Evaluation of Implantable Tibial Neuromodulation Pivotal Study
Phase: NA
Conditions: Overactive Bladder
Sponsor: MedtronicNeuro

Evaluation of Implantable Tibial Neuromodulation Pivotal Study (TITAN 2) 
Clinical Investigational Plan Version 4.0 
18-Jul-2022 
NCT05226286 

TITAN 2 Pivotal Study Clinical Investigation Plan 
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Clinical Investigation Plan 
Clinical Investigation Plan/Study Title Evaluation of Implantable Tibial 
Neuromodulation (TITAN 2) Pivotal Study 
Clinical Investigation Plan Identifier MDT20061 
Study Product Name Tibial Neuromodulation (TNM) System 
Sponsor Medtronic, Inc. 
Neuromodulation  
7000 Central Ave NE 
Minneapolis, MN 55432 USA 
Document Version 4.0 
Version Date 18-July-2022
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of 
Medtronic. Any distribution, copying, or disclosure without the prior written authorization of 
Medtronic is strictly prohibited. Persons to whom the information is disclosed must know that it is 
confidential and that it may not be further disclosed by them. 

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1. Investigator Statement and Signature Page 
Participating investigators will be provided with a separate investigator agreement to document their 
obligations and commitment with respect to study conduct. 
 
 
 

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Table of Contents 
1. 
Investigator Statement ...................................................................................................... 2 
Table of Contents ...................................................................................................................... 3 
2. 
Glossary .............................................................................................................................. 8 
3. 
Synopsis ........................................................................................................................... 11 
4. 
Introduction ..................................................................................................................... 22 
4.1 Background ........................................................................................................................ 22 
4.1.1 
Overactive Bladder Syndrome ............................................................................................ 22 
4.1.2 
Tibial Neuromodulation ...................................................................................................... 22 
4.2 Purpose .............................................................................................................................. 23 
5. 
Objectives and Endpoints ................................................................................................. 23 
5.1 Objectives .......................................................................................................................... 23 
5.1.1 
Primary Objective ................................................................................................................ 23 
5.1.2 
Secondary Objectives .......................................................................................................... 24 
 
 ...........................................................................................................
 
6. 
Study Design .................................................................................................................... 24 
6.1 Duration ............................................................................................................................. 25 
6.2 Rationale ............................................................................................................................ 25 
7. 
Product Description.......................................................................................................... 25 
7.1 General .............................................................................................................................. 25 
7.1.1 
TNM Neurostimulator ......................................................................................................... 26 
7.1.2 
Programming Subsystem .................................................................................................... 27 
7.1.3 
Wireless Recharger Subsystem ........................................................................................... 27 
7.1.4 
Study Aids ............................................................................................................................ 28 
7.2 Manufacturer ...................................................................................................................... 28 
7.3 Packaging ........................................................................................................................... 28 
7.4 Intended Population ............................................................................................................ 28 
7.5 Product Use ........................................................................................................................ 28 
7.6 Product Training Materials .................................................................................................... 29 
7.7 Product Receipt and Tracking ............................................................................................... 29 
7.8 Product Storage .................................................................................................................. 29 

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7.9 Product Return .................................................................................................................... 29 
7.10 Product Accountability ......................................................................................................... 30 
8. 
Study Site Requirements ................................................................................................. 30 
8.1 Investigator/Investigation Site Selection ................................................................................ 30 
8.2 Study Site Activation............................................................................................................ 30 
8.3 Role of the Sponsor Representatives ..................................................................................... 31 
9. 
Selection of Subjects ........................................................................................................ 32 
9.1 Study Population ................................................................................................................. 32 
9.2 Subject Enrollment .............................................................................................................. 32 
9.3 Inclusion Criteria ................................................................................................................. 32 
9.4 Exclusion Criteria................................................................................................................. 33 
10. 
Study Procedures .......................................................................................................... 35 
10.1 Schedule of Events .............................................................................................................. 36 
10.2 Data Collection .................................................................................................................... 49 
10.3 Scheduled Follow-up Visit Windows ...................................................................................... 50 
10.4 Subject Screening ............................................................................................................... 50 
10.5 Prior and Concomitant Medications/Therapies ........................................................................ 51 
10.6 Subject Consent .................................................................................................................. 51 
10.7 Device Programming ........................................................................................................... 53 
10.8 Device Explants ................................................................................................................... 53 
10.9 Assessment of Efficacy ........................................................................................................ 54 
10.10 
Assessment of Quality of Life ........................................................................................ 54 
10.11 
Assessment of Safety ................................................................................................... 55 
10.12 
Recording Data ............................................................................................................ 55 
10.13 
Deviation Handling ....................................................................................................... 56 
10.14 
Subject Exit, Withdrawal or Discontinuation .................................................................... 57 
10.14.1 Study Exit ............................................................................................................................. 58 
10.14.2 Study Completed ................................................................................................................. 59 
11. 
Risks and Benefits ........................................................................................................ 59 
11.1 Potential Risks .................................................................................................................... 59 
11.2 General Study Risk/Inconveniences....................................................................................... 60 
11.3 Risk Minimization ................................................................................................................ 60 

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11.4 Potential Benefits ................................................................................................................ 61 
11.5 Risk-Benefit Rationale .......................................................................................................... 61 
11.6 Risk Determination .............................................................................................................. 62 
12. 
Adverse Events and Device Deficiencies ...................................................................... 62 
12.1 Adverse Events ................................................................................................................... 62 
12.2 Device Deficiency ................................................................................................................ 63 
12.3 Processing Updates and Resolution ....................................................................................... 64 
12.4 Definitions/Classifications ..................................................................................................... 64 
12.5 Reporting of Adverse Events ................................................................................................ 70 
12.5.1 
Adverse Event and Device Deficiency Classification ........................................................... 70 
12.5.2 
Adverse Event and Device Deficiency Reporting Requirements ........................................ 71 
12.6 Subject Death ..................................................................................................................... 73 
12.7 Product Complaint Reporting ................................................................................................ 74 
13. 
Data Review Committees ............................................................................................. 74 
13.1 Clinical Events Committee Review ......................................................................................... 74 
13.2 CRO ................................................................................................................................... 75 
14. 
Statistical Design and Methods .................................................................................... 75 
14.1 General Aspects of Analysis .................................................................................................. 75 
14.1.1 
Analysis Sets ........................................................................................................................ 76 
14.1.2 
Handling Missing Data ........................................................................................................ 76 
14.1.3 
Multiplicity Adjustments ..................................................................................................... 77 
14.1.4 
Study Site Pooling ............................................................................................................... 78 
14.1.5 
Diary Data Analysis .............................................................................................................. 79 
14.2 Analysis Execution ............................................................................................................... 80 
14.3 Interim Analysis .................................................................................................................. 80 
14.4 Primary Objective ................................................................................................................ 80 
14.4.1 
Primary Objective – UUI Responder Rate ........................................................................... 80 
14.5 Secondary Objective(s) ........................................................................................................ 82 
14.5.1 
Secondary Objective – UI Change ....................................................................................... 82 
14.5.2 
Secondary Objective – UF Change ...................................................................................... 83 
14.5.4 
Secondary Objective – OAB-q Change ................................................................................ 86 

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 ............................................................................................................ 
 
14.7 Sample Size Determination .................................................................................................. 89 
14.8 Minimization of Bias ............................................................................................................. 89 
14.9 Safety Evaluation ................................................................................................................ 90 
15. 
Ethics ............................................................................................................................ 90 
15.1 Statement(s) of Compliance ................................................................................................. 90 
16. 
Study Administration .................................................................................................... 91 
16.1 Monitoring .......................................................................................................................... 91 
16.1.1 
Monitoring Visits ................................................................................................................. 92 
16.2 Data Management ............................................................................................................... 92 
16.3 Direct Access to Source Data/Documents .............................................................................. 93 
16.4 Confidentiality ..................................................................................................................... 93 
16.5 Liability .............................................................................................................................. 94 
16.6 CIP Amendments ................................................................................................................ 94 
16.7 Record Retention ................................................................................................................ 94 
16.7.1 
Investigator Records ........................................................................................................... 95 
16.7.2 
Sponsor Records ................................................................................................................. 96 
16.8 Reporting Requirements ...................................................................................................... 97 
16.8.1 
Investigator Reports ............................................................................................................ 97 
16.8.2 
Sponsor Reports .................................................................................................................. 98 
16.9 Publication and Use of Information ..................................................................................... 100 
16.9.1 
Publication Committee ..................................................................................................... 100 
16.10 
Suspension or Early Termination ................................................................................. 100 
17. 
References .................................................................................................................. 101 
18. 
Appendices ................................................................................................................. 103 
18.1 Informed Consent Materials ............................................................................................... 103 
18.2 Participating Investigators and Institutions .......................................................................... 103 
18.3 Labeling ........................................................................................................................... 103 
19. 
Version History ........................................................................................................... 104 
 
 

