction in the number of 
UUI episodes from baseline. At the day 28 or day 42 clinic visit post-implant the responder rate will be 
determined. As an as-treated mITT analysis will be completed, all implanted subjects will continue in the 
post-implant follow-up period regardless of responder rate outcome. 
7.5.8.3 
Phase I Post-Trial Procedure Final Visit 
The enrollment and trialing phase has been completed for Phase I of the trial. The end of trialing phase 
visit schedule will remain in the protocol until all subjects complete 3-months of follow-up.   
Phase I subjects determined to be SNS responders at the end of the trial period (either day 21, day 35, or 
day 49) will have a post-trial procedure final visit. The following procedures will be completed at this 
visit: 
• 
Wound check 
• 
Neurostimulator position confirmation lateral and anterior/posterior radiographic image  
• 
Subject User Experience Questionnaire  
 
Phase I subjects will have the post-trial procedures occur at the trial visit at which they were determined 
to be a SNS responder (either the 21-day, 35-day, or 49-day visit).  A wound check will be completed, and 
radiographic images will be taken to confirm position of the neurostimulator. Follow-up visits will occur 
from the last trial visit, for example, if the last trial visit was at the 21-day visit, the one-month follow-up 
will be one month from the 21-day visit. Instructions will be provided on the daily stimulation 
requirement for the post-trial follow-up. 
7.5.8.4 
Phase II Responder Rate Assessment (Day 28 or Day 42 Clinic Visit)  
At the Day 28 or Day 42 clinic visit post-implant the responder rate will be determined. This responder 
rate will be used for comparison to current clinical literature.  Subjects determined to be responders and 
those determined to be non-responders will continue in the study. A decision to continue a subject with 
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less than a 50% improvement at the end of the 42-day period will be made by the investigator based on 
what they determine is in the best interest of the subject.  
 
The following procedures will be completed at the Day 28 or Day 42 clinic visit post-implant: 
• 
Wound check 
• 
Neurostimulator position confirmation lateral and anterior/posterior radiographic image  
• 
Subject User Experience Questionnaire  
 
Phase II subjects will have a wound check completed, and radiographic images taken to confirm position 
of the neurostimulator at the time the subject is determined to be a responder or non-responder post-
implant (day 28 or day 42 clinic visit).  Investigators will make an assessment of the radiographic image 
to determine if any movement of the device has occurred.  The CEC will review all images to determine if 
movement has occurred, and any disagreement between the CEC and the investigator will be reviewed 
by the DSMB, who will make the final decision.  
All follow-up visits will occur from date of implant, for example, the Month 6 visit is six months from the 
date the device was implanted.  Instructions will be provided on the daily stimulation requirement for 
the remainder of the post-implant follow-up. 
7.5.8.5 
Follow-up Clinic Visits  
Phase I: Only subjects determined to be responders will complete follow-up clinic visits. 
Phase II: All subjects, responders and non-responders, will complete follow-up clinic visits. 
Subjects enrolled in Phase I and II will return to the clinic for monthly visits up to the 6-month post-trial 
(Phase I) and the 6-month post-implant (Phase II) procedure. After the 6-month visit, clinic visits will 
occur every three months up through the 12-month visit, and then every 6 months until regulatory 
approval is achieved. 
The following will be completed and documented using the appropriate CRFs during the follow-up visits:   
• 
Review of subject therapy and usage history 
• 
Device data will be periodically recorded. 
• 
Adjustments of device stimulation parameters on Clinician Programmer  
• 
Vital Signs 
• 
Body Weight assessment (at 12, 24, 36 month visits only – and 42 and 60 month for Phase I). 
• 
Changes to medication (including OAB medications) and OAB therapies 
• 
Adverse event assessment  
• 
72-hour bladder diary (reviewed) 
• 
Stimulation Diary (reviewed) 
• 
Wexner Scale (reviewed, only in subjects with FI at baseline) 
• 
Health-related quality of life questionnaires (ICIQ-OABqol, MLUTS/FLUTS) as listed in Table 7 
(Phase I) and Table 9 (Phase II).   
• 
PGI-I as listed in Table 7 (Phase I) and Table 9 (Phase II).  
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• 
Subject User Experience Questionnaire as listed in Table 7 (Phase I) and Table 9 (Phase II).  
 
7.5.8.6 
Follow-up Telephone Visits  
Phase I: Only subjects determined to be responders will complete follow-up telephone visits. 
Phase II: All subjects, responders, and non-responders, will complete one scheduled follow-up telephone 
visit at 5.5 months. Unscheduled telephone visits can be made to check on subject status. 
The following will be completed and documented in electronic data capture (EDC) for Telephone Visits:   
• 
Changes to medication (including OAB medications) and OAB therapies 
• 
Adverse event assessment  
• 
Stimulation Diary (reviewed) 
 
7.5.8.7 
Programming Sessions 
During follow-up visits, subjects will bring their Wireless Transmitter for interrogation and data transfer 
to the Clinician Programmer. Subjects may be asked to bring their Charging Pads to the follow-up visits 
for retraining purposes. 
Data from the Wireless Transmitter will be periodically downloaded on subject therapy and usage. 
Device programs will be reviewed and adjusted per Investigator discretion.   
Programming adjustments may occur as many times as needed during the study to optimize treatment. 
Programming will be performed in accordance with the Clinician Manual.  
7.5.8.8 
Unscheduled Follow-Up Visits in the Clinic or via Telephone 
If a subject is seen for an unscheduled visit the following will be completed and documented in the EDC. 
• 
Changes to medication (including OAB medications) and OAB therapies 
• 
Adverse event assessment 
If the reason for the unscheduled visit is due to troubleshooting loss of efficacy or painful stimulation, 
the subject may be asked to complete the following procedures in addition to the above listed 
procedures. 
• 
72-hour bladder diary within 7 days. Voided volume not needed on diary.  
• 
Radiographic imaging of the implanted device  
• 
Device Parameter/Download  
• 
Adjustments of device stimulation parameters on Clinician Programmer  
 
7.5.8.9 
Device Replacements 
During the course of the study, subjects may require a replacement of the neurostimulator. If a subject 
receives a neurostimulator replacement prior to Month 3 clinic visit in Phase I, the subject will repeat 
trialing and follow-up, as the newly replaced device may not be in the identical location as the previous 
device (i.e., new location on ipsilateral side, contralateral side or different foramen). If a subject receives 
a device replacement prior to Month 6 clinic visit in Phase II, the subject will repeat all post-implant 
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procedures including the Day 28 and Day 42 (if needed) response rate assessment and follow-up visits. 
Both in Phase I and Phase II, the date of replacement will be considered the new device implant date for 
analysis and follow-up purposes. Subjects with device replacement will begin with procedures listed in 
Section 7.5.6.6 (Sacral Nerve Stimulation Pre-Implant Assessments), with the exception of the 
inclusion/exclusion checklist, and continue in the study as outlined following an implant for Phase I or 
Phase II, as appropriate. If a device replacement is required after the time periods indicated above 
(Month 3, Phase I; Month 6, Phase II), subjects will be managed as determined best by the investigator 
to obtain optimal programming settings, that is, no trialing (Phase I) and no response rate assessment 
(Phase II).  Subjects will continue on their original follow-up schedule without repeating any of the 
assessments or follow-up visits already completed. 
The following data will be collected for device replacements: 
• 
Reason for device replacement  
• 
Device Parameter/Download (prior to device explant)  
• 
Replacement/explant procedure data 
• 
Fluoroscopy images for replacement 
• 
Vital Signs 
• 
Changes to medication (including OAB medications) and OAB therapies 
• 
Adverse event assessment (any signs or symptoms associated with the reason for replacement, 
will be reported as an adverse event) 
 
The explanted neurostimulator should be placed in a biohazard kit and shipped to the Sponsor for 
investigation. The neurostimulator must be handled carefully and as little as possible to prevent damage 
and preserve its integrity. The Sponsor must be contacted for shipping and packaging materials and to 
arrange for transport.   
7.5.8.10 
Device Explants 
At study exit or during the course of the study, subjects may require a neurostimulator explant. The 
subject will be prepped according to local practice. A small incision (approximately 2.5 cm) will be made 
at the site of implantation and the tether will be located. The device will be removed by pulling the 
tether in the direction of the implantation path. If the device cannot be completely removed using the 
tether, the investigator will locate the top of the implant by palpating or using fluoroscopy. The 
investigator will retrieve the device using forceps to grip the top of the implant. The wound site will be 
closed, and the subject will proceed to post-procedure recovery. Post-recovery procedures will be 
according to local practice. The following data will be collected for explants: 
• 
Reason for device explant 
• 
Device Parameter/Download (prior to device explant) 
• 
Explant procedure data 
• 
Fluoroscopy images prior to device explant 
• 
Vital Signs 
• 
Changes to medication (including OAB medications) and OAB therapies 
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• 
Adverse event assessment (any signs or symptoms associated with the reason for explant, will be 
reported as an adverse event) 
 
Subjects will return the Wireless Transmitter(s), Wireless Transmitter Charging Pad, Magnet and Patient 
Controller to the investigational center. Following explant, the neurostimulator should be placed in a 
biohazard kit and shipped to the Sponsor for investigation. The neurostimulator must be handled 
carefully and as little as possible to prevent damage and preserve its integrity. Subjects may dispose of 
used custom undergarments or Wearable at their discretion. The Sponsor must be contacted for 
shipping and packaging materials and to arrange for transport.   
All relevant data pertaining to the explant must be documented and supporting documentation (i.e., 
radiographic images and photographs) will be made available to the sponsor.  
7.5.8.11 
Post-Explant 30-Day Follow-up  
A 30-day follow-up visit is required for all subjects where the implant procedure was attempted but the 
device was not implanted or where the device was explanted. The following measures are required: 
• 
Vitals signs 
• 
Changes to medication (including OAB medications) and OAB therapies 
• 
Adverse event assessment 
• 
Wound check 
 
7.5.8.12 
Device Programming and Wireless Transmitter Positional Testing 
The Neuspera system will be programmed in accordance with the Clinician Manual. Additionally, the 
following testing will occur at therapy initiation and as needed, during trial visits, post-trial and post-
implant follow-up visits, and unscheduled visits: 
• 
Sensory threshold responses with different electrode configurations.  
• 
RF Power level adjustment of Wireless Transmitter.  
 
 
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7.5.8.13 
Troubleshooting Loss of Efficacy or Painful Stimulation  
In the event of loss of efficacy or painful stimulation a troubleshooting guidance flowchart has been 
prepared in Figure 17 below. This troubleshooting guidance is based on established International 
Continence Society best practice for use of sacral neuromodulation.10 The guidance is a stepwise 
assessment starting with medical assessment of the subject, assessment of device function, 
reprogramming and follow-up and radiographic assessment, if indicated. The investigator will lead care 
and management of each subject while Neuspera may provide device technical support.   
 