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Listing of Tables 
Table 1: Investigational System component information ........................................................................... 26 
Table 2: Therapy Schedule Options ............................................................................................................ 27 
Table 3: Study Aids ...................................................................................................................................... 28 
Table 4: Data collection and study procedure requirements at subject visits ........................................... 49 
Table 5: Study Follow-up Visit Windows ..................................................................................................... 50 
Table 6: Adverse Event and Device Deficiency Definitions ......................................................................... 65 
Table 7: Adverse Event Relatedness ........................................................................................................... 68 
Table 8: Common Terminology Criteria for Adverse Events (CTCAE)24 ...................................................... 70 
Table 9: Adverse Event Classification Responsibilities ............................................................................... 71 
Table 10: Reporting Requirements ............................................................................................................. 72 
Table 11: Investigator reports applicable per Medtronic requirements .................................................... 97 
Table 12: Additional Investigator reports applicable to the United States per FDA regulations ............... 98 
Table 13: Sponsor reports for the United States ........................................................................................ 99 
Listing of Figures 
Figure 1: TNM Neurostimulator .................................................................................................................. 27 
Figure 2: Study Visits ................................................................................................................................... 35 
 

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3. Synopsis 
Title 
Evaluation of Implantable Tibial Neuromodulation (TITAN 2) Pivotal 
Study 
Clinical Study Type 
Investigational Pivotal Study 
Product Name 
Tibial Neuromodulation (TNM) System:  
▪ TNM Neurostimulator (4NR040) 
▪ Handset with Communicator (TH90 which contains: 
- Handset (HH90) and Communicator (TM90)) 
▪ Ankle Cuff (4NR041) 
▪ Wireless Recharger kit (RS5200) which contains: 
− Wireless Recharger (WR9220) and Charging Dock (CD9000) 
▪ Patient and clinician therapy application software (4NR039, 4NR038) 
▪ Recharger application software (A90300) 
Sponsor  
Medtronic Neuromodulation  
7000 Central Ave NE 
Minneapolis, MN 55432 USA   
Indication under 
investigation  
The indication under investigation is for the treatment of overactive 
bladder (OAB) and associated symptoms including urgency, urinary 
frequency, and/or urinary urge incontinence (UUI). 
Investigation Purpose 
The purpose of this prospective, multicenter study is to assess 
the safety and efficacy of tibial neuromodulation using the Medtronic 
Tibial Neuromodulation (TNM) system.   
Product Status 
Investigational 
Primary Objective 
To demonstrate that the percentage of subjects considered a UUI 
responder after 6 months of tibial neuromodulation exceeds a 
performance goal of 40%.  
 
 

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Primary Endpoint 
Proportion of TNM subjects experiencing a reduction of 50% or more 
in daily urinary urge incontinence (UUI) episodes (UUI responder rate) 
at 6 months after device implant.  
Secondary Objectives 
 
To demonstrate an improvement from baseline to 6 months in 
number of UUI episodes in subjects with UUI at baseline 
 
To demonstrate an improvement from baseline to 6 months in 
number of urinary frequency (UF) episodes in subjects with UF at 
baseline 
 
To demonstrate an improvement from baseline to 6 months in 
urinary urgency using the Urgency Perception Scale (UPS) 
 
To demonstrate an improvement from baseline to 6 months in 
quality of life (QoL) using the Overactive Bladder Symptom 
Quality of Life Questionnaire (OAB-q) 
Secondary Endpoints 
 Change in UUI episodes at 6 months compared to baseline in 
subjects with UUI at baseline 
 Change in daily UF episodes at 6 months compared to baseline in 
subjects with UF at baseline  
 Change in urinary urgency assessed through the UPS at 6 months 
compared to baseline 
 Change in OAB-q HRQL (health related quality of life) Total Score 
at 6 months compared to baseline 
 
 

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Study Design 
This is a prospective, multicenter, pivotal study to assess safety and 
efficacy for the implantable TNM device in subjects with overactive 
bladder. The study is intended to be conducted at up to 30 
institutions in the United States.  
Eligible subjects will sign a study-specific informed consent form (ICF).  
Subjects will complete an Enrollment/Baseline Visit, a Device Implant 
Visit, and 7-day, 1-month, 2-month, 3-month, 6-month, 12-month and 
24-month Follow-up Visits.    
A Clinical Events Committee will periodically review adverse events 
reported during the study to assure appropriate and consistent 
classification of adverse events, as well as issues regarding individual 
study subjects and adverse event trend reporting. 
Sample Size 
Up to 200 subjects will be enrolled. Enrollment will be closed once the 
number of completed implants reaches 121; all enrolled subjects who 
meet eligibility criteria may be implanted (not to exceed 130 total 
implants). Implanted subjects who exit from the study will not be 
replaced. 
 
 

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Inclusion/Exclusion Criteria 
Inclusion Criteria:  
1. Subjects 18 years of age or older 
2. A 3-day voiding diary demonstrating a minimum of 3 episodes of 
urinary urge incontinence in 72 hours  
3. Have a diagnosis of UUI for at least 6 months 
4. No OAB pharmacotherapy for 2 weeks prior to completion of the 
baseline voiding diary and Overactive Bladder Quality of Life 
(OAB-q) questionnaire 
5. Failed, or are not a candidate for, conservative non-
pharmacologic treatment (e.g., pelvic floor training, biofeedback, 
behavioral modification) 
6. Failed and/or are intolerant* to at least 2 overactive bladder 
medications (antimuscarinics or beta-3 agonist) or 
contraindicated to all pharmacological therapies for the 
treatment of overactive bladder  
7. Willing and able to accurately complete study diaries, 
questionnaires, attend visits, operate the system, and comply 
with the study protocol 
8. Willing and able to provide signed and dated informed consent  
Exclusion Criteria:  
1. Have neurological conditions such as multiple sclerosis, clinically 
significant peripheral neuropathy or spinal cord injury (e.g., 
paraplegia) 
2. Severe uncontrolled diabetes  
3. History of urinary retention within the previous 6 months 
4. Current symptomatic urinary tract infection   
5. Have primary stress incontinence or mixed incontinence where 
the stress component overrides the urge component [see 
enrollment/baseline requirements for use of the Medical, 
Epidemiological, and Social Aspects of Aging urinary incontinence 
questionnaire (MESA) questionnaire] 
6. Diagnosis of bladder pain syndrome, pelvic pain, or interstitial 
cystitis  
7. Current urinary tract mechanical obstruction (e.g., benign 
prostatic enlargement or urethral stricture) 
8. History of a prior implantable tibial neuromodulation system 
9. Knowledge of planned diathermy procedures  

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10. Have had treatment of urinary symptoms with sacral 
neuromodulation in the past 6 months, botulinum toxin therapy 
in the past 9 months or percutaneous tibial nerve stimulation 
(PTNS)/percutaneous tibial neuromodulation (PTNM) in the past 3 
months 
11. Skin lesions or compromised skin integrity (e.g., skin atrophy, 
thinning, fragility, etc.) which may affect incision healing at the 
implant site 
12. Current or a recent history (within the past 6 months) of a 
medical condition such as venous insufficiency and/or venous 
stasis ulcers, clinically significant malnutrition, 
immunocompromised state, or other relevant chronic disease 
which may indicate a higher risk for delayed or poor wound 
healing. 
13. Anatomical defects, clinically significant edema or previous 
surgeries which precludes use of the device (including any metal 
implant that is within 20 cm of the intended neurostimulator 
location) 
14. Previous pelvic floor surgery in the last 6 months  
15. Women who are pregnant or planning to become pregnant during 
the course of the study  
16. Any subject who is considered to be part of a vulnerable patient 
population.** 
17. Characteristics indicating a poor understanding of the study or 
characteristics that indicate the subject may have poor 
compliance with the study protocol requirements. 
18. Concurrent participation in another clinical study that may add 
additional safety risks and/or confound study results.*** 
*Defined as stopped taking medication due to lack of efficacy or intolerable 
side effects 
**See Section 10.6 for the definition of a vulnerable patient population. 
***Subjects in concurrent studies can only be enrolled with permission from 
Medtronic.  Contact Medtronic’s study manager to determine if the subject 
can be enrolled in both studies. 
 
 
 

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Study Procedures and 
Assessments 
Study Visits:  
 
Enrollment/Baseline Visit 
 
Device Implant Visit  
 
7-day Post-Procedure Follow-up Visit   
 
1-month Follow-up Visit  
 
2-month Follow-up Visit  
 
3-month Follow-up Visit  
 
6-month Follow-up Visit  
 
12-month Follow-up Visit  
 
24-month Follow-up Visit 
Enrollment/Baseline Visit:  
The study-specific informed consent form must be signed prior to any 
study-related activities, at which time a subject will be considered 
enrolled in the study. Each subject must meet all inclusion and no 
exclusion criteria to be eligible to participate in the study. At the 
baseline visit, data will be gathered from subjects including relevant 
medical history and recent OAB medications. The MESA Urinary 
Incontinence Questionnaire will be used to exclude predominant 
stress incontinence. Subjects are prohibited from additional OAB 
treatment until after the 12-month follow-up visit, starting two weeks 
prior to the baseline voiding diary and completion of the baseline 
Overactive Bladder Quality of Life (OAB-q) questionnaire. A negative 
pregnancy test is required for women of childbearing potential.   
The urinary voiding diary will be explained and given to the subject to 
be completed for 3 consecutive days. The Overactive Bladder Quality 
of Life Questionnaire (OAB-q), 
 
 and Urgency Perception Scale (UPS) questionnaires, 
will be collected.  
Between consent and prior to the neurostimulator placement, an 
ultrasound image to assess measurements related to the tibial nerve 
may be completed in a subset of patients to summarize the subject’s 
anatomical characteristics. 
Any adverse events reported following informed consent will be 
collected. 
 

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Device Implant Visit:  
It is recommended that the device is implanted within 30 days of the 
subject’s enrollment in the study. The device will be implanted in 
accordance with the Medtronic TNM Clinician Guide. Motor and 
sensory thresholds will be assessed during the procedure.   
During this visit, the device will be interrogated, sensory/motor 
thresholds assessed, the amplitude will be set, and the subject will be 
discharged with a compression sock. An ultrasound of the tibial nerve 
may be completed following the neurostimulator implant procedure.  
The investigator or delegated personnel may initiate the therapy for 
the first time. If the subject would prefer a different time to start 
therapy, the subject will be instructed to initiate their therapy 
schedule for their first therapy session at a time convenient for them 
within approximately 24 hours of their visit. The subject will receive 
30 minutes of stimulation every other day.  
The subject will be provided instructions which cover post procedure 
care, activity guidelines, and how to interact with their implanted 
device. Any adverse events and/or device deficiencies will be 
collected. 
7-Day Post-Procedure Follow-up Visit:  
During the 7-day post-procedure follow-up visit, the device will be 
interrogated, sensory/motor thresholds assessed, and the amplitude 
will be set. The investigator or delegated personnel may initiate the 
therapy at this time. If the subject would prefer a different time to 
start therapy, the subject will be instructed to initiate their therapy 
schedule for their therapy session at a time convenient for them 
within approximately 24 hours of their visit. It is recommended that 
the subject receives 30 minutes of stimulation every other day. The 
therapy schedule may be adjusted based on symptom control and/or 
patient preference. Programming data will be collected.   
Subjects will be trained on neurostimulator recharging which will be 
recommended weekly starting at the 7-day post procedure follow-up 
visit. If the wound is not healed, a sterile barrier should be provided 
by the institution to be placed between the wound and recharger. 

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Continued compression may be recommended based on the study-
specific guidance.  
Any adverse events and/or device deficiencies will be collected. 
1-Month and 2-Month Follow-up Visits: 
The 3-day urinary voiding diary should be started approximately one 
week prior to the study visit.   
The device will be interrogated, sensory/motor thresholds assessed, 
and the amplitude will be set. The investigator or delegated personnel 
may initiate the therapy at this time. If the subject would prefer a 
different time to start therapy, the subject will be instructed to 
initiate their therapy schedule for their therapy session at a time 
convenient for them within approximately 24 hours of their visit. It is 
recommended that the subject receives 30 minutes of stimulation 
every other day. The therapy schedule may be adjusted based on 
symptom control and/or patient preference. Programming data will 
be collected.   
Any adverse events and/or device deficiencies will be collected.   
3-Month Follow-up Visit: 
The 3-day urinary voiding diary should be started approximately one 
week prior to the study visit.   
During the follow-up visit, the Overactive Bladder Quality of Life 
Questionnaire (OAB-q), 
 
 
 Urgency Perception Scale (UPS) 
 
 will be collected.    
The device will be interrogated, sensory/motor thresholds assessed, 
and the amplitude will be set. The investigator or delegated personnel 
may initiate the therapy at this time. If the subject would prefer a 
different time to start therapy, the subject will be instructed to 
initiate their therapy schedule for their therapy session at a time 
convenient for them within approximately 24 hours of their visit. It is 
recommended that the subject receives 30 minutes of stimulation 
every other day. The therapy schedule may be adjusted based on 

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symptom control and/or patient preference. Programming data will 
be collected.   
Any adverse events and/or device deficiencies will be collected.   
6-Month Follow-up Visit:  
The 3-day urinary voiding diary should be started approximately one 
week prior to the study visit.   
During the follow-up visit, the Overactive Bladder Quality of Life 
Questionnaire (OAB-q), 
 
 
 Urgency Perception Scale (UPS) and 
 
will be collected.    
The device will be interrogated, sensory/motor thresholds assessed, 
and the amplitude will be set. The therapy schedule may be adjusted 
based on symptom control and/or patient preference. The 
investigator or delegated personnel may initiate the therapy at this 
time. If the subject would prefer a different time to start therapy, the 
subject will be instructed to initiate their therapy schedule for their 
therapy session at a time convenient for them within approximately 
24 hours of their visit. Programming data will be collected.   
Any adverse events and/or device deficiencies will be collected.   
12-Month and 24-Month Follow-up Visits:  
The 3-day urinary voiding diary should be started approximately one 
week prior to the study visit.   
During the follow-up visit, the Overactive Bladder Quality of Life 
Questionnaire (OAB-q), 
 
 
 Urgency Perception Scale (UPS) and 
 
 will be collected.    
The device will be interrogated, sensory/motor thresholds assessed, 
and the amplitude will be set.  The therapy schedule may be adjusted 
based on symptom control and/or patient preference. The 
investigator or delegated personnel may initiate the therapy at this 
time. If the subject would prefer a different time to start therapy, the 
subject will be instructed to initiate their therapy schedule for their 

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therapy session at a time convenient for them within approximately 
24 hours of their visit. Programming data will be collected.   
Any adverse events and/or device deficiencies will be collected.   
The subject will exit the study at the 24-month follow-up visit. The 
TNM neurostimulator may remain implanted following study exit; the 
decision whether to explant will be per physician and patient 
discretion. 
System Modification  
A system modification may be needed for explant or replacement of 
the neurostimulator during the study. Prior to neurostimulator 
removal and/or after a new neurostimulator is placed, an ultrasound 
image to assess measurements related to the tibial nerve may be 
completed. 
During the visit, any relevant medication changes, procedural data, 
reportable adverse events and/or device deficiencies will be 
collected. It is recommended that a voiding diary, sensory/motor 
thresholds, and device data are also collected prior to any system 
modifications, when possible.   
For neurostimulator replacement procedures, upon completion of 
any programming, threshold and programming data will be collected.  
The therapy schedule will be set based on the timeframe in the study 
when the system modification was completed, and the therapy 
session may be initiated during the visit or within 24 hours.    
Following a system modification, the subject should complete a 7-day 
Post Procedure Follow-up Visit and the subject will receive a 1-month 
post-procedure phone call. Further follow-up visits will be based on 
the original implant date.   
 Statistics 
The primary objective will be met by the percentage of subjects who 
are considered a UUI responder which is statistically superior to a 
performance goal of 40%. To determine responder status, the 3-day 
urinary voiding diary data at baseline and the 6-month follow-up visit 
will be used to determine daily urinary urge incontinence episodes 
per subject. Each subject’s daily values at baseline and at 6 months 
will be compared to the UUI responder definition to determine if the 
subject is a responder. The UUI responder rate, corresponding two-

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sided 95% confidence interval, and p-value from the comparison to 
the 40% performance goal will be calculated. 
All p-values will be reported as 2-sided tests with alpha=0.05. The 
primary objective will be tested with a binomial test or a Z-test, 
depending on the use of imputation. If the primary objective is 
passed, the secondary objectives will each be tested using the 
Hochberg multiple testing strategy using a t-test or Wilcoxon signed-
rank test, depending on the normality of the data.  
The sample size was estimated using a binomial distribution for a one-
sided alpha=0.025 test to show a 15% increase for the proportion 
compared to a performance goal of 40%. Assuming the alternative 
hypothesis of 55% of subjects who are considered an UUI responder, 
a minimum of 121 implanted subjects achieves at least 90% power to 
reject a performance goal of 40%. Sample size was computed in PASS 
19. 
Primary and secondary objectives will be analyzed using the Full 
Analysis Set (FAS). The FAS includes all subjects, using the intention-
to-treat (ITT) principle, who have device implant attempted. All 
attempts will be made to minimize missing data. If 5% of the data or 
fewer are missing for the analysis, no imputation will be used, and the 
data will be analyzed using the Complete Case analysis set. Otherwise, 
if missing data are observed, multiple imputation will be used for the 
primary and secondary objectives. In the case of non-normal 
secondary objective data imputation, last observation carried forward 
(LOCF) imputation may be needed to test the hypothesis. Sensitivity 
analyses will be completed for the primary and secondary objectives 
including using only subjects with outcome data at baseline and 
follow-up (“Complete Case Analysis”) and using only those complete 
case subjects who received stimulation (“As Treated Analysis”).  
 
 
 Comprehensive descriptions of subject 
accountability and safety will be provided.  
 