FIGURE 17: TROUBLESHOOTING GUIDANCE FOR LOSS OF EFFICACY OR PAINFUL STIMULATION 
 
 
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7.5.8.14 
Magnetic Resonance Imaging (if required for subject) 
Non-clinical testing has demonstrated that the neurostimulator is MR Conditional and subjects with the 
implanted device may be safely scanned in an MR system meeting the conditions described in the 
Clinician Manual. All external components must be removed before scanning.  If a subject has an MR 
scan while in the study, the following information will be collected: 
• 
Date of MR scan.  
• 
Anatomical location of scan. 
• 
Strength of scan (Tesla).  
• 
Reason for the scan. 
• 
MRI image and information describing any artifacts by the radiologist. 
 
7.5.8.15 
Collection of Economic Data 
The FDA has assigned Category B (non-experimental / investigational device) for the clinical trial.  The 
Center for Medicare and Medicaid Services (CMS) may pay for the Category B IDE device and routine 
care items and services furnished in an FDA-approved Category B IDE study if CMS determines that the 
Medicare coverage IDE study criteria is met.  
Once Neuspera obtains CMS coverage for the clinical trial, economic information may be gathered 
during the trial. 
A subset of Medicare beneficiaries (subjects 65 years of age or older) was enrolled in Phase I of the 
SANS-UUI trial.  This group of subjects composed 44% (15/34) of the implanted population. Safety and 
efficacy data from the subjects implanted demonstrated results similar to the overall study population.   
7.5.9 Study Assessments 
7.5.9.1 
History and Physical Examination 
At baseline, a standard physical examination and complete medical history must be taken including co-
morbidities and co-existing medical conditions. This includes UUI and genitourinary history. 
7.5.9.2 
Vital Signs  
Clinical status including vital signs must be evaluated and documented at baseline and all follow-up 
visits. Vital signs include heart rate, respiratory rate, blood pressure and temperature. 
7.5.9.3 
Questionnaires 
Subjects will enter data on an electronic patient reported outcome (ePRO) system. 
7.5.9.3.1 Wexner Scale (Fecal Incontinence Assessment) 
The Wexner scale assesses the frequency and severity of FI. The score takes into account the type and 
frequency of incontinence and the extent to which it alters the subject’s life.  The Wexner scale will only 
be completed by subjects who have FI concomitant with UUI at baseline. 
7.5.9.3.2 ICIQ-OAB 
The ICIQ-OAB is a robust, subject-completed questionnaire for evaluating quality of life (QoL) in subjects 
with overactive bladder, for use in research and clinical practice. The questionnaire explores in detail the 
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impact on subject’s lives of overactive bladder and can be used as an outcome measure to assess impact 
of different treatment modalities. The questionnaire consists of 26 questions answered by the subject.   
7.5.9.3.3 ICIQ-Male/Female Lower Urinary Tract Symptoms 
The ICIQ-MLUTS and ICIQ-FLUTS is a subject-completed questionnaire evaluating male and female lower 
urinary tract symptoms in research and clinical practice. This questionnaire helps to obtain a brief yet 
comprehensive summary of the impact of urinary symptoms. It also helps to facilitate subject-clinician 
discussions and assess outcomes from various treatment modalities. The ICIQ-MLUTS consists of 13 
questions and ICIQ-FLUTS consists of 12 questions.   
7.5.9.3.4 Patient Global Impression of Improvement (PGI-I) 
The PGI-I is a subject-completed transition scale that is a single question asking the subject to rate their 
urinary tract condition now, as compared with how it was prior to beginning treatment on a 7-point 
scale. 
7.5.9.3.5 Subject User Questionnaire 
Enrolled subjects will complete a subjective questionnaire. This questionnaire will collect data on the use 
of, and satisfaction with the Neuspera Implantable SNS System.   
7.5.9.3.6 Physician User Experience Questionnaire 
The investigator (or a delegated implanting sub-investigator) will complete a subjective questionnaire. 
This questionnaire will collect data on the use of and satisfaction with the Neuspera Implantable SNS 
System. 
7.5.9.4 
Bladder Diary 
Subjects will complete 72-hour bladder diaries at the required timeframes. The bladder diary is expected 
to be completed electronically but paper may be used as a backup. 
The 72-hour bladder diary will collect voiding frequency (voids), void volume (specified times), urgency, 
urinary urgency incontinence (UUI) episodes (leaks), activity during UUI (at baseline only), and pad use. 
Subjects will record events for a consecutive 72-hour period, starting from when they first begin 
recording events. 
Subjects will be trained on proper methods for completing the diary, collecting, and measuring the urine 
volume, and distinguishing between urge and stress incontinence episodes.  
Baseline Bladder Diary: A baseline 72-hour bladder diary will be completed after the subject has stopped 
OAB medication for period determined appropriate based on type of OAB medication (at least five half-
lives) to confirm the UUI inclusion criterion.  At the discretion of the investigator, subjects who failed to 
accurately complete their diary may be allowed to repeat the diary evaluation.  Those who failed to 
qualify after a second diary attempt will be withdrawn from further study participation. 
Follow-up Bladder Diaries: Subjects will complete a 72-hour bladder diary prior to each scheduled clinic 
visit. Voided volume will only be collected at baseline and at Month 6 and 12 clinic visits.  The bladder 
diary will be completed for a consecutive 72-hour period starting 4-7 days prior to each required follow-
up visit. If a subject fails to complete the diary before the scheduled visit date, they may start the 72-
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hour diary within 24-hours of the scheduled visit date.  If a subject continues to miss the start of the 72-
hour diary completion prior to a scheduled visit date, they will be assessed for protocol non-compliance.  
If a subject is symptomatic with a UTI prior to beginning or in the middle of a 72-hour bladder diary, it is 
recommended to the subject start the diary after the subject is asymptomatic after standard-of-care 
treatment.  
Subjects may be requested to complete an additional diary following programming changes to assess the 
impact of the changes. Subjects completing additional diaries will not need to collect void volume.  
7.5.9.5 
Stimulation Diary  
Enrolled subjects in Phase I and Phase II who receive the Neuspera SNS neurostimulator will complete a 
stimulation diary during follow-up. Subjects will complete a daily stimulation diary for the first 12 months 
and a weekly stimulation diary after 12 months. The stimulation diary is expected to be completed 
electronically but paper may be used as a backup. 
Through Month 12 Visit (≤12 Months) 
In the first 12 months of therapy subjects will document daily start and stop time of stimulation/therapy 
session and stimulation sensation.  At the end of the therapy session subjects will be asked to answer 
questions on the diary about that session regarding the consistency of stimulation and how difficult it 
was to achieve consistent stimulation. 
Following 12 Month Visit (> 12 Months) 
After the subject has completed their 12-month follow-up visit, they will be required to complete a 
weekly stimulation diary. The weekly diary will collect how many days the subject used their system in 
the past week and the average duration of therapy.  
The overall goal at each stimulation/therapy session is that subjects feel a comfortable level of 
stimulation throughout the stimulation period. Subjects will be encouraged to contact the study 
coordinator if they are having difficulty with the therapy sessions and/or log their difficulty on their 
stimulation diary. Instructions on completion of the stimulation diary will be reviewed with subjects to 
ensure understanding of completion requirements. 
7.5.9.6 
Medications 
All current medication subjects are using will be documented at the screening baseline visit.  Any 
changes to medications will be recorded at each subsequent study visit until study exit.  Additionally, 
current and historical OAB and incontinence medications will be reviewed and documented.  Subjects 
must remain off OAB medications for a period determined appropriate based on type of OAB medication 
(at least five half-lives) prior to completion of the baseline voiding diary and through 12-months post-
trial period.   
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7.5.9.7 
Conservative OAB Therapy Log 
All current OAB therapies subjects are using will be documented at the screening baseline visit.  Any 
changes to OAB therapies will be recorded at each subsequent study visit until study exit (Phase I) and 
12-months post-implant (Phase II).    
7.5.9.8 
Clinical Laboratory Tests 
The following tests will be completed during Screening/Baseline. All blood and urine samples will be 
disposed of after test is performed. 
Hemoglobin A1c (HbA1c): HbA1c will be measured for all subjects, regardless of if they have a history of 
diabetes, to assess and document exclusion criterion for uncontrolled diabetes.  
Urinalysis: A urinalysis will be completed with culture if indicated to assess and document the exclusion 
criterion of urinary tract infection.  
Pregnancy Test:  A blood or urine pregnancy test will be completed if subject is a female of childbearing 
potential and it will be used to assess and document the exclusion criterion for pregnancy.    
7.5.9.9 
Urodynamics Testing 
Subjects must have urodynamics testing to assess study eligibility. Tests performed within 6 months of 
the subject’s screening baseline visit date are acceptable or a test may be conducted at the screening 
baseline visit.  The following tests are required: 
Uroflowmetry: Uroflowmetry will be used to assess and document inclusion criterion for Post-Void 
Residual Volume (PVR), absence of obstruction, and to confirm symptoms of UUI. 
Cystometry: Cystometry will be used to assess and document exclusion criterion for neurogenic bladder 
syndrome. 
Pressure Flow: Pressure flow study will be used to assess and document exclusion criterion for bladder 
obstruction.  
7.5.9.10 
Assessment of Subject’s Sacral Anatomy 
A radiographic image (X-ray or fluoroscopy) must be obtained to determine sacral thickness and the 
distance from the skin surface to the bone edge of the S3 foramen on all subjects.  
For the distance from the sacral foramen to the surface of the skin, two images will be obtained: 
1. Prone position (similar to how subject would be during implant procedure) 
2. Seated position (to estimate sacral depth while seated, using the therapy)  
 
Measurements may be completed by investigational site personal, a radiologist or by Neuspera.  
The images will be reviewed by Neuspera with the investigator prior to the implant procedure.  Based on 
the analysis, if it is determined that the distance from the surface of the skin in the prone or seated 
position to the bone edge is greater than the capabilities of the system, then the subject will not be 
implanted with the Neuspera system. 
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For sacral thickness of 16.5 mm or less the SNS-28 neurostimulator is recommended for implant and for 
sacral thickness >16.5 mm, the SNS-35 is recommended for implant.  Final device model implanted will 
be based on the investigator’s assessment at the time of implant. 
7.5.9.11 
Cystoscopy 
A cystoscopy will be required to assess and document exclusion criteria for the absence of bladder neck 
obstruction, presence or absence of urethral strictures, and other bladder pathology. A cystoscopy 
completed within 6 months of the screening baseline visit date is acceptable or a test conducted at 
screening baseline visit may be used to qualify the subject for trial entry. 
7.5.9.12 
Stimulation Characteristics/Programming Parameters 
Data from the Wireless Transmitter and Clinician Programmer will be collected and saved during each 
visit. 
7.5.9.13 
Adverse Events 
All adverse events (AEs) that occur to any subject during study participation must be documented on an 
AE case report form (CRF). Refer to section 8.4 for further reporting requirements.  
7.5.9.14 
Physician User Experience Questionnaire 
The investigator will complete a Physician User Experience Questionnaire at the following time points:  
• 
Phase I: At the time the first subject enrolled completes the final trial visit. 
• 
Phase I: At the time the last subject enrolled completes the Month 3 visit. 
• 
Phase II: At the time the last subject enrolled completes the Month 6 visit. 
 
7.5.9.15 
Subject User Experience Questionnaire 
The subjects will complete a Subject User Experience Questionnaire at the following time points: 
• 
Phase I: At the final trial visit (Day 21, 35 or 49) and at the Month 3 visit. 
• 
Phase II: At the completion of the Day 28 or Day 42 visit and at the Month 6 visit. 
 