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4. Introduction 
4.1 Background 
4.1.1 Overactive Bladder Syndrome 
The medical condition of overactive bladder (OAB) is recognized as a symptom syndrome characterized 
by the symptoms of urinary urgency (UU), with or without urinary urge incontinence (UUI), usually with 
urgency frequency (UF) and nocturia (waking at night one or more times to void)1,2,3. OAB may be 
treated with one or a combination of the treatments described in clinical guidelines developed by 
various professional organizations, including the American Urological Association (AUA)/Society of 
Urodynamics, Female Pelvic Medicine, and Urogenital Reconstruction (SUFU) Guideline for Diagnosis 
and Treatment of Overactive Bladder (Non-Neurogenic) In Adults4. Conservative measures are typically 
recommended as first-line treatment and include simple clinical interventions, lifestyle interventions, 
and behavioral and physical therapies. When conservative measures fail, pharmacologic management is 
typically recommended as second-line treatment. Pharmacologic management includes anti-
muscarinics, anticholinergics and β3 adrenergic receptor agonists.  
For patients who are refractory to pharmacologic treatment or unable to tolerate associated side 
effects, advanced therapy options may be offered. These include percutaneous tibial neuromodulation 
(PTNM also known as percutaneous tibial nerve stimulation), botulinum toxin-A (BTA) injections, and 
implantable sacral neuromodulation (SNM). The AUA/SUFU guidelines note that reported adverse 
events (AEs) for PTNM are minor; furthermore, the European Association of Urology (EAU) Guidelines 
recommend PTNM before advancing to surgical options such as BTA injections or SNM5, and PTNM is 
considered a conservative or second-line treatment in several other articles6–9.   
4.1.2 Tibial Neuromodulation 
Tibial neuromodulation (TNM) devices are designed to deliver electrical pulses that stimulate the tibial 
nerve that runs posterior to the tibia and extends to the sacral nerve plexus. These pulses are thought to 
relieve OAB symptoms by modulating communication between the bladder and central nervous system.  
PTNM is a Food and Drug Administration (FDA) cleared, in-office procedure that delivers adjustable 
electrical pulses through a needle to stimulate the tibial nerve. The needle electrode is placed into the 
lower, inner aspect of either leg, slightly cephalad to the medial malleolus. Treatment usually consists of 
30-minute therapy sessions delivered weekly for 12 weeks, followed by maintenance therapy delivered 
approximately monthly. PTNM is a medical guideline indicated therapy4 and is accepted as a safe and 
effective treatment for OAB10. Two independent multicenter, randomized controlled 12-week trials 
demonstrated that PTNM therapy is safe and showed superior efficacy to sham11 and comparable 
efficacy to medication12. 

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While these results are promising, therapy adherence can be an issue in patients for whom it is a burden 
to return to the clinic for weekly therapy sessions (or monthly for long-term maintenance therapy). In a 
large retrospective analysis, Gordon et al. reported that 347 of 1331 patients (26%) completed 12 PTNM 
sessions while 158 (46%) of these continued with long term PTNM defined as completion of 8 additional 
sessions13. The gap between clinical efficacy and therapy dropout rates suggests that frequent office 
visits are a barrier to care for both patients and physician offices. The need for frequent, recurrent office 
visits for therapy delivery may prove to be a significant barrier to care as the global medical community 
adapts to the need to reduce clinic visits and explores way to treat more patients in their home setting. 
In order to eliminate the barrier of frequent clinic visits for PTNM sessions while retaining the efficacy 
and positive safety profile of tibial neuromodulation, implantable tibial neuromodulation (ITNM) devices 
have been proposed as an alternative to PTNM. Two feasibility studies and one pivotal study have been 
published to date with promising results. Clinical success was observed in 69.6% and 68% of UUI 
patients at 12 weeks and 48 weeks, respectively14,15 and 70.6% of OAB patients at 6 months16. All three 
studies report significant improvements from baseline in quality of life. Incision site infection, implant 
site pain and stimulation discomfort were reported14–16.  
This pivotal study is intended to assess the safety and efficacy of the Medtronic TNM system for the 
treatment of overactive bladder. Early learnings from the TITAN 1 feasibility study provided information 
about procedural learnings to further inform the pivotal study protocol.   
4.2 Purpose 
Medtronic, Inc. is sponsoring the Evaluation of Implantable Tibial Neuromodulation (TITAN 2) Pivotal 
Study, a prospective, multicenter, pivotal clinical study. The purpose of this study is to is to assess 
the safety and efficacy of tibial neuromodulation using the Medtronic Tibial Neuromodulation (TNM) 
system.   
5. Objectives and Endpoints 
5.1 Objectives 
5.1.1 Primary Objective 
To demonstrate that the percentage of subjects considered a UUI responder after 6 months of tibial 
neuromodulation exceeds a performance goal of 40%.  
5.1.1.1 Primary Endpoint  
Proportion of TNM subjects experiencing a reduction of 50% or more in daily urinary urge incontinence 
(UUI) episodes (UUI responder rate) at 6 months after device implant.  

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5.1.2 Secondary Objectives 
 
To demonstrate an improvement from baseline to 6 months in number of UUI episodes in subjects 
with UUI at baseline 
 
To demonstrate an improvement from baseline to 6 months in number of UF episodes in subjects 
with UF at baseline 
 
To demonstrate an improvement from baseline to 6 months in urinary urgency using the Urgency 
Perception Scale (UPS) 
 
To demonstrate an improvement from baseline to 6 months in quality of life (QoL) using the 
Overactive Bladder Symptom Quality of Life Questionnaire (OAB-q) 
5.1.2.1 Secondary Endpoints  
 Change in UUI episodes at 6 months compared to baseline in subjects with UUI at baseline 
 Change in daily UF episodes at 6 months compared to baseline in subjects with UF at baseline  
 Change in urinary urgency assessed through the UPS at 6 months compared to baseline 
 Change in OAB-q HRQL (health related quality of life) Total Score at 6 months compared to baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
   
 
 
6. Study Design 
This is a prospective, multicenter, pivotal study to assess safety and efficacy for the implantable TNM 
device in subjects with overactive bladder.   
Eligible subjects will sign a study-specific informed consent form (ICF), at which time they will be 
considered enrolled in the study. All eligible subjects will complete baseline procedures, including a 
baseline diary and assessment of medical history. Subjects must be consented and meet all inclusion 
and no exclusion criteria to continue to the neurostimulator implant procedure. Any subject who does 

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not meet all inclusion/exclusion criteria will be excluded from study participation and exited from the 
study. 
Study requirements, including diaries, questionnaires and safety assessments will be completed as 
required in Section 10. Subject follow-up is expected to last approximately 24 months following the 
neurostimulator implant procedure. Subjects will be exited from the study after the 24-month follow-up 
visit is completed. Any subjects who have the device explanted and not replaced during follow-up will be 
exited from the study. 
The study is expected to be conducted at up to 30 study sites located in the United States. Up to 200 
subjects will be enrolled to obtain 121 subjects who have the study device implanted. Enrollment will be 
closed once the number of completed implants reaches 121; all enrolled subjects who meet eligibility 
criteria may be implanted (not to exceed 130 total implants). 
To ensure a widespread distribution of data and minimize study site bias in study results, the maximum 
number of subjects to be implanted at a single study site is 24 subjects. 
6.1 Duration 
The estimated study duration, from first subject enrollment to last subject visit, is expected to last 
approximately 36 months. The duration of individual subject participation will vary based on timing of 
study visits; however, participation of an individual subject will be approximately 24 months. Study 
completion is defined as Sponsor approval of the Final Study Report and closure of all sites. 
6.2 Rationale 
This pre-market study will collect data in an organized, systematic manner based on product use to 
assess safety and efficacy of the Medtronic TNM System for tibial neuromodulation. No comparator is 
required in the study design due to performance goals being based on the literature available on 
advanced therapy options for OAB. Relevant pre-clinical and clinical testing are outlined in the Report of 
Prior Investigations.   
Data related to the performance of the study device will be collected, and this may be used to support 
claims and intended performance of the study product. See Section 5.1 for study objectives. Evidence 
gathered from this study will be useful for clinicians and patients evaluating tibial neuromodulation as a 
potential treatment option. 
7. Product Description 
7.1 General  
The TNM neurostimulator is a rechargeable, implantable pulse generator implanted subcutaneously 
over the tibial nerve in the lower leg. A recharger is used to recharge the implanted device. An ankle cuff 

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7.6 Equipment 
Ultrasound equipment may be used at each study site to support study activities and equipment will be 
provided by Medtronic.  
7.7 Product Training Materials 
Principal Investigator and delegated individuals performing the implant/explant procedure and 
programming activities for the TNM system will be required to undergo training on use of the system 
prior to completing the delegated activities. 
7.8 Product Receipt and Tracking 
Distribution of the investigational products to study centers during the clinical study will be managed by 
Medtronic, can only be ordered by Medtronic personnel and will be labeled in accordance with 21 
CFR§812.5. A Device Accountability Log will be used by centers for tracking of all investigational 
products by unique identifiers, (e.g., by assignment of serial numbers, lot numbers, batch numbers). 
Logs must be maintained at each study center and updated when investigational product is received, 
used, explanted, disposed of by the institution/subject, or returned to Medtronic. It is the responsibility 
of the investigator to correctly handle, store, and track the investigational products maintained at the 
study site as outlined on the Device Accountability Log. Product accountability of investigational product 
will be reviewed during monitoring visits. 
Subjects will be informed to contact the research coordinator in the event that any study product is lost, 
damaged or malfunctions. 
7.9 Product Storage 
Investigational product, once received at the study site, must be stored in a secure location at the study 
site. It is the responsibility of the investigator to correctly handle, store, and track the investigational 
products maintained at the study site. Investigational products will be used only in the clinical study 
according to the CIP.  
7.10 Product Return 
It is recommended that all explanted devices are returned to Medtronic for analysis when permissible 
by local laws and regulations. In addition, it is recommended that all external TNM system components 
are returned to Medtronic at the time of explant. If the products are explanted but not returned, a 
justification will be reported on the appropriate Device Accountability Log. Contact the Medtronic Study 
Team for return instructions.   
All unused investigational product will be returned to Medtronic upon the completion of the study, 
unless instructed by Medtronic to dispose of product at the institution.  

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7.11 Product Accountability 
The TNM system is considered investigational. Investigational product will be distributed to a study site 
only when Medtronic has received all required documentation and has notified the study site of study 
site activation. Distribution of an investigational product to study sites during the study will be managed 
by Medtronic and can only be ordered by Medtronic personnel. 
The study site is responsible for maintaining tracking of the investigational devices during the study. An 
electronic device accountability log will be located in the study-specific Electronic Data Capture (EDC) for 
tracking. The Device Accountability Log must be maintained at each study site and updated when the 
investigational product is received, used, explanted, disposed of by the institution/subject, or returned 
to Medtronic. In addition to tracking the date of events, the Device Accountability Log tracks product 
information which may include, but is not limited to, date, model/serial/lot (as applicable) number, and 
expiration date for the received product, subject ID of the implanted subject, reason(s) for and method 
of destruction/disposal for explanted components not returned to Medtronic (if applicable), and name 
of the person responsible for return or destruction/disposal (if applicable). 
Medtronic will perform periodic reconciliation of the investigational product to ensure traceability. 
Non-investigational study aids should be retained for use in the study, but individual component 
tracking is not required.  
8. Study Site Requirements 
8.1 Investigator/Investigation Site Selection 
The role of the principal investigator is to implement and manage the day-to-day conduct of the study as 
well as ensure data integrity and the rights, safety and well-being of the patients involved in the study. 
Site selection criteria will be documented and utilized to ensure adequate site selection. Study site 
personnel training in accordance with the study-specific training plan will be completed and 
documented prior to participation in this study. 
8.2 Study Site Activation 
During the activation process (prior to subject consenting), Medtronic will train study site personnel on 
the clinical investigation plan, on relevant standards and regulations, informed consent (IC), product 
accountability, data collection and reporting tools. If new members join the study site team, they will 
receive training on the applicable study requirements relevant to their role before participating in the 
study. 
 

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Prior to performing study related activities, all regulatory requirements shall be fulfilled, including, but 
not limited to the following:  
• 
Institutional Review Board (IRB) approval (and voting list, as required) of the current version 
of the Clinical Investigation Plan (CIP) and ICF.  
• 
FDA approval  
• 
Fully executed Clinical Trial Agreement (CTA)  
• 
Financial disclosure  
• 
Curriculum Vitae (CV) of investigators and key members of the investigation study site team 
(as required)  
• 
Documentation of delegated tasks 
• 
Documentation of study training  
• 
Additional requirements imposed by the IRB and FDA shall be followed 
In addition, all participating study site staff must be trained on the current version of the CIP, 
investigational system, implant procedure, as well as on the applicable study requirements depending 
on their role and must be delegated by the principal investigator to perform study related activities.   
Medtronic will provide each study site with documentation of study site/investigator readiness; this 
letter must be received prior to performing study related activities. 
8.3 Role of the Sponsor Representatives 
In addition to performing monitoring and auditing activities, Medtronic representatives may participate 
in the conduct of the study under supervision of the Principal Investigator to the extent listed below.  
Medtronic representatives responsible for human factors may observe study activities (e.g., implant 
procedure).  
Medtronic representatives can provide technical support to the investigator and other health care 
personnel as needed during study visits. This support may include the training of site personnel on use 
of Medtronic equipment, TNM system and components (including software/applications) and/or 
protocol-related procedures and forms. In addition, Medtronic personnel may perform certain activities 
to ensure study quality. These activities may include: 
• 
Provide study training relevant and pertinent to the involvement of personnel conducting 
study activities and investigator responsibilities 
• 
Observe implant, follow-up visits and/or medical procedures to provide information 
relevant to protocol completion 
• 
Review collected data and study documentation for completeness and accuracy 
 

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In addition, for this study, sponsor representatives may be authorized by the principal investigator to 
perform the following significant trial related duties:  
• 
Provide technical support for setting up investigational product 
• 
Perform device programming or device interrogation under the direction of the 
investigator(s) 
• 
Perform ultrasound assessments 
 
Any data collection completed by Medtronic personnel will be clearly identified as such.  
Medtronic personnel will not: 
• 
Practice medicine 
• 
Provide medical diagnosis or treatment to subjects 
• 
Discuss a subject’s condition or treatment with a subject without the approval and presence 
of the health care provider. 
• 
Complete eCRFs or make entries in the subject’s medical record 
9. Selection of Subjects 
9.1 Study Population 
The study will enroll patients with overactive bladder, who meet eligibility criteria in Sections 9.3 and 
9.4.   
9.2 Subject Enrollment 
Eligible subjects will sign a study-specific informed consent form (ICF) at which time they will be 
considered enrolled. Each subject must meet all the inclusion criteria and no exclusion criteria to be 
eligible to participate in the study. Any subject not meeting eligibility criteria will be excluded from study 
participation and exited from the study. Site personnel must complete logs related to recruitment and 
enrollment as required by the study. 
9.3 Inclusion Criteria 
To be eligible to participate in the study, a subject must meet all the following inclusion criteria: 
1. Subjects 18 years of age or older 
2. A 3-day voiding diary demonstrating a minimum of 3 episodes of urinary urge incontinence in 
72 hours  
3. Have a diagnosis of UUI for at least 6 months 

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4. No OAB pharmacotherapy for 2 weeks prior to completion of the baseline voiding diary and 
Overactive Bladder Quality of Life (OAB-q) questionnaire 
5. Failed, or are not a candidate for, conservative non-pharmacologic treatment (e.g., pelvic floor 
training, biofeedback, behavioral modification) 
6. Failed and/or are intolerant* to at least 2 overactive bladder medications (antimuscarinics or 
beta-3 agonist) or contraindicated to all pharmacological therapies for the treatment of 
overactive bladder 
7. Willing and able to accurately complete study diaries, questionnaires, attend visits, operate the 
system, and comply with the study protocol 
8. Willing and able to provide signed and dated informed consent  
 
9.4 Exclusion Criteria 
A potential subject who meets any of the following criteria will be excluded from participating in the 
study: 
1. Have neurological conditions such as multiple sclerosis, clinically significant peripheral 
neuropathy or spinal cord injury (e.g., paraplegia) 
2. Severe uncontrolled diabetes  
3. History of urinary retention within the previous 6 months 
4. Current symptomatic urinary tract infection   
5. Have primary stress incontinence or mixed incontinence where the stress component overrides 
the urge component [see enrollment/baseline requirements for use of the Medical, 
Epidemiological, and Social Aspects of Aging urinary incontinence questionnaire (MESA) 
questionnaire] 
6. Diagnosis of bladder pain syndrome, pelvic pain, or interstitial cystitis  
7. Current urinary tract mechanical obstruction (e.g., benign prostatic enlargement or urethral 
stricture) 
8. 
History of a prior implantable tibial neuromodulation system 
9. 
Knowledge of planned diathermy procedures  

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10. Have had treatment of urinary symptoms with sacral neuromodulation in the past 6 months, 
botulinum toxin therapy in the past 9 months or percutaneous tibial nerve stimulation 
(PTNS)/percutaneous tibial neuromodulation (PTNM) in the past 3 months 
11. Skin lesions or compromised skin integrity (e.g., skin atrophy, thinning, fragility, etc.) which 
may affect incision healing at the implant site 
12. Current or a recent history (within the past 6 months) of a medical condition such as venous 
insufficiency and/or venous stasis ulcers, clinically significant malnutrition, 
immunocompromised state, or other relevant chronic disease which may indicate a higher risk 
for delayed or poor wound healing. 
13. Anatomical defects, clinically significant edema or previous surgeries which precludes use of 
the device (including any metal implant that is within 20 cm of the intended neurostimulator 
location) 
14. Previous pelvic floor surgery in the last 6 months  
15. Women who are pregnant or planning to become pregnant during the course of the study  
16. Any subject who is considered to be part of a vulnerable patient population.** 
17. Characteristics indicating a poor understanding of the study or characteristics that indicate the 
subject may have poor compliance with the study protocol requirements. 
18. Concurrent participation in another clinical study that may add additional safety risks and/or 
confound study results.*** 
* Defined as stopped taking medication due to lack of efficacy or intolerable side effects. 
**See Section 10.6 for the definition of a vulnerable patient population. 
***Subjects in concurrent studies can only be enrolled with permission from Medtronic.                                                       
Contact Medtronic’s study manager to determine if the subject can be enrolled in both studies. 