7.5.9.16 
Schedule of Assessments 
Follow-up visits must occur according to the visit schedule. Follow-up visit windows will open when the 
prior visit is complete and will close when the sequential visit occurs.  Below Table 6 and Table 7 provide 
details on Phase I follow-up schedule and required testing, Table 8 and Table 9 provide details on Phase 
II follow-up schedule and required testing. 
 
 
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TABLE 6 : PHASE I FOLLOW-UP SCHEDULE 
 
NOTE: OAB medication washout for at 
least five half-lives.  Completed prior to 
baseline bladder diary 
Visit 
Visit Target 
Screening/Baseline 
N/A 
Implant Visit 
Within the six weeks following the Screening/Baseline Visit  
SNS Trial Period 7-day Visit 
7 (-/+2) days from Implant 
SNS Trial Period 14-day Visit 
(telephone visit allowed if criteria met*) 
14 (-/+2) days from Implant 
SNS Trial Period 21-day Visit 
21 (-/+2) days from Implant 
SNS Trial Period 28-day Visit 
(if required) (telephone allowed visit if criteria met*) 
 28 (-/+2) days from Implant 
SNS Trial Period 35-day Visit 
(if required) 
 35 (-/+2) days from Implant 
SNS Trial Period 42-day Visit 
(if required) (telephone visit allowed if criteria met*) 
42 (-/+2) days from Implant 
SNS Trial Period 49-day Visit 
(if required) 
49 (-/+2) days from Implant 
 Post-Trial Period Visit Schedule:  Days (-/+) from Final Trial Visit 
Month 1 Clinic Visit: 30 (-/+ 14) days  
Month 1.5 Telephone Visit 
Month 2 Clinic Visit: 60 (-/+ 14) days 
Month 2.5 Telephone Visit 
Month 3 Clinic Visit: 90 (-/+ 14) days 
Month 3.5 Telephone Visit 
Month 4 Clinic Visit: 120 (-/+ 14) days 
Month 4.5 Telephone Visit 
Month 5 Clinic Visit: 150 (-/+ 14) days 
Month 5.5 Telephone Visit 
Month 6 Clinic Visit: 180 (-/+ 14) days 
Month 9 Clinic Visit 270 (-/+ 14) days 
Month 12 Clinic Visit: 360 (-/+14) days 
Month 18 Clinic visit: 540 (-/+ 21) days 
Month 24 Clinic Visit: 720 (-/+ 21) days 
Month 30 Clinic visit: 900 (-/+ 21) days 
Month 36 Clinic Visit: 1080 (-/+ 21) days 
Month 42 Clinic Visit: 1260 (-/+ 21) days 
Month 48 Clinic Visit: 1440 (-/+ 21) days 
Month 54 Clinic Visit: 1620 (-/+ 21) days 
Month 60 Clinic Visit: 1800 (-/+ 21) days 
 
 
 
 
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TABLE 7 : VISIT PROCEDURE SCHEDULE – PHASE I 
 
 
 
SNS Trial Period 
 Post-Trial Period 
Study Exit 
 Procedure 
Screening/ 
Baseline 
Baseline 
Assess- 
ments 
Device 
Implant 
SNS Trial 
Follow-up 
Period 
 
Final 
Trial 
Visit 
Clinic Visits 
Month 1 to 6  
 Every 3 Months to 
Month 12, every  
6 Months to Month 
60  
Telephone 
Visits 
Monthly 1.5 
to 5.5.  
Unscheduled 
Follow-up 
Visit 
Device 
Explant 
30-Day 
Post-
Explant 
F/U 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
X 
 
 
 
 
 
 
 
Baseline Evaluation (Demographics, Medical 
History, OAB History, Physical Exam) 
X 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
X 
 
X 
 
 
X 
X 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test (if applicable) 
X 
 
 
 
 
 
 
 
 
 
 Assessment of Subject’s Sacral Anatomy 
X 
 
 
 
 
 
 
 
 
 
Urodynamics (within 6 months) 
X 
 
 
 
 
 
 
 
 
 
Cystoscopy (within 6 months) 
X 
 
 
 
 
 
 
 
 
 
OAB Medication Washout (at least 5 half-lives)  
X 
 
 
 
 
 
 
 
 
 
Medication Use and Changes (including OAB 
Medication) & Conservative OAB Therapies Log 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
Body Weight 
X 
 
 
 
 
Month 12, 24, 36, 42, 
60 
 
 
 
 
Adverse Events 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
Wound Check 
 
 
 
X 
X 
 
 
 
 
X 
1-3 Day Post Implant Telephone 
 
 
 
X 
 
 
 
 
 
 
Neurostimulator position confirmation image 
 
 
X 
 
X 
 
 
 
X 
 
Therapy Review and Adjust Stimulation  
 
 
 
X 
 
X 
 
 
 
 
72-Hour Bladder Diary 
 
X 
 
X 
 
X  (Voided volume at 
Month 6 and 12) 
 
 
 
 
Stimulation Diary 
 
 
 
X 
 
X (Daily ≤ Month 12 
Weekly > Month 12) 
X 
 
 
 
Wexner Scale (only if FI)  
 
X 
 
X 
 
X 
 
 
 
 
ICIQ-OABqol, ICIQ-MLUTS/FLUTS 
 
X 
 
 
 
X  
Month 3,6,12,24,36, 
42, 48, 54, 60 
 
 
 
 
 PGI-I 
 
 
 
 
 
X 
Month 3,6,12,24,36, 
42, 48, 54, 60 
 
 
 
 
Subject User Experience Questionnaire 
 
 
 
 
X 
X (Month 3) 
 
 
 
 
Device Explant 
 
 
 
 
 
 
 
 
X 
 
Study Exit 
 
 
 
 
 
 
 
 
 
X 
 
 
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TABLE 8 : PHASE II FOLLOW-UP SCHEDULE VISIT 
Visits 
NOTE: OAB medication washout for at least five half-lives.  
Completed prior to baseline bladder diary 
Screening/Baseline Visit 
 
Implant Visit 
Goal of within the six weeks following the date of Informed 
Consent but no later than 12 weeks after the 72-hour Baseline 
Bladder Diary  
 Post Implant Visit Schedule:  Days (-/+) from Implant 
Day 7 Clinic Visit: 7 (-/+ 2) days  
Day 14 Clinic Visit: 14 (-/+ 2) days 
Day 21 Clinic Visit: 21 (-/+ 2) days 
Day 28 Clinic Visit: 28 (-/+ 2) days (Response Rate 
Assessment) 
Day 35 Clinic Visit: (if required): 35 (-/+ 2) days 
Day 42: Clinic Visit (if required): 42 (-/+ 2) days 
(Response Rate Assessment) 
responder at Day 28 Visit. 
Month 2 Clinic Visit: 60 (-/+ 14) days 
Month 3 Clinic Visit: 90 (-/+ 14) days 
Month 4 Clinic Visit: 120 (-/+ 14) days 
Month 5 Clinic Visit: 150 (-/+ 14) days 
Month 5.5 Telephone Visit 
Month 6 Clinic Visit: 180 (-/+14) days 
Month 9 Clinic Visit: 270 (-/+ 14) days 
Month 12 Clinic Visit: 360 (-/+ 14) days 
Month 18 Clinic Visit: 540 (-/+ 21) days 
Month 24 Clinic Visit: 720 (-/+ 21) days 
Month 30 Clinic Visit: 900 (-/+ 21) days 
Month 36 Clinic Visit: 1080 (-/+ 21) days 
 
 
 
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TABLE 9 : VISIT PROCEDURE SCHEDULE – PHASE II 
 
 
 
 
Post-Implant  
 
Study Exit 
Procedure  
Screening
/ 
Baseline 
Baseline 
Assess- 
ment 
Device 
Implant 
Clinic Visit (Day 7, 
14, 21, 28) & Day 
35, 42  
(if required) 
Clinic Visits 
Month 2 to 6   
Every 3 Months to 
Month 12, every 
6 Months to Month 36 
Telephone 
Visits 
At 5.5 
months.  
Unscheduled 
Follow-up 
Visit 
Device 
Explant 
30-Day 
Post-
Explant 
F/U 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
X 
 
 
 
 
 
 
Baseline Evaluation 
(Demographics, Medical History, 
OAB History, Physical Exam) 
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
X 
X 
 
 
X 
X 
HbA1c 
X 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
Pregnancy Test (if applicable) 
X 
 
 
 
 
 
 
 
 
 Assessment of Subject’s Sacral 
Anatomy  
X 
 
 
 
 
 
 
 
 
Urodynamics (within 6 months) 
X 
 
 
 
 
 
 
 
 
Cystoscopy (within 6 months) 
X 
 
 
 
 
 
 
 
 
OAB Medication Washout (at 
least 5 half-lives of OAB 
medications)  
X 
 
 
 
 
 
 
 
 
 
Medication Use & Changes 
(including OAB Medication) & 
Conservative OAB Therapies Log) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Body Weight  
X 
 
 
 
Month 12, 24, and 36 
 
 
 
 
Adverse Events 
X 
 
X 
X 
X 
X 
X 
X 
X 
Wound Check 
 
 
 
X 
 
 
 
 
X 
1-3 Day Post Implant Telephone 
Check 
 
 
 
X 
 
 
 
 
 
Neurostimulator position 
confirmation image 
 
 
X 
X (Day 28 or Day 42) 
 
 
 
X 
 
Response Rate Assessment 
 
 
 
X (Day 28 and/or 42) 
 
 
 
 
 
Therapy Review and Adjust 
Stimulation  
 
 
 
X 
X 
 
 
 
 
72-Hour Bladder Diary 
 
X 
(Voided 
volume 
required)  
 
X 
X (Voided volumes at  
Month 6 and 12) 
 
 
 
 
 Stimulation Diary 
 
 
 
X 
X (Daily ≤ Month 12 
Weekly > Month 12) 
X 
 
 
 
Wexner Scale (if FI)  
 
X 
 
X 
X 
 
 
 
 
ICIQ-OABqol, MLUTS/FLUTS 
 
X 
 
 
X (Month 3,6,12,24 & 36)  
 
 
 
 
PGI-I  
 
 
 
 
X (Month 3,6,12,24 & 36) 
 
 
 
 
Subject User Experience 
Questionnaire 
 
 
 
X (Day 28 or 42) 
X (Month 6) 
 
 
 
 
Device Explant 
 
 
 
 
 
 
 
X 
 
Study Exit 
 
 
 
 
 
 
 
 
X 
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7.5.9.17 
Equipment for Assessment 
Prior to enrollment of a subject, the sponsor shall ensure that all products from the Neuspera 
Implantable SNS System are available for the investigator. If updates for the Patient Controller, Clinician 
Programmer, or Wireless Transmitter are available, the Sponsor shall ensure these updates are provided 
to the devices of the investigator and the investigator is instructed on how to update the Patient 
Controller and Wireless Transmitter on the next follow-up visit of each subject.  
Equipment used for study assessments, outside of the Neuspera SNS System, are maintained according 
to the institute’s standard operation procedures and hospital procedures.   
7.5.9.18 
Factors that may Compromise the Outcome of the Clinical Trial or the 
Interpretation of Results  
Any known or foreseeable factors that may compromise the outcome of the clinical trial or the 
interpretation of results are, to the best of the Sponsor’s knowledge, obviated by the inclusion and 
exclusion criteria, the clinical investigational plan, and careful definition of clinical investigation 
procedures and outcome analyses. 
 
 
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8 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES 
8.1 
Definitions  
8.1.1 Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence, unintended disease or injury, or 
any untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other persons, 
in the context of a clinical investigation, whether or not related to the investigational device. Definitions 
here are compatible with Regulation (EU) 2017/745 of the European Parliament. 
This definition includes events that are anticipated as well as unanticipated events. This definition 
includes events occurring in the context of a clinical investigation related to the investigational device or 
the procedures involved. For the purpose of safety reporting all activities related to the use of a medical 
device may be considered procedures. 
Any signs or symptoms associated with the reason for device replacement or explant should be reported 
as an adverse event (e.g. loss of stimulation). 
Note:  Because the protocol requires surgical procedures, mild pain, swelling, etc. should not be 
considered untoward and not considered an AE; however, any event that is more severe or lasts longer 
than typical should be considered an AE. 
Subjects in the study, by definition, have UUI.  Unless the UUI is worsened (more frequent or more 
severe), then UUI should not be considered untoward and should not be considered an AE. 
Subjects may experience unpleasant sensations during the course of the device programming 
procedures.  If the condition resolves immediately with re-programming, then these events should not 
be considered as untoward and are not AEs.  Similarly, ongoing paresthesias should not be considered an 
AE unless they are bothersome to the subject.  
8.1.2 Serious Adverse Event 
A serious adverse event (SAE) is defined as an AE that led to any of the following: 
a) Death, 
b) Serious deterioration in the health of the subject, that resulted in any of the following; 
1) Life-threatening illness or injury, or 
2) Permanent impairment of a body structure or a body function, or 
3) Hospitalization or prolongation of 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, 
5) Chronic disease, 
c) Fetal distress, fetal death or a congenital physical or mental impairment or birth defect. 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the study 
protocol, without serious deterioration in health, is not considered a serious adverse event.   
In addition, per the FDA website: 
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https://www.fda.gov/safety/reporting-serious-problems-fda/what-serious-adverse-event -  
Other Serious (Important Medical Events) should be reported as a serious adverse event if the event 
does not fit the other outcomes cited above, but the event may jeopardize the subject and may require 
medical or surgical intervention (treatment) to prevent one of the other outcomes cited above. 
8.1.3 Device Deficiency 
Any inadequacy in the identity, quality, durability, reliability, safety or performance of an investigational 
device, including malfunctions, use errors, and inadequacy of information supplied by the manufacturer. 
Malfunction 
Failure of an investigational medical device to perform in accordance with its intended purpose when 
used in accordance with the instructions for use or clinical study protocol.   
Use Error 
Act or omission of an act that results in a different medical device response than intended by the 
manufacturer or expected by the user.   
Inadequacy of Information Supplied by the Manufacturer. 
Failure of an investigational medical device to perform in accordance with its instructions for use or 
visually not conform to the labeled device description. 
8.1.4 Serious Public Health Threat 
A serious public health threat means an event which could result in imminent risk of death, serious 
deterioration in a person's state of health, or serious illness, that may require prompt remedial action, 
and that may cause significant morbidity or mortality in humans, or that is unusual or unexpected for the 
given place and time. 
8.1.5 Adverse Device Effect 
An adverse device effect is an adverse event related to the use of an investigational medical device.  
This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical 
device. This definition includes any event resulting from use error or from intentional misuse of the 
investigational medical device. 
8.1.6 Serious Adverse Device Effect 
A serious adverse device effect (SADE) is an adverse event that is both serious and device related. 
8.1.7 Unanticipated Adverse Device Effect 
An unanticipated adverse device effect (UADE) means any serious adverse effect on health or safety or 
any life-threatening problem or death caused by, or associated with, a device, if that effect, problem or 
death was not previously identified in nature, severity, or degree of incidence in the investigational plan 
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or application (including a supplementary plan or application), or any other unanticipated serious 
problem associated with a device that relates to the rights, safety or welfare of subjects. 
An event will not be considered a UADE if it is a known consequence of the underlying disease or 
condition under investigation, surgery, or other events that commonly occur in the study population 
independent of the investigational device. 
The final determination of whether an AE meets the definition of a UADE will be made by the 
independent Clinical Events Committee for this study. 
8.1.8 Unanticipated Serious Adverse Device Effect  
An unanticipated serious adverse device effect (USADE) is any serious adverse device effect which by 
nature, incidence, severity or outcome has not been identified in the current risk assessment.   
An event will not be considered a USADE if it is a known consequence of the underlying disease or 
condition under investigation, surgery, or other events that commonly occur in the study population 
independent of the investigational device. 
The final determination of whether an AE meets the definition of a USADE will be made by the 
independent Clinical Events Committee for this study. 
8.1.9 Anticipated Serious Adverse Device Effect 
An anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, severity 
or outcome has been identified in the risk analysis report. 
8.2 
Adverse Events Causality and Severity Rating 
8.2.1 Causality 
Safety reporting in clinical investigations of medical devices will be performed in line with the 
requirements of the Regulation (EU) 2017/745: Medical Device Regulation (MDR) Article 80(2), including 
the guidance document MDCG 2020-10/1. The relationship between the use of the investigational device 
(including the medical-surgical procedure) and the occurrence of each serious adverse event will be 
assessed and categorized using terms below.  This guidance document only applies to serious adverse 
events; however, for ease of investigator reporting, Neuspera will use the same categorization terms for 
both serious adverse events and non-serious adverse events.   
The investigator must specify whether an adverse event has a causal relationship to one of the following: 
• 
Study device: Involves function of the device, or the presence of the device in the body, events 
directly related to the device. 
• 
Implant procedure: Results from the implant procedure, including events directly related to the 
general procedural sequelae. 
• 
Subject’s condition: Results from the worsening of a pre-existing condition or cannot be 
attributed to the device procedure.  
• 
Unknown: Cannot be assigned to any of the above three conditions. 
 
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The causal relationship of an adverse event to the investigational device or implant procedure will be 
rated as follows:  
• 
Not related: Relationship to the device, comparator or procedure can be excluded when:  
- 
the event has no temporal relationship with the use of the investigational device or the 
procedures related to application of the investigational device;  
- 
the serious adverse event does not follow a known response pattern to the medical device 
(if the response pattern is previously known) and is biologically implausible;  
- 
the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible - and reintroduction of its use (or increase of 
the level of activation/exposure), do not impact on the serious adverse event;  
- 
the event involves a body-site or an organ that cannot be affected by the device or 
procedure; 
- 
the serious adverse event can be attributed to another cause (e.g. an underlying or 
concurrent illness/ clinical condition, an effect of another device, drug, treatment or other 
risk factors);  
- 
the event does not depend on a false result given by the investigational device used for 
diagnosis4, when applicable; 
In order to establish the non-relatedness, not all the criteria listed above might be met at the same time, 
depending on the type of device/procedures and the serious adverse event. 
• 
Possible: The relationship with the use of the investigational device or comparator, or the 
relationship with procedures, is weak but cannot be ruled out completely. Alternative causes are 
also possible (e.g. an underlying or concurrent illness/ clinical condition or/and an effect of 
another device, drug or treatment). Cases where relatedness cannot be assessed or no 
information has been obtained should also be classified as possible.  
• 
Probable: The relationship with the use of the investigational device or comparator, or the 
relationship with procedures, seems relevant and/or the event cannot reasonably be explained 
by another cause.  
• 
Causal relationship: the serious adverse event is associated with the investigational device, 
comparator, or with procedures beyond reasonable doubt when:  
- 
the event is a known side effect of the product category the device belongs to or of similar 
devices and procedures;  
- 
the event has a temporal relationship with investigational device use/application or 
procedures;  
- 
the event involves a body-site or organ that  
• 
the investigational device or procedures are applied to;  
 
4 If an investigational device gives an incorrect diagnosis, the patient might, for example, receive an  
unnecessary treatment and incur all the risks that accompany that treatment, or might be incorrectly  
diagnosed with a serious disease. In other cases, the patient might not receive an effective treatment (thereby  
missing out on the benefits that treatment would confer), or might not be diagnosed with the correct disease  
or condition. 
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• 
the investigational device or procedures have an effect on;  
- 
the serious event follows a known response pattern to the medical device (if the response 
pattern is previously known); 
- 
the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious adverse event (when clinically feasible); 
- 
other possible causes (e.g. an underlying or concurrent illness/clinical condition or/and an 
effect of another device, drug or treatment) have been adequately ruled out; 
- 
harm to the subject is due to error in use; 
- 
the event depends on a false result given by the investigational device used for diagnosis5, 
when applicable; 
In order to establish the relatedness, not all the criteria listed above might be met at the same time, 
depending on the type of device/procedures and the serious adverse event. 
The adjudication decision of the CEC will be used for the final classification of events, including 
relatedness to the study procedures and/or the investigational device, for the determination of safety 
endpoints and for all regulatory reports, product labeling, and publications or presentations.  
 
5 If an investigational device gives an incorrect diagnosis, the patient might, for example, receive an  
unnecessary treatment and incur all the risks that accompany that treatment, or might be incorrectly  
diagnosed with a serious disease. In other cases, the patient might not receive an effective treatment (thereby  
missing out on the benefits that treatment would confer), or might not be diagnosed with the correct disease  
or condition. 
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8.2.2 Severity 
All adverse events will have a severity classification according to the Clavien-Dindo classification 
system.12,13 
Grades  
Definitions 
Grade I 
Any deviation from the normal postoperative course without the need for pharmacological 
treatment or surgical, endoscopic, and radiological interventions. Acceptable therapeutic 
regimens are: drugs such as antiemetics, antipyretics, analgesics, diuretics, and electrolytes, 
and physiotherapy. This grade also includes wound infections opened at the bedside. 
Grade II 
Requiring pharmacological treatment with drugs other than those allowed for grade I 
complications. Blood transfusions and total parenteral nutrition are also included. 
Grade III 
Requiring surgical, endoscopic, or radiological intervention 
Grade III-a 
Intervention not under general anesthesia 
Grade III-b 
Intervention under general anesthesia 
Grade IV 
Life-threatening complication (including CNS complications: brain hemorrhage, ischemic 
stroke, subarachnoid bleeding, but excluding transient ischemic attacks) requiring IC 
(intermediate care)/ICU (intensive care unit) management 
Grade IV-a 
Single organ dysfunction (including dialysis) 
Grade IV-b 
Multi-organ dysfunction 
Grade V 
Death of a patient 
Suffix “d” 
If the patient suffers from a complication at the time of discharge the suffix “d” (for disability) is 
added to the respective grade of complication. This label indicates the need for a follow-up to 
evaluate the complication fully. 
 