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10.1 Schedule of Events 
Enrollment/Baseline Visit:  
The study-specific informed consent form must be signed prior to any study-related activities. OAB 
medications must have a washout of 2 weeks prior to starting the baseline voiding diary and the 
baseline Overactive Bladder Quality of Life (OAB-q) questionnaire. The 
 and UPS questionnaires 
will also be provided for the subject’s completion. The urinary voiding diary will be explained and given 
to the subject to be completed for 3 consecutive days.   
Data will be gathered from subjects including relevant medical history and overactive bladder 
medications. The MESA urinary incontinence questionnaire will be used to exclude 
predominant stress incontinence. If the Investigator’s assessment differs from the results of the MESA 
questionnaire, rationale must be documented to explain the decision to implant the subject.   
Women of child-bearing potential must undergo a pregnancy test (e.g., serum, urine), with a clear 
negative result, prior to the device implant procedure. During the course of this study, women of child-
bearing potential must agree to use a medically acceptable form of birth control. Women who are 
pregnant or plan to become pregnant during the course of the trial cannot participate in the trial. If 
unanticipated pregnancy occurs while participating in the trial, the subject should consult with the study 
physician to determine programming of the device and therapy decisions.   
The correct fitting compression sock should be determined prior to the implant procedure. Compression 
may be used for up to two weeks post-implant, if needed. Reference the compression sock labeling for 
sizing and study specific recommendation for compression duration.   
Prior to the implant procedure, the Investigator should assess the subject’s implant site location based 
on the study eligibility criteria. Each subject must meet all inclusion and no exclusion criteria to be 
eligible to participate in the study.   
Between consent and prior to the neurostimulator (device) placement, an ultrasound image to assess 
measurements related to the tibial nerve may be completed in a subset of patients to summarize the 
subject’s anatomical characteristics. It is estimated that ultrasound data may be collected on 
approximately 30 patients.  
Any adverse events reported following informed consent will be collected. Subjects should not receive 
additional OAB treatment (such as OAB medication, tibial neuromodulation, Botox injections, or sacral 
neuromodulation) during the first 12 months of the study. If additional treatment is added prior to the 
12-month follow-up visit, a protocol deviation is required. Throughout the study, a voiding diary is 
required prior to starting any OAB medication or additional advanced therapies to confirm the patient is 
a non-responder (< 50% improvement from baseline) to tibial neuromodulation therapy. If additional 
OAB treatment is added without confirmation of non-response to the therapy based on a voiding diary, 
a deviation is required. 

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The following information should be collected at the enrollment/baseline visit: 
• 
Informed Consent details  
• 
Subject demographics, height, weight, ethnicity, & race data 
• 
Diagnoses and medical history  
• 
Pregnancy test (required for women of childbearing potential) 
• 
OAB Treatment History  
• 
Voiding diary 
• 
MESA/OAB-q/
/UPS Questionnaires 
• 
Eligibility Confirmation (required prior to device implant; once all eligibility information is 
available) 
• 
Any adverse events 
 
Device Implant Visit:  
It is recommended that the device is implanted within 30 days of the subject’s enrollment in the study.  
The implant procedure may occur in a clinic, ambulatory surgical center, or hospital.   
A sterile surgical marker and ruler will be provided for use during the implant procedure. The device will 
be implanted in accordance with the Medtronic TNM Clinician Guide.  
During the procedure, amplitude should be increased using 20 hertz, 200 microsecond pulse width 
stimulation and Therapy Schedule #1 (30 minutes of stimulation every other day) until sensory and 
motor thresholds are reached:  
- 
Sensory threshold: defined as the lowest amplitude where the subject first perceives sensation 
in the sole of the foot, heel, or toes during stimulation.  
- 
Motor threshold: defined as the lowest amplitude to elicit movement of the foot or toes.  
If the sensory and/or motor thresholds are not observed within a tolerable setting for the subject, this 
will be documented. The device may also be repositioned, if deemed necessary by the Investigator.   
Following Device Implant: 
Following device implant, an impedance check should be completed.  Perform threshold testing by 
increasing amplitude using 20 hertz, 200 microsecond pulse width stimulation and Therapy Schedule #1 
(30 minutes of stimulation every other day) until the following thresholds are reached without 
compression, with the foot in a relaxed position:  
- 
Sensory threshold: defined as the lowest amplitude where the subject first perceives sensation 
in the sole of the foot, heel, or toes during stimulation.  
- 
Motor threshold:  defined as the lowest amplitude to elicit movement of the foot or toes.  
- 
Highest acceptable amplitude: defined as the highest amplitude following a sensory and/or 
motor response where the stimulation level is still comfortable.  

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An ultrasound of the tibial nerve may be completed following the device implant procedure. 
A compression sock will be applied, an impedance check will be completed, and the neurostimulator 
amplitude will be set to the highest acceptable amplitude. If highest acceptable amplitude is unable to 
be found, it is recommended to set the amplitude to two times the motor or sensory threshold, 
whichever is lower. The comfort of the programmed amplitude will be verified while the subject is in 
expected positions and adjusted for comfort, if needed. If no motor or sensory response is observed, the 
investigator or delegated personnel should try repeating the motor and sensory assessment with the 
foot in a different position. If no motor or sensory response is observed, the investigator or delegated 
personnel should set neurostimulator amplitude to 3 mA unless an alternative amplitude level is 
recommended by the Sponsor.    
Programming and device data (e.g., Session Report) will be collected in accordance with device 
instructions and documented on the programming worksheet at the time of the implant procedure. Use 
of the handset (TNM My Therapy app) and communicator will be reviewed with the subject. The 
investigator or delegated personnel may initiate the therapy at this time. If the subject would prefer a 
different time to start therapy, the subject will be instructed to initiate their therapy schedule for their 
therapy session at a time convenient for them within approximately 24 hours of their visit. The subject 
will receive 30 minutes of stimulation every other day. 
All subjects must wear a compression sock for at least 72 hours and possibly up to two weeks after 
device implant. The duration of compression will be determined by the Investigator using the study-
specific recommendations which are based on pocket size, motor and/or sensory thresholds and 
pertinent medical history of the subject.    
The subject will be provided post-implant care instructions within the informed consent form and Post-
Implant Subject Instructions (outlined below) to explain how to manage their implanted device. Post-
implant care and activity guidelines identified below should be reviewed with subjects prior to the end 
of the visit.   
Post-implant Care 
To aid healing and minimize the chance for device movement, provide the following guidance to 
subjects.  
Following the implant procedure:  
• 
Subjects should be instructed to consult study physician if they notice any unusual symptoms or 
signs (for example, swelling, or redness at the incision site). 
• 
Cold packs may be used after implant for comfort. A barrier (for example a towel) may be placed 
between the cold pack and the compression sock to keep the sock dry. 

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• 
Subjects may experience soreness or pain when with walking or flexing the ankle while healing 
from the implant procedure. 
• 
Subjects must be instructed to wash hands before handling the bandage or compression sock 
and avoid touching the implant site. 
For the first 3 days:  
• 
The implant site must be kept covered with the bandage applied during procedure for 72 hours 
or based on the physician’s instructions. 
• 
The implant site must be kept dry for 72 hours. Shower bags can be used to help keep the site 
dry. 
• 
A compression sock must be used for at least 72 hours, or longer if the physician advises the 
subject to. This will aid in healing around the device. If the subject is advised to use a 
compression sock for longer than 72 hours, a shower bag should be used while showering to 
keep the site dry for the duration that the subject wears the compression sock.   
• 
If the compression sock gets wet, replace with a dry compression sock. 
For the first 2 weeks:  
• 
Avoid scrubbing the incision site for 2 weeks or until the wound is closed. 
For the first 4 weeks:  
• 
Avoid soaking the incision site (e.g., taking a bath, swimming, using a hot tub) for 4 weeks.  
• 
Avoid strenuous, long duration and high impact activities; for example: aerobics, cycling, 
running, swimming, long walks, recreational sports, and gym exercises involving the foot, leg, or  
ankle (elliptical, leg   press, etc.) during the 4 weeks while the device is encapsulating. Subjects 
should limit physical activities to short duration (30 minutes) and low intensity activities during 
this time. 
• 
Wear flat shoes (no heels) for 4 weeks. Avoid wearing shoes or boots that rub or are tight 
around the implanted device. 
In addition to post-implant care, the following guidance will be provided to study subjects: 
• 
Subjects should turn on stimulation for the next therapy session following the instructions 
(Therapy Schedule #1; stimulation for 30 minutes every other day) during the visit or at a time 
convenient for them within 24 hours of the visit.      
• 
During recovery it is recommended that subjects receive therapy with their leg is in a relaxed 
position, or in the position where sensory testing was assessed during the post implant testing. 
• 
Subjects may feel sensation or notice a motor response during their therapy sessions. 
• 
Any changes to the stimulation should be made within the first five minutes of each therapy 
session. 