8.3 
Foreseeable Adverse Events and Anticipated Adverse Device Effects 
See Section 4.4 for risks associated with the Neuspera’s Implantable SNS System.  
8.4 
Reporting Requirements 
8.4.1 Adverse Event Recording 
Investigators are responsible for providing a description of all AEs, including the date of the event, 
treatment, and the clinical outcomes for the subject. Investigators will evaluate each event for 
seriousness, severity and relatedness to the procedure, device, or stimulation therapy. Investigators 
must supply the Sponsor with additional information related to safety reporting of a particular event. 
Pre-existing conditions must be documented as medical history so that related AEs can be correctly 
recorded.  An event that is a continuation of an unresolved AE must be recorded as ongoing, not as a 
new AE. Worsening of a pre-existing condition must be recorded.  Complications and hospitalizations 
must also be recorded.  
Sponsor shall fully record any adverse event of a type identified in the clinical investigation plan as being 
critical to the evaluation of the results of the clinical investigation. 
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8.4.2 Adverse Event Reporting 
Investigators are required to report all AEs during the course of the study (except as outlined below).  
Investigators shall report AEs to the Sponsor, and to their reviewing IRB/ECs per the IRB/EC reporting 
requirements.  
Investigators are required to report UADEs to the Sponsor and their reviewing IRB as soon as possible 
but in no event later than 10 working days after the Investigator first learns of the effect, per 21 CFR 
812.150. Per MDCG 2020-10/1, UADE shall immediately be reported by the investigators, but no later 
than 3 calendar days after investigational site study personnel’s awareness of the event.  
AE reporting exceptions: 
• 
AEs that would be reasonably expected to be associated with any surgical procedure (e.g. 
anesthesia associated symptoms, surgical site pain, post- procedure pain) will not be required to 
be reported as AEs unless, in the opinion of the Investigator, the nature and/or severity is 
outside of what is typical for SNS procedures and recovery. 
8.4.3 Emergency Contact Details for Reporting Serious Adverse Events and Serious 
Adverse Device Effects 
In the event of an emergency the following individual may be contacted at the sponsor organization: 
Mark Vollmer 
Clinical Director, Neuspera Medical 
Mark.vollmer@neuspera.com 
1-612-281-4875 
8.4.4 Reporting Device Deficiencies 
Investigators are responsible for providing a description of all device deficiencies, including any impact 
on the subject.  Notification of device deficiencies should be made to the Sponsor or representative as 
soon as possible for appropriate investigation.  Device deficiencies are reported on the appropriate case 
report form.   
The investigator shall report initially (and any new findings) and the sponsor shall fully record and report 
without delay to all EU Member states in which the study is occurring any device deficiency that might 
have led to a serious adverse event if appropriate action had not been taken, intervention had not 
occurred, or circumstances had been less fortunate. Sponsor shall report this without delay per 
applicable guidelines and local regulations. 
The period for reporting shall take account of the severity of the event. Where necessary to ensure 
timely reporting, the sponsor may submit an initial report that is incomplete followed up by a complete 
report. 
 
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8.4.4.1 
Events or Malfunctions (Lead Migration/Dislodgement, Fractures, Revisions) 
Investigators shall report to Neuspera as soon as possible but no event later than 30 working days after 
the investigator first learns of the effect of all device events or malfunctions, that is, lead 
migration/dislodgement and fractures, whether clinically significant or not.  In addition, a further 
breakdown of how device events or malfunctions are dealt with will be provided (e.g. no action needed, 
reprogramming, permanent loss of therapy and/or surgical revision/explantation). These events will be 
recorded by subject and event, since multiple events may occur in a single subject.   
All events (lead migration/dislodgement and fractures), whether determined to be clinically significant or 
non-clinically significant, will be identified and reported to the DSMB and the FDA as soon as possible but 
in no event later than 10 working days after Neuspera first receives notice of the event from the clinical 
investigator. 
Clinically significant events are those events that can only be corrected by surgical revision or result in 
permanent loss of therapy.  If the therapy is still providing benefit after reprogramming, Neuspera 
considers the event not to be clinically significant. Any investigator who corrects a clinically significant 
event of lead migration/dislodgement, fracture, and loss of therapy with a revision surgery will be asked 
to notify Neuspera as soon as possible but in no event later than 30 working days after the investigator 
completes the revision surgery. Neuspera anticipates that Field Clinical Engineers will support all revision 
surgeries, and Neuspera will then report any clinically significant events of lead migration/dislodgement, 
fracture, and loss of therapy corrected by revision surgery to the FDA and DSMB as soon as possible but 
in no event later than 10 working days. 
8.4.5 Reporting Serious Adverse Events and Serious Adverse Device Effects 
Investigators shall report SAEs and SADEs to the Sponsor, and to their reviewing IRB/ECs per the IRB/EC 
reporting requirements. Investigators are required to report SADEs to the Sponsor and their reviewing 
IRB as soon as possible but in no event later than 10 working days after the Investigator first learns of the 
effect, per 21 CFR 812.150. Per MDCG 2020-10/1, SAE and SADEs shall immediately be reported by the 
investigators, but no later than 2 calendar days after investigational site study personnel’s awareness of 
the event for reportable events which indicate an imminent risk of death, serious injury, or serious illness 
and that require prompt remedial action for other subjects, users or other persons or a new finding.  
Sponsor shall report any SAE that has a causal relationship with the investigational device or the 
procedure or where such causal relationship is possible, without any delay per applicable guidelines and 
local regulations. This is also applicable for any new findings in this category. Per MDCG 2020-10/1 these 
SAEs should be reported immediately, but not later than 7 calendar days following the date of 
awareness.  
8.5 
Sponsor Responsibilities 
The Sponsor is responsible for the classification of adverse events and ongoing safety evaluation of the 
clinical investigation and shall:  
A. Review all device deficiencies and determine and document in writing whether they could have 
led to a serious adverse device effect; in case of disagreement between the Sponsor and the 
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principal investigator(s), the sponsor shall communicate both opinions to concerned parties, as 
defined in b and c given below 
B. Report or ensure the reporting, to the Ethics Committees by the principal investigators(s), of all 
serious adverse events and device deficiencies that could have led to a serious adverse device 
effect, if required by the Ethics Committee. 
C. Report to regulatory authorities, within the required time period, all serious adverse events and 
device deficiencies that could have led to a serious adverse device effect, including serious 
health threat 
D. Inform all principal investigators in writing of all the serious adverse events at all investigation 
sites that have been reported to the Sponsor, and ensure that they are reported to their Ethics 
Committee, if required by the Ethics Committee: this information shall be sent to all the principal 
investigators within a time frame established based on the perceived risk as defined in the risk 
assessment (analysis and evaluation)  
E. Ensure that the Ethics Committees and the regulatory authorities are informed of significant new 
information about the clinical evaluation 
F. In case of serious adverse device effects and device deficiencies that could have led to serious 
adverse device effects, determine whether the risk analysis needs to be updated and assess 
whether corrective or preventive action is required.  
8.6 
Investigator Responsibilities 
The principal investigator shall: 
A. Record every adverse event and observed device deficiency, together with an assessment 
B. Report to the Sponsor, without unjustified delay, all serious adverse events and device 
deficiencies that could have led to a serious adverse device effect; this information shall be 
promptly followed by detailed written reports 
C. Report to the Ethics Committees serious adverse events and device deficiencies that could have 
led to a serious adverse device effect, if required by the Ethics Committee 
D. Report to regulatory authorities serious adverse events and device deficiencies that could have 
led to a serious adverse device effect, if required by the Ethics Committee 
Supply the Sponsor, upon Sponsor’s request, with any additional information related to the safety 
reporting of a particular event. 
 
 
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9 
SITE INITIATION ACTIVITIES 
9.1 
Investigator and Site Selection 
The Sponsor will assess potential investigators to ensure that they are experienced and have the 
necessary expertise. Investigators must have the ability to enroll an adequate number of subjects. 
The Sponsor will assess the site to ensure that it is equipped with adequate facilities for the study. The 
Sponsor will ensure that qualified personnel are available to conduct the study, including a designated 
research coordinator. 
Investigators must agree to comply with this protocol, all institutional review board requirements/ethics 
committee requirements, and all applicable laws and regulations. 
9.2 
Initiation Requirements 
Investigative sites may begin enrolling subjects after all initiation requirements are met and the Sponsor 
has given notice of approval to start. Initiation requirements include Institutional Review Board 
(IRB)/Ethics Committee (EC) approval of this protocol and the informed consent, training of all 
participating site personnel, a site initiation visit by the Sponsor, and submission of all required 
documents to the Sponsor. Required documentation includes IRB/EC approvals, curricula vitae (CVs), 
signed investigator agreements, conflict of interest/financial disclosure statements, documentation of 
site training, and any other documents requested by the Sponsor. 
9.3 
Site Training 
The Investigator Brochure (IB) will be provided to the principal investigator who shall acknowledge the 
receipt in writing. On-site training of investigators and site study personnel will be conducted by the 
Sponsor as part of the initiation activities. Training sessions may be tailored to fit site personnel’s roles in 
the study. The Sponsor will ensure adequate training is provided on the following: 
• 
Investigational device, principle of operation and system components 
• 
Device implant and explant procedures 
• 
Neuspera’s SNS System Instructions for Use 
• 
Protocol 
• 
Data collection and CRFs 
• 
Diary instructions for use 
• 
Investigator responsibilities 
• 
Device accountability 
• 
Good Clinical Practice 
 
 
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10 ETHICS 
10.1 
Ethics Review 
The final study protocol and written Informed Consent must be approved in writing by an IRB or EC, as 
applicable. The principal investigator is responsible for informing the IRB/EC of any amendments to the 
protocol in accordance with local requirements. In addition, the IRB/EC must approve all advertising used 
to recruit subjects to the study. The protocol must be re-approved by the IRB/EC annually, as local 
regulations require. 
Progress reports and notifications of serious, unexpected adverse events will be provided to the IRB/EC 
according to local regulations and guidelines. 
10.2 
Ethics Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the Declaration 
of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable regional regulatory 
requirements. 
10.3 
Written Informed Consent 
Written Informed Consent must be obtained prior to any study-related procedure. Electronic or written 
informed consent will be obtained in compliance with local regulations.  The Principal Investigator will 
ensure that proper informed consent is conducted, including ensuring the subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and benefits of the 
study.  Subjects will have appropriate time to review the Informed Consent, ask questions and will be 
provided with additional information as requested.  When new information becomes available during 
the study, subjects will be informed as needed.  Subjects must also be notified that they are free to 
discontinue/withdraw from the study at any time. The subject must be given the opportunity to ask 
questions and allowed time to consider the information provided.  
A copy of the consent document must be provided to the subject and the original signed consent 
document should be retained in the study records. Any modifications made to the informed consent 
form must be approved by the IRB/EC and Sponsor. 
10.4 
Subject Withdrawal 
A subject’s participation in the study is voluntary. Subjects may withdraw their consent from 
participation in the study at any time. Should a subject exit the study for any reason, the investigator will 
document the reason for study exit, if known and record in the study database. 
 
 
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11 DATA MANAGEMENT 
11.1 
Contract Support Groups 
Three external organizations have been retained to manage aspects of the SANS-UUI study.  
Fortrea, Inc. – Medical Device & Diagnostic Development 
8 Moore Drive 
Durham, North Carolina 27703, USA  
 
The Sponsor has identified an independent statistician at Fortrea a third-party to conduct the interim 
analysis. 
 
Axiom Real-Time Metrics  
5205 Satellite Dr.  
Mississauga, Ontario, Canada 
L4W 5P9 
 
Axiom, refer to as “the CRO” is responsible for overall study management including monitoring, study 
reports, Trial Master File, safety, and data management including management of the CEC and DSMB.  
Axiom will be providing and managing the EDC including all subject reported outcomes.   
 
AVANIA Europe -Bilthoven 
3723 MB Bilthoven 
The Netherlands 
+31 30 299 2727 
 
AVANIA is responsible for providing requirements to achieve ethics committee (EC) and competent 
authority (CA) approvals for the clinical trial in Canada and Europe. Avania reviews submissions prior to 
submitting to the EC and CA as well as manages all correspondence with the EC and CA on behalf of 
Neuspera as Neuspera’s local representative in Europe. 
 
The sponsor may retain additional contractors and/or replace the contractors listed above; a current list 
of the retained contractors will be maintained in the Manual of Operations. 
11.2 
Subject Identification 
Each subject will be assigned a unique identification code (ID) for the purpose of identity protection. Any 
subject names that may inadvertently appear on study documents submitted to the Sponsor will be 
redacted upon receipt. 
11.3 
Central Database 
All study documentation, not including subject data, will be collected, and stored using an electronic Trial 
Master File. The CRO will use appropriate quality control measures established to ensure accurate and 
complete transfer of information from the study documentation to the central database following 
internal Standard Operating Procedures. 
11.4 
Case Report Forms 
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An electronic data capture system will be used to collect subject data on case report forms.  The 
investigator is responsible for completing all appropriate sections of the CRFs and submitting them to the 
Sponsor in a timely manner. The investigator is also responsible for responding to queries from the 
Sponsor to clarify any pending questions about the data. 
11.5 
Protocol Deviations 
An Investigator is required to conduct this study in accordance with the signed Clinical Trial Agreement 
and Investigator Agreement, study protocol, regulatory requirements, Good Clinical Practice, Declaration 
of Helsinki, and any conditions of approval imposed by the reviewing IRB/EC and FDA. 
In accordance with applicable regulations, under emergency circumstances, deviations from the Clinical 
Investigational Plan to protect the rights, safety and well-being of human subjects may proceed without 
prior approval of the sponsor and the Investigational Review Board / Ethics Committee. Such deviations 
shall be documented and reported to the sponsor and the Investigational Review Board / Ethics 
Committee as soon as possible, but no later than five (5) working days after the emergency occurred. 
The investigator must document any deviation to this protocol using the appropriate CRF. Except in an 
emergency, prior approval by the Sponsor is required for an anticipated change in or deviation from the 
plan and if these changes or deviations could affect the scientific soundness of the plan or the rights, 
safety or welfare of human subjects, prior FDA and IRB/EC approval is also required. 
No waivers for deviations from the clinical investigation plan will be provided by the study sponsor.  
Waivers are strictly prohibited. 
11.6 
Corrective and Preventive Actions 
Neuspera or its representatives will evaluate deviations to the clinical investigation plan during 
monitoring visits. Individual event corrective and preventive actions may be recommended at that time. 
In addition, deviations occurring across investigational sites will be reviewed by Neuspera on a periodic 
basis to determine if more global preventive actions may be required.    
11.7 
Investigator Disqualification Criteria 
Neuspera reserves the right to terminate an investigator/investigational site for any of the following 
reasons: 
• 
Failure to secure subject informed consent including protection of personal data prior to 
enrollment 
• 
Failure to report safety events within 10 working days of discovery after learning of the event 
• 
Failure to report serious adverse device effects within 10 working days of discovery 
• 
Repeated investigational plan deviations 
• 
Repeated failure to appropriately complete case report forms 
 
• 
Failure to enroll an adequate number of subjects 
• 
Loss of or unaccounted for investigational product inventory 
11.8 
Site Noncompliance 
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Protocol deviations will be closely monitored. If unacceptable deviations, repeated deviations, or other 
compliance problems are noted, the Sponsor reserves the right to suspend study enrollment or 
discontinue study enrollment at that site until a sufficient system is in place to reduce further deviations 
and ensure compliance.   
11.9 
Data Processing and Management 
Data will be reviewed manually and electronically for accuracy and completeness. Standard checks such 
as range checks will be incorporated into the central database.  Queries will be issued to resolve data 
discrepancies. Study monitoring will be conducted to ensure that the site is submitting complete and 
accurate data, and to verify source data.  The CRO will use appropriate quality control measures 
established to finalize and lock the database following internal Standard Operating Procedures. 
 The CRO maintains Standard Operating Procedures for CRF tracking, data review, database cleaning, and 
issuing and resolving queries.   The CRO maintains timely and reliable processes for recording data and 
rectifying errors and omissions, medical coding uniformity and reconciliation to ensure delivery of a 
quality database to support the implementation of the planned analyses.  These systems maintained by 
the CRO are also supported by the study Data Management Plan and the Clinical Management Plan.   
11.10  Data Protection 
11.10.1 
Subjects Enrolled in the US  
In accordance with the Health Portability and Accountability Act (HIPAA), the written Informed Consent 
Form must include a subject authorization to release medical information to the study Sponsor and/or 
allow the Sponsor or their designate, a regulatory authority, or IRB/EC access to subject’s medical 
information that includes all hospital records relevant to the study, including subjects’ medical history. 
11.10.2 
Subjects Enrolled in Canada 
In accordance with the Personal Information Protection and Electronic Document Act (PIPEDA). The 
written Informed Consent Form must include collection, use and disclosure of personal information.  
Subjects must be provided clear information explaining what organizations are doing with their 
information.  Therefore, the written Informed Consent Form must include a subject authorization to 
release medical information to the study Sponsor and/or allow the Sponsor or their designate, a 
regulatory authority, or IRB/EC access to subject’s medical information that includes all hospital records 
relevant to the study, including subjects’ medical history. 
11.10.3 
Subjects Enrolled in Europe 
Data protection will be ensured in accordance with Regulation (EU) 2016/679 (General Data Protection 
Regulation, GDPR). Personal data shall be:  
• 
processed lawfully, fairly and in a transparent manner in relation to the data subject (‘lawfulness, 
fairness and transparency’);  
• 
collected for specified, explicit and legitimate purposes and not further processed in a manner 
that is incompatible with those purposes; further processing for archiving purposes in the public 
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interest, scientific or historical research purposes or statistical purposes shall, in accordance with 
Article 89(1), not be considered to be incompatible with the initial purposes (‘purpose 
limitation’);  
• 
adequate, relevant and limited to what is necessary in relation to the purposes for which they 
are processed (‘data minimization’);  
• 
accurate and, where necessary, kept up to date; every reasonable step must be taken to ensure 
that personal data that are inaccurate, having regard to the purposes for which they are 
processed, are erased or rectified without delay (‘accuracy’);  
• 
kept in a form which permits identification of data subjects for no longer than is necessary for 
the purposes for which the personal data are processed; personal data may be stored for longer 
periods insofar as the personal data will be processed solely for archiving purposes in the public 
interest, scientific or historical research purposes or statistical purposes in accordance with 
Article 89(1) subject to implementation of the appropriate technical and organizational 
measures required by this Regulation in order to safeguard the rights and freedoms of the data 
subject (‘storage limitation’);  
• 
processed in a manner that ensures appropriate security of the personal data, including 
protection against unauthorized or unlawful processing and against accidental loss, destruction, 
or damage, using appropriate technical or organizational measures (‘integrity and 
confidentiality’). 
11.11   
Confidentiality and Protection of Study Files 
All information and data concerning subjects and their participation in this study will be considered 
confidential. Only authorized personnel will have access to confidential files. Passwords will be issued for 
Sponsor personnel to ensure confidentiality and protection of electronic data. Hard copy data will be 
stored in a locked file. No data will show subject names. 
11.12   
Monitoring 
The Sponsor will be responsible for monitoring at each site to ensure adequate protection of the rights 
and safety of study subject, and to verify the quality and integrity of the data collected and submitted. 
The Sponsor will identify and train qualified personnel to conduct monitoring visits. Monitoring will 
consist of review of subject records, source documents, and other required documentation, including 
IRB/EC approvals and correspondence. 
Monitors will conduct site visits to ensure accuracy of data, timeliness of data submission, adequate 
subject enrollment, compliance with applicable laws and regulations, compliance with this protocol, 
compliance with the signed investigator agreement, and compliance with IRB/EC conditions and 
guidelines. Any noncompliance with these items that is not adequately addressed by the investigator is 
cause for the Sponsor to put the investigator on probation or withdraw the investigator or site from the 
study. 
The site staff must be available to meet with the monitor or other Sponsor representative during 
monitoring visits. The investigator must allow monitoring by the Sponsor and its authorized 
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representatives and any other local governmental body to review the study subjects’ medical records, 
including any test or laboratory data. 
Frequency of monitoring will be based on enrollment, study duration, site compliance, and any 
suspected inconsistency in data that requires investigation.  During the COVID-19 pandemic monitoring 
visits may be conducted remotely. 
11.13   
Audits and Inspections 
Audits of the study sites may be performed by the Sponsor or designee, independent of and separate 
from routine monitoring or quality control functions, to evaluate study conduct and compliance with the 
study protocol, applicable regulatory requirements, GCP, Declaration of Helsinki, and any conditions of 
approval imposed by the reviewing IRB and FDA. 
The FDA or other regulatory agencies may perform inspections of the study sites before, during or after 
the conclusion of the study. The investigator shall contact the Sponsor immediately upon notification of 
inspection and must fully cooperate with the regulatory agency by permitting inspections at reasonable 
times and in a reasonable manner. 
11.14   
Access to Study Records 
The Investigator must permit monitoring and auditing by the Sponsor or designee, and inspection by the 
appropriate regulatory authorities, and provide direct access to all requested study-related records. 
11.15   
Record Retention 
The investigator and Sponsor shall maintain the required records during the investigation and for a 
period of 2 years, or country specific reporting requirement if different than 2 years, after the latter of 
either the completion/termination of the study or the date the Neuspera Implantable SNS System 
receives market approval for the indication being studied.  
The clinical investigation will be conducted in Canada. Canada Food and Drug Regulation requires the 
sponsor to maintain all trial related records for a period of 15 years.  
As the investigation will be conducted at centers in Europe, consistent with the new European medical 
device requirements, documentation shall be kept for a period of at least 15 years after the clinical 
investigation with the device has ended or in the event that the device is subsequently placed on the 
market, at least 15 years after the last device has been placed on the market.   
An investigator or Sponsor may withdraw from the responsibility to maintain records for the period 
required and transfer custody of the records to any other person who will accept responsibility for them. 
The investigator’s study records may be discarded only upon approval from the Sponsor. The 
investigator must contact the Sponsor before destroying any records pertaining to the study to ensure 
that they no longer needed to be retained. 
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12 RESPONSIBILITIES 
This study will be performed in conformance with this protocol and all applicable laws and regulations. 
12.1 
Investigator Responsibilities 
12.1.1 Coordinating Investigator  
The sponsor will assign one investigator in the trial as the Coordinating Investigator.  This investigator is 
assigned the responsibility for the coordination of investigators at the different centers participating in 
the trial. These responsibilities may include but are not limited to: 
• 
Meeting regularly with the sponsor to review progress in the trial 
• 
Review clinical management issues which may involve correspondence with one of the clinical 
investigators 
• 
Review inclusion / exclusion criteria for potential trial participants as needed 
• 
Review and provide consultation on individual adverse events 
• 
Review and provide consultation on the clinical protocol, case report forms, informed consent, 
investigator’s brochure  
• 
Review and provide consultation on clinical and regulatory submissions 
12.1.2 Investigator Responsibilities for Centers Participating in the Clinical Trial 
The Investigator is responsible for ensuring the study is conducted according to the signed Clinical Trial 
Agreement (CTA)/Investigator Agreement (IA), study protocol, regulatory requirements, GCP, 
Declaration of Helsinki, and any conditions of approval imposed by the reviewing IRB and FDA; for 
protecting the rights, safety, and welfare of subjects under the Investigator's care; and for the control of 
devices under investigation.  An investigator also is responsible for ensuring that informed consent is 
obtained in accordance with the regulations. 
12.1.3 Specific Responsibilities of Investigators 
Awaiting approval. An investigator may determine whether potential subjects would be interested in 
participating in an investigation, but shall not request the written informed consent of any subject to 
participate, and shall not allow any subject to participate before obtaining IRB and FDA approval. 
Compliance. An investigator shall conduct an investigation in accordance with the signed agreement 
with the sponsor, the investigational plan, 21 CFR part 812 and other applicable FDA regulations, and any 
conditions of approval imposed by an IRB or FDA. 
Supervising device use. An investigator shall permit an investigational device to be used only with 
subjects under the investigator's supervision. An investigator shall not supply an investigational device to 
any person not authorized under 21 CRF part 812 to receive it. 
Disposing of device. Upon completion or termination of a clinical investigation or the investigator's part 
of an investigation, or at the sponsor's request, an investigator shall return to the sponsor any remaining 
supply of the device or otherwise dispose of the device as the sponsor directs. 
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12.1.4 Investigator Agreement and Financial Disclosure 
The Principal Investigator at each site will be required to sign the Investigator’s Agreement, as per 
applicable regulations. 
In addition, in accordance with regulations, all investigators will be required to sign a Financial Disclosure 
form, which discloses the Investigator’s and his/her immediate family’s financial interests and 
arrangements with Neuspera.  Investigators must inform the Sponsor of any changes to the information 
within the financial disclosure throughout the course of the study and for a period of two years after the 
device is approved by the FDA or the study is terminated, whichever is later. 
12.1.5 Investigator Records 
Participating investigators will maintain in the study site’s essential study files accurate, complete and 
current records relating to the investigator’s participation:  
• 
Study protocol and all amendments 
o with documents showing the dates of and reasons for each deviation from the protocol. 
• 
Signed Investigator Agreement for the Principal Investigator 
• 
Signed Financial Disclosure for all investigators 
• 
IRB/EC approval letters(s) including approved consent and HIPAA authorization form(s), and 
subject materials 
• 
IRB membership list(s) or Letter of Assurance 
• 
All correspondence with another investigator, an IRB or EC, sponsor, a monitor, FDA or 
regulatory authority, including required reports.  
• 
Curriculum Vitae (CV) for all investigators 
• 
Training documentation 
• 
Delegation of Authority 
• 
Investigational device accountability records including date of receipt, quantity, lot/serial 
numbers of all devices, device use and final disposition of the device. 
• 
Why and how many units of the device have been returned to the sponsor, repaired, or 
otherwise disposed of 
• 
Names of all persons who received, used, or disposed of each device.  
The following records must be maintained for each subject enrolled in the study: 
• 
Signed informed consent form and Authorization for the Use and Disclosure of Health 
Information. The case history for each individual shall document that informed consent was 
obtained prior to participation in the study. 
• 
For any use of a device by the investigator without informed consent, any written concurrence of 
a licensed physician and a brief description of the circumstances justifying the failure to obtain 
informed consent.  
• 
Case report forms and supporting documentation  
• 
AEs and any supporting documentation 
• 
Medical history, physical exams and results of diagnostic tests 
• 
Information regarding exposure to the device 
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• 
Protocol deviations 
• 
Source documentation: complete medical records, including procedure reports, professional 
notes, radiographic images, etc. 
12.1.6 Investigator Reports 
Investigators are required to prepare and submit the following complete, accurate, and timely reports: 
• 
An investigator shall submit to the Sponsor and to the reviewing IRB/EC a report of any 
UADE/USADE occurring during an investigation as soon as possible, but in no event later than 10 
working days after the investigator first learns of the effect. 
• 
The investigator shall report initially (and any new findings) to the sponsor any device deficiency 
that might have led to a serious adverse event if appropriate action had not been taken, 
intervention had not occurred, or circumstances had been less fortunate. 
• 
An investigator shall report to the Sponsor, within 5 working days, a withdrawal of approval by 
the reviewing IRB/EC of the investigator’s part of an investigation. 
• 
An investigator shall submit progress reports on the investigation to the sponsor, the monitor, 
and the reviewing IRB at regular intervals, but in no event less often than yearly. 
• 
An investigator shall notify the Sponsor and the reviewing IRB of any deviation from the 
investigational plan to protect the life or physical well-being of a subject in an emergency.  Such 
notice shall be given as soon as possible, but in no event later than 5 working days after the 
emergency occurred. Except in such an emergency, prior approval by the Sponsor is required for 
changes in or deviations from a plan, and if these changes or deviations may affect the scientific 
soundness of the plan or the rights, safety, or welfare of human subjects, prior FDA and IRB/EC 
approval in accordance with applicable regulations also is required. 
• 
If an investigator uses a device without obtaining prior informed consent, the investigator shall 
report such use to the Sponsor and reviewing IRB/EC within five (5) working days after the use 
occurs. 
• 
An investigator shall, within 3 months after termination or completion of the investigation or the 
investigator’s part of the investigation, submit a final report to the Sponsor and the reviewing 
IRB. 
• 
An investigator shall, upon request by a reviewing IRB/EC or FDA, provide accurate, complete 
and current information about any aspect of the investigation. 
 