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• 
Subjects will be reminded they are prohibited from taking overactive bladder pharmacotherapy 
until after the 12-month follow-up visit.    
Any adverse events and/or device deficiencies will be collected.   
The following information should be collected at the implant visit: 
• 
Procedure details  
• 
System information (e.g., model number, serial/lot number, etc.) 
• 
Motor and sensory threshold data 
• 
Programming and device data  
• 
Ultrasound images (if applicable) 
• 
Post-operative care (e.g., infection control, compression sock duration, etc.) 
• 
Any adverse events and/or device deficiencies 
• 
Any study deviations 
 
7-Day Post-Procedure Follow-up Visit:  
The compression sock will be removed if it was still recommended for the subject.  
Following this, the subject will have an impedance check and sensory/motor threshold testing done with 
their foot in the same relaxed position as the time of implant. The subject’s sensory and motor threshold 
without compression will be identified using 20 hertz, 200 microseconds pulse width stimulation and 
titrating up amplitude until the sensory threshold, highest acceptable amplitude, and motor threshold 
are confirmed. The neurostimulator amplitude should be set to the highest acceptable amplitude. If 
highest acceptable amplitude is unable to be found, it is recommended to set the amplitude to two 
times the motor or sensory threshold, whichever is lower. The comfort of the programmed amplitude 
will be verified while the subject is in expected positions and adjusted for comfort, if needed.  
If the sensory threshold, highest acceptable amplitude and/or motor threshold are not observed, this 
will be documented.  The Investigator or delegated personnel should try repeating the motor and 
sensory assessment with the foot in a different position. If the motor and/or sensory response is still not 
observed, the Investigator or delegated personnel should set neurostimulator amplitude to 3 mA unless 
an alternative amplitude level is recommended by the Sponsor.    
Continued compression until two weeks following the implant will be determined using the study-
specific recommendations based on pocket size, motor/sensory thresholds, and pertinent medical 
history of the subject.   
If continued compression is required, comfort of the programmed amplitude will be verified while the 
subject is in expected positions with the compression sock worn by the subject.  

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Subjects will be trained on neurostimulator recharging which will be recommended weekly starting at 
the 7-day post-procedure follow-up visit. If the wound is not healed, a sterile barrier provided by the 
institution should be placed between the wound and recharger. The investigator or delegated personnel 
may initiate the therapy at this time. If the subject would prefer a different time to start therapy, the 
subject will be instructed to initiate their therapy schedule for their therapy session at a time convenient 
for them within approximately 24 hours of their visit.  
Programming and device data (e.g., Usage Report, Session Report) will be collected in accordance with 
device instructions prior to the subject leaving the visit and transferred to Medtronic using the 
application on the handset and/or collected on the programming worksheet provided. 
The following guidance will be provided to study subjects: 
• 
If the subject decides to turn therapy on after the visit, turn on stimulation for the next therapy 
session following the instructions:  
o It is recommended that the subject will receive 30 minutes of stimulation (Therapy 
Schedule #1) every other day. The therapy schedule may be adjusted based on symptom 
control and/or patient preference.    
• 
During recovery it is recommended that subjects receive therapy with their leg is in a relaxed 
position, or in the position where sensory testing was done during post implant testing. 
• 
Subjects may feel sensation or notice a motor response during their therapy sessions. 
• 
Any changes to the stimulation should be made within the first five minutes of each therapy 
session. 
• 
Following this visit it is recommended that the device is recharged weekly. If the wound is not 
healed, subject should be instructed to place a sterile barrier between the wound and 
recharger.  
Any adverse events and/or device deficiencies will be collected. 
 
1-Month and 2-Month Follow-up Visits:  
The 3-day urinary voiding diary should be started approximately one week prior to the study visit.  If the 
diary is not able to be completed prior to the visit, it will be completed immediately following the study 
visit.   
The subject will have an impedance check and sensory/motor threshold testing done with their foot in 
the same relaxed position as the time of implant. The subject’s sensory and motor threshold will be 
identified using 20 hertz, 200 microseconds pulse width stimulation and titrating up amplitude until the 
sensory threshold, highest acceptable amplitude and motor threshold are confirmed. The 
neurostimulator amplitude should be set to the highest acceptable amplitude. If highest acceptable 
amplitude is unable to be found, it is recommended to set the amplitude to two times the motor or 

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sensory threshold, whichever is lower. The comfort of the programmed amplitude will be verified while 
the subject is in expected positions and adjusted for comfort, if needed.  
If the sensory threshold, highest acceptable amplitude and/or motor threshold are not observed, this 
will be documented.  The Investigator or delegated personnel should try repeating the motor and 
sensory assessment with the foot in a different position. If the motor and/or sensory response is still not 
observed, the Investigator or delegated personnel should set neurostimulator amplitude to 3 mA unless 
an alternative amplitude level is recommended by the Sponsor.    
The investigator or delegated personnel may initiate the therapy at this time. If the subject would prefer 
a different time to start therapy, the subject will be instructed to initiate their therapy schedule for their 
therapy session at a time convenient for them within approximately 24 hours after their visit. 
Programming and device data (e.g., Usage Report, Session Report) will be collected in accordance with 
device instructions prior to the subject leaving the visit and transferred to Medtronic using the 
application on the handset and/or collected on the programming worksheet provided.  
The following guidance will be provided to study subjects: 
• 
You may return to normal activity levels 
• 
If the subject decides to turn therapy on after the visit, turn on stimulation for the next therapy 
session following the instructions:  
o It is recommended that the subject will receive 30 minutes of stimulation (Therapy 
Schedule #1) every other day. The therapy schedule may be adjusted based on symptom 
control and/or patient preference.    
• 
If the subject is comfortable with the stimulation sensation, they can resume normal activities 
during their therapy sessions. 
• 
Subjects may feel sensation or notice a motor response during their therapy sessions. 
• 
Any changes to the stimulation should be made within the first five minutes of each therapy 
session. 
• 
It is recommended that the device is recharged weekly. 
Any adverse events and/or device deficiencies will be collected. 
3-Month Follow-up Visit:  
The 3-day urinary voiding diary should be started approximately one week prior to the study visit.  If the 
diary is not able to be completed prior to the visit, it will be completed immediately following the study 
visit. The Overactive Bladder Quality of Life Questionnaire (OAB-q), 
 
, 
 Urgency Perception 
Scale (UPS) 
 will be collected.   

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The subject will have an impedance check and sensory/motor threshold testing done with their foot in 
the same relaxed position as the time of implant. The subject’s sensory and motor threshold will be 
identified using 20 hertz, 200 microseconds pulse width stimulation and titrating up amplitude until the 
sensory threshold, highest acceptable amplitude and motor threshold are confirmed. The 
neurostimulator amplitude should be set to the highest acceptable amplitude. If highest acceptable 
amplitude is unable to be found, it is recommended to set the amplitude to two times the motor or 
sensory threshold, whichever is lower. The comfort of the programmed amplitude will be verified while 
the subject is in expected positions and adjusted for comfort, if needed. 
 
If the sensory threshold, highest acceptable amplitude and/or motor threshold are not observed, this 
will be documented.  The Investigator or delegated personnel should try repeating the motor and 
sensory assessment with the foot in a different position. If the motor and/or sensory response is still not 
observed, the Investigator or delegated personnel should set neurostimulator amplitude to 3 mA unless 
an alternative amplitude level is recommended by the Sponsor.    
The investigator or delegated personnel may initiate the therapy at this time. If the subject would prefer 
a different time to start therapy, the subject will be instructed to initiate their therapy schedule for their 
therapy session at a time convenient for them within approximately 24 hours after their visit. 
Programming and device data (e.g., Session Report, Usage Report) will be collected in accordance with 
device instructions prior to the subject leaving the visit and transferred to Medtronic using the 
application on the handset and/or collected on the programming worksheet provided.  
The following guidance will be provided to study subjects: 
• 
If the subject decides to turn therapy on after the visit, turn on stimulation for the next therapy 
session following the instructions: 
o It is recommended that the subject will receive 30 minutes of stimulation (Therapy 
Schedule #1) every other day. The therapy schedule may be adjusted based on symptom 
control and/or patient preference.    
• 
If the subject is comfortable with the stimulation sensation, they can resume normal activities 
during their therapy sessions. 
• 
Subjects may feel sensation or notice a motor response during their therapy sessions. 
• 
Any changes to the stimulation should be made within the first five minutes of each therapy 
session. 
• 
It is recommended that the device is recharged weekly. 
Any adverse events and/or device deficiencies will be collected. 
 
 
 

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6-Month Follow-up Visit:  
The 3-day urinary voiding diary should be started approximately one week prior to the study visit. If the 
diary is not able to be completed prior to the visit, it will be completed immediately following the study 
visit. The Overactive Bladder Quality of Life Questionnaire (OAB-q), 
 
 Urgency Perception 
Scale (UPS) 
 will be collected.    
The subject will have an impedance check and sensory/motor threshold testing done with their foot in 
the same relaxed position as the time of implant. The subject’s sensory and motor threshold will be 
identified using 20 hertz, 200 microseconds pulse width stimulation and titrating up amplitude until the 
sensory threshold, highest acceptable amplitude and motor threshold are confirmed. The 
neurostimulator amplitude should be set to the highest acceptable amplitude. If highest acceptable 
amplitude is unable to be found, it is recommended to set the amplitude to two times the motor or 
sensory threshold, whichever is lower. The comfort of the programmed amplitude will be verified while 
the subject is in expected positions and adjusted for comfort, if needed. 
If the sensory threshold, highest acceptable amplitude and/or motor threshold are not observed, this 
will be documented.  The Investigator or delegated personnel should try repeating the motor and 
sensory assessment with the foot in a different position. If the motor and/or sensory response is still not 
observed, the Investigator or delegated personnel should set neurostimulator amplitude to 3 mA unless 
an alternative amplitude level is recommended by the Sponsor.    
Following the 6-month follow-up visit, the programmed therapy session may include any of the 
following based on symptom control and/or patient preference: remaining on 30 minutes stimulation 
every other day (Therapy Schedule #1), stimulation for 30 minutes every day (Therapy Schedule #2), 
stimulation for 30 minutes every third day (Therapy Schedule #3), stimulation for 60 minutes every 
other day (Therapy Schedule #4), stimulation for 30 minutes once per week (Therapy Schedule #5), 
stimulation for 60 minutes every day (Therapy Schedule #6), stimulation for 4 hours every day (Therapy 
Schedule #7), stimulation for 8 hours every day (Therapy Schedule #8) or custom stimulation (Therapy 
Schedule #9). The investigator or delegated personnel may initiate the therapy at this time. If the 
subject would prefer a different time to start therapy, the subject will be instructed to initiate their 
therapy schedule for their therapy session at a time convenient for them within approximately 24 hours 
after their visit. 
Programming and device data (e.g., Usage Report, Session Report) will be collected in accordance with 
device instructions prior to the subject leaving the visit and transferred to Medtronic using the 
application on the handset and/or collected on the programming worksheet provided.  
The following guidance will be provided to study subjects:  
• 
If the subject decides to turn therapy on after the visit, turn on stimulation for the next therapy 
session within 24 hours after their visit.  

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initiate their therapy schedule for their therapy session at a time convenient for them within 
approximately 24 hours after their visit. 
Programming and device data (e.g., Usage Report, Session Report) will be collected in accordance with 
device instructions prior to the subject leaving the visit and transferred to Medtronic using the 
application on the handset and/or collected on the programming worksheet provided.  
At the completion of the 24-month follow-up visit (along with the final voiding diary), the subject will be 
exited from the study. All programming completed at the visit will be up to the investigator’s discretion.  
Any adverse events and/or device deficiencies will be collected. 
The TNM neurostimulator may remain implanted following study exit; the decision whether to explant 
will be per physician and patient discretion. 
 
 
 Subjects should be given instructions to contact 
the study doctor or research coordinator if any component of the TNM system is lost, damaged or 
malfunctions following completion in the study. 
Follow-up Visit Data Collection:  
Table 4 outlines requirements for each follow-up visit, including unscheduled visits. Based on the visit 
requirements, the following data points may be collected.  
For logistical and public safety issues (e.g., global pandemic), remote collection of follow-up data will be 
allowed along with remote device access/programming with enabling software (as applicable). If 
available during the study, Medtronic may use remote support to access programming data.  
In addition to collection of adverse events, device deficiencies, OAB medications, protocol deviations 
and study exit data, data points are described, but not limited to, the following sections.    
• 
Post-operative care (e.g., wound healing, compression use, activity level assessment 
questions, etc.)  
• 
Voiding diary 
• 
Questionnaires: OAB-q,
 UPS, 
 
• 
Motor and sensory threshold data 
• 
Programming/device/recharge data 
Periodic Progress Check-in Calls:  
Following the device implant, it is recommended that site personnel contact study subjects within 
approximately 48 hours after each study visit and approximately one week prior to each upcoming visit.   
In addition to these calls, monthly check-in calls will be recommended to start following the 3-month 
follow-up visit. The intent of the call will be to verify the handset “stimulation on” slide button is on, 

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provide recharge reminders for the handset, communicator and wireless recharger and provide any 
reminders for upcoming visits (e.g., diary completion). 
Any adverse events and/or device deficiencies will be collected. 
Unscheduled Visits 
An unscheduled visit may be needed for any device-related reason. During the visit, any OAB medication 
changes, adverse events and/or device deficiencies will be collected. A 3-day urinary voiding diary may 
be completed.   
If any programming changes are made during the visit, the subject will have an impedance check and 
sensory/motor threshold testing done with their foot in the same relaxed position as the time of 
implant. The subject’s sensory and motor threshold will be identified using 20 hertz, 200 microseconds 
pulse width stimulation and titrating up amplitude until the sensory threshold, highest acceptable 
amplitude and motor threshold are confirmed. The neurostimulator amplitude should be set to the 
highest acceptable amplitude. If highest acceptable amplitude is unable to be found, it is recommended 
to set the amplitude to two times the motor or sensory threshold, whichever is lower. The comfort of 
the programmed amplitude will be verified while the subject is in expected positions and adjusted for 
comfort, if needed.   
If the sensory threshold, highest acceptable amplitude and/or motor threshold are not observed, this 
will be documented.  The Investigator (or delegated personnel) should try repeating the motor and 
sensory assessment with the foot in a different position. If the motor and/or sensory response is still not 
observed, the Investigator (or delegated personnel) should set neurostimulator amplitude to 3 mA 
unless an alternative amplitude level is recommended by the Sponsor.    
The subject should have the appropriate program set based on study requirements.  
Programming and device data (e.g., Usage Report, Session Report) will be collected in accordance with 
device instructions prior to the subject leaving the visit and transferred to Medtronic using the 
application on the handset and/or collected on the programming worksheet provided. 
System Modification:  
If the device needs to be explanted or replaced at any time after the implant procedure, a System 
modification procedure will be scheduled. System modifications will include device replacements and 
explants. Subjects will be encouraged to complete a voiding diary prior to any system modification 
procedure. Prior to neurostimulator removal and/or after a new neurostimulator is placed, an 
ultrasound image to assess measurements related to the tibial nerve may be completed. 
During the visit, any relevant medication changes, procedural data, adverse events and/or device 
deficiencies will be collected. Sensory and/or motor thresholds should be assessed (when possible) prior 
to the implant procedure. Device programming (e.g., Usage Report, Session Report) will be collected in 

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accordance with device instructions and documented on the programming worksheet prior to the 
explant (when possible) and at the time of any new implant procedures. The therapy schedule will be 
set based on the timeframe in the study when the system modification was completed, and the therapy 
session may be initiated during the visit or within 24 hours.    
Post-operative instructions should be followed for any replacement neurostimulators. Following a 
system modification, the subject should complete a 7-day post procedure visit. In addition, the subject 
will receive a 1-month post-procedure call in order to assess compression, wound healing, activity levels, 
etc. The subject will then continue their follow-up schedule based on the initial device implant date.   
Post-operative instructions should be followed for any device explant which is not associated with a 
device replacement procedure. The subject will receive a 1-month phone call in order to confirm 
resolution of any ongoing adverse events. It is recommended to follow the subject until all ongoing 
related AEs are resolved or unresolved with no further actions planned.  
No replacement neurostimulators will be provided after participation in the study has ended.  
 

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A pre-screen (recruitment) log will be available to track subjects screened but not consented for the 
study. No subject-specific information will be collected on this log, only the date of review and the 
reason for the screen failure. 
A screening log will be completed by the site to maintain a cumulative log of all screened subjects with 
reason for any screening failures. 
The Investigator will maintain a listing of all subjects enrolled in the study (Subject Identification & 
Enrollment Log). 
10.5 Prior and Concomitant Medications/Therapies 
Restrictions related to use of OAB treatments prior to enrollment in the study is outlined in the study-
specific exclusion criteria. Subjects will be prohibited from taking overactive bladder medications and 
starting any additional advanced therapies for OAB during the first 12 months of their study 
participation. If the subject is consented while taking overactive bladder medications, they must have a 
washout of 2 weeks prior to starting the baseline voiding diary and the baseline Overactive Bladder 
Quality of Life Questionnaire (OAB-q). Any overactive bladder medications will be captured on a study-
specific medication log, and any new advanced therapies for OAB will be captured within the follow-up 
visit.   If additional treatment is added prior to the 12-month follow-up visit, a protocol deviation is 
required. Throughout the study, a voiding diary is required prior to starting any OAB medication or 
advanced therapies to confirm the patient is a non-responder (< 50% improvement from baseline) to 
tibial neuromodulation therapy. If additional treatment is added without confirmation of non-response 
to the therapy documented on a voiding diary, a deviation is required. 
10.6 Subject Consent 
Informed consent is defined as a legally effective documented confirmation of a subject’s voluntary 
agreement to participate in a particular study after information has been given and explained to the 
subject on all aspects of the study that are relevant to the subject’s decision to participate. This process 
includes obtaining