12.1.7 Investigator Contact Information 
The CRO maintains a Neuspera Study Contacts list that contains information on each investigational site 
including the coordinating investigator, the address details for each investigational site and the contact 
information for the principal investigator at each site.  This information will be stored in the electronic 
trial master file Clinical Trial Management System. This information is accessible for reporting serious 
adverse events and serious adverse device effects. 
 
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12.2 
Sponsor Responsibilities 
Neuspera Medical Inc. is the Sponsor of this study and is responsible for selecting qualified investigators 
and providing them with the information they need to conduct the study properly, ensuring proper 
monitoring of the study, ensuring that IRB review and approval are obtained, submitting an IDE 
application to FDA, and ensuring that any reviewing IRB and FDA are promptly informed of significant 
new information about the study. Sponsor responsibilities include, but are not limited to, the following: 
• 
Select and qualify investigative sites and principal investigators 
• 
Provide training to investigators and investigative site staff 
• 
Ensure approval/permission from FDA 
• 
Select qualified monitors and ensure that adequate monitoring of clinical data occurs at the 
study sites 
• 
Retain ownership of all data generated in this study, and control the use of the data for 
appropriate purposes only 
• 
Collaborate with investigators on publishing study results 
12.2.1 Sponsor Representatives 
Sponsor representatives may participate in the conduct of the study to the extent described in this 
protocol. Participation in the study will be limited to Sponsor personnel who are appropriately trained. 
Sponsor representative’s tasks may include: 
• 
Provide training to the investigator and study staff. 
• 
Clarifying device behavior, operation, and output 
• 
Provide technical support and direction during the Neuspera Implantable SNS System implant 
and explant procedures including operating the external stimulator for the Neuspera system 
during intraoperative testing under the direction of the investigator, and address procedure and 
device questions. 
• 
Device Parameter/Download – download information from the Wireless Transmitter to the 
Neuspera device database 
• 
Be available (in person or on the phone) during subject follow-up visits to provide technical 
support on programming and use of the Neuspera SNS system.  
 
At no point shall personnel from the Sponsor: 
• 
Practice medicine 
• 
Provide medical diagnosis or treatment to subjects  
• 
Discuss a subject’s condition or treatment with a subject without the oversight of a healthcare 
professional 
 
 
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12.3 
Physician Review Panel 
A Physician Review Panel experienced in the implant of sacral neuromodulation devices will be 
established. The panel will consist of at least two physicians.  The physicians may or may not be 
investigators in the trial. The physicians will review all required study eligibility data prior to making a 
recommendation on subjects for implant in the trial.  Reviews will be divided among the physicians.  
Investigators in the trial may not review subjects from their own center.  The Physician Review Panel 
operations will be formalized in a charter. 
12.4 
Clinical Events Committee (CEC) 
An independent Clinical Events Committee (CEC) will be established. The CEC will consist of clinicians 
who are not investigators in the study and who do not have any significant investment in the Sponsor or 
its competition. At least three clinicians will serve on the CEC. 
The CEC will be responsible for reviewing and classifying all adverse events, including deaths. Adverse 
events will be reviewed for causality and seriousness.  
The CEC will meet periodically throughout the study. CEC operations will be formalized in a CEC charter. 
The CEC will review all adverse events and adjudicate causality and seriousness. The definitions to be 
used during the adverse event review and classification process are outlined in the study protocol. If the 
CEC adjudication is different than what was documented by the investigator there will be a notification 
to the investigator.  The adjudication of the CEC will be used for the final classification of events. 
The adjudication decision of the CEC will be used for the final classification of events, including 
relatedness to the study procedures and/or the investigational device, for the determination of safety 
endpoints and for all regulatory reports, product labeling, and publications or presentations.  
The CEC will also be responsible for reviewing post implant neurostimulator images, following the image 
review by the implanting physician, to determine if movement has occurred. If the CEC assesses that 
movement has occurred, that has not been documented by the implanting physician, there will be 
follow-up discussion with the implanting physician and CEC facilitated by the sponsor or CRO.  If final 
disagreement between the CEC members, or if there is disagreement between the implanting physician 
and the CEC, the DSMB will be notified for final assessment.  
12.5 
Data Safety Monitoring Board (DSMB) 
An independent DSMB has been established.  Members are not investigators in the study and all 
members do not have any significant investment in the Sponsor or its competition.   
The DSMB has reviewed all safety data, has provided recommendations on the daily stimulation duration 
that are consistent with the Phase II trial design, and supports the trial expansion to the pivotal Phase II.  
The DSMB will continue to monitor safety data in Phase I of the trial and also Phase II. The DSMB will 
meet following the implant of approximately every 36 subjects during Phase II of the study until 
completion of the 120 attempted implants.  The DSMB may meet more frequently if determined 
necessary by the Sponsor, CRO or FDA based on adverse event rates, stopping rules and perceived risk of 
the study device and procedures in Phase I and II.  Phase II study stopping rules based on event rates for 
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fractures, dislodgements/migrations and surgical revisions will be monitored by the DSMB following 
guidance presented in Study Stopping Rules for Phase II (Section 6.4). The DSMB report and meeting 
minutes will be provided to the FDA after each DSMB meeting.  Enrollment in Phase II of the trial will 
continue unless one of the study stopping rules is met or the DSMB or FDA makes a recommendation to 
stop the enrollment and implantation of new subjects in the clinical trial. 
DSMB will make the final review assessment of radiological images assessed by the CEC for movement if 
there is a disagreement between CEC members, or if there is disagreement between the implanting 
physician and the CEC.  
DSMB operations are formalized in a DSMB charter.   
12.6 
Publications Committee 
The Sponsor may form a publications committee to make decisions regarding authorship and content of 
publications. Neuspera’s criteria for authorship may include involvement in the design and development 
of the clinical trial, enrollment of subjects, quality of data, experience with authorship and presentation 
at major journals and congresses, respectively. Publication of clinical data will conform to standards set 
forth in peer-reviewed journals and Uniform Requirements for Manuscripts Submitted to Biomedical 
Journal published by the International Committee of Medical Journal Editors (ICMJE).  All publications 
must be reviewed and approved in advance by the Sponsor.  Publication timing will occur as early as 
within one year of study completion. Publication during the duration of the trial is forbidden without 
review and agreement by the publication committee. 
 
 
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13 STUDY MATERIAL AND PRODUCT 
13.1 
Shipping 
An initial supply of the investigational products will be shipped to the investigational site when the site is 
approved by the Sponsor after all requirements, such as IRB/EC approval, are completed. Resupply of 
investigational products during the study will be facilitated by the Sponsor, and/or designate. 
13.2 
Labeling 
Labeling of the investigational devices will be performed in accordance with Good Manufacturing 
Practices (GMP) for Medical Devices of the Quality System Regulations (QSR). The devices will be labeled 
with the statement “CAUTION: Investigational device. Limited by Federal (or United States) to 
investigational use. Exclusively for Clinical Investigations.”  
Information on the investigational device label will indicate the identity, quantity, and storage 
conditions. 
13.3 
Storage 
All investigational devices must be kept in a secure place under appropriate storage conditions. A 
description of the appropriate storage and shipment conditions will be specified on the device label 
and/or the appropriate Instructions for Use (IFU). The stored device supplies must be accessible to 
authorized staff only. The storage area must also have adequate control of temperature in order to 
maintain stability of the device supplies, according to the appropriate IFU. The investigational devices 
should be stored in the original pack until use. For further information, investigators should refer to the 
investigational device label and/or appropriate IFU. 
13.4 
Product Accountability 
Sponsor description of procedures for accountability of investigational devices is outlined in the 
Neuspera Study Device Management Plan and SOP on Investigational Device Accountability. Access to 
investigational devices shall be controlled and the investigational devices shall be used only in the clinical 
investigation and according to the Clinical Investigational Plan. The sponsor shall keep records to 
document the physical location of all investigational devices from shipment of investigational devices to 
the investigation sites until return or disposal. The sponsor shall have instructions in place and make 
packaging materials available, if applicable, for the safe return or disposal of investigational devices, 
including potentially hazardous devices. The principal investigator or an authorized designee shall keep 
records documenting the following: 
a) name(s) of person(s) who received, used, returned, or disposed of the device; 
b) the date of receipt, identification, and quantity of each investigational device (i.e., batch 
number/serial number or unique code); 
c) the expiry date, if applicable; 
d) the date or dates of use; 
e) subject identification; 
f) date on which the investigational device was returned/explanted from subject, if applicable; 
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g) the date of return of unused, expired, or malfunctioning investigational devices, if applicable; 
h) the date and documentation of disposal of the investigational devices as per instructions of the 
sponsor, if applicable. 
 
All explanted devices must be returned to the Sponsor. Subjects may dispose of used custom 
undergarments or Wearable at their discretion.  At study closeout, the Sponsor will collect all unused 
devices.   
 
 
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14 STUDY AMENDMENTS AND CLOSURE 
14.1 
Amendments to the Protocol 
Any amendments to the study protocol will be clearly documented and approved by the Sponsor and the 
IRB/EC prior to implementation. Appropriate training will be completed on the study protocol 
amendment. 
14.2 
Suspension or Early Termination 
The Sponsor reserves the right to suspend or terminate the study at an individual study site or entirely at 
any time. Suspension or early termination of a study site may occur due to serious or repeated non-
compliance on the part of an investigator. There are no criteria for termination of the clinical 
investigation on statistical grounds. 
Reasons for suspension or early termination of the entire study may include, but are not limited to, the 
following: 
The incidence and seriousness of AEs in this or other studies indicates a potential health hazard to 
subjects; 
New information on efficacy from this or other studies 
In the event of suspension or early termination, the Sponsor will promptly inform principal investigators 
and ensure that IRB/ECs are notified of the stoppage and the reason for it. Subjects must continue to be 
followed per the protocol unless there is other direction from the Sponsor. If the trial is terminated, the 
sponsor will notify the FDA and all reviewing IRBs within 30 days. The sponsor will submit a final report 
to the FDA and all reviewing IRBs and participating investigators within 6-months after termination of 
the investigation. 
Suspension or (Early) Termination language in the Clinical Trial Agreement for clinical sites in Canada and 
the EU will supersede the wording listed in this section. 
14.3 
Routine Closeout 
At the end of the study, routine closeout activities will be conducted to ensure site records are complete, 
study data are complete and accurate, remaining study materials and investigational devices are 
returned to the Sponsor, arrangements are made for record retention, and IRB/ECs are notified. 
14.4 
Final Study Report 
At the completion of the trial, the sponsor will notify the FDA and all reviewing IRBs within 30 days.  The 
sponsor will submit a final report to the FDA and all reviewing IRBs and participating investigators within 
6-months after completion of the investigation. 
 
 
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15 CLINICAL TRIALS REGISTRY (CLINICALTRIALS.GOV) 
This study will be registered on www.clinicaltrials.gov and the results will be made public through the 
website. Study Results will be submitted as required. Per the regulatory requirements, the informed 
consent form will contain a statement that the clinical trial information will be entered into this registry.  
 
 
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16 STATEMENTS OF COMPLIANCE 
This clinical investigation will be conducted in compliance with the principles that have their origin in the 
latest version of the Declaration of Helsinki, this clinical investigation plan, requirements of the 
approving Ethics Committees, ISO 14155, MDD 93/42/EEC Annex X – Clinical Evaluation, AIMDD 
90/385/EEC, Regulation (EU) 2017/745 of the European Parliament and of the Council Article 120.11 (EU 
Medical Device Regulation), United States Food and Drug Administration Code of Federal Regulations 
Title 21 Parts 11, 50, 54, 56, 58 and 812 and other applicable regulatory requirements whichever 
provides the greater protection of the individual.  
This clinical investigation will not be initiated until approval has been obtained from the applicable Ethics 
Committees. Any requirements imposed by the applicable Ethics Committees will be followed. No 
deviation from the clinical investigation will be implemented without the prior review and approval of 
the applicable Ethics Committees except where it may be necessary to eliminate an immediate hazard to 
a subject. In such case, the deviation will be reported to the applicable Ethics Committees in accordance 
with their specific reporting policies and procedures.  
A human subject insurance will be secured prior to the start of the clinical investigation.  
 
 
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17 VULNERABLE POPULATION 
The subject population of this clinical investigation does not meet the criteria for a vulnerable population 
as defined in ISO 14155, Section 3.55 and ICH-GCP, Section 1.61. If a subject loses ability to consent 
during the course of the clinical investigation, this will lead to study exit. Such subjects will be followed 
for safety for the course of the study, but their data will not be used for data analysis. 
 
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18 BIBLIOGRAPHY  
1. Irwin DE, Kopp ZS, Agatep B, Milsom I, Abrams P. Worldwide prevalence estimates of lower 
urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. 
BJU Int 2011 Oct; 108:1132-1138 
2. Kobelt G, Kirchberger I, Malone-Lee J. Review. Quality-of-life aspects of the overactive bladder 
and the effect of treatment with tolterodine. BJU Int 1999;  83:583–90 
3. Lightner DJ, Gomelsky A, Souter L et al: Diagnosis and treatment of overactive bladder (non-
neurogenic) in adults: AUA/SUFU Guideline amendment 2019. J Urol 2019; 202: 558.  .   
4. Siegel  S, Noblett K, Mangel J, Griebling TL, Sutherland SE, Bird ET, Comiter C, Culkin   D, Bennett 
J, Zylstra S, Berg KC, Kan F, Irwin CP. Results of a prospective, randomized, multicenter study 
evaluating sacral neuromodulation with InterStim therapy compared to standard medical 
therapy at 6-months in subjects with mild symptoms of overactive bladder. Neurourol Urodyn. 
2015 Mar;34(3):224-30 
5. Siegel S, Noblett K, Mangel J, Bennett J, Griebling TL, Sutherland SE, Bird ET, Comiter   C, Culkin 
D, Zylstra S, Kan F, Berg KC. Five-Year Follow-up Results of a Prospective, Multicenter Study of 
Patients with Over Active Bladder Treated with Sacral Neuromodulation. Journal of Urology. 
2018 Jan;199(1):229-236 
6. Mc Crery, R., et al., Treatement of Urinary Urgency Incontinence Using a Rechargeable SNM 
System: 6-Month Results of the ARTISAN-SNM Study. The Journal of Urology, 2020. 203:p.1-8. 
7. Benson, K., et al., One-year outcomes of the ARTISAN-SNM study with the Axonics System for 
the treatment of urinary urgency incontinence. Neurology and Urodynamics, 2020. 39: p.1482-
1488. 
8. Coyne, K., et al., Determining the importance of change in the overactive bladder questionnaire. 
Journal of Urology. 2006: Aug; 176(2):627-32. 
9. Herbison GP, Arnold EP. Sacral neuromodulation with implanted devices for urinary storage and 
voiding dysfunction in adults. Cochrane Database Syst Rev 2009 Apr 15;(2):CD004202. 
10. Medtronic 2020 Neuromodulation Product Performance Report. 
https://www.medtronic.com/content/dam/medtronic-com/products/product-performance/ppr-
reports/2020-neuromodulation-product-performance-report-combined.pdf?bypassIM=true 
11. Goldman,et al.International Continence Society best practice statement for use of sacral 
neuromodulation. Neurourology and Urodynamics, 2018;37:1823-1848. 
12. Dindo, D., Demartines, N., and Dlavien, PA. Classification of Surgical Complications A New 
Proposal with Evaluation in a Cohort of 6336 Patients and Results of a Survey. Annals of Surgery. 
2004;240(2):205-213. 
13. Mitropoulos, D., Artibani, W., Graefen, M., Remzi, M., Roupret, M., Truss, M.C., Guidelines on 
Report and Grading of Complications after Urological Surgical Procedures. European Association 
of Urology 2016. Retrieved from: https://uroweb.org/wp-content/uploads/2016-Reporting-
Complications.pdf 
 
 
 
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19 APPENDIX A: PHASE I SUB-STUDY 
 
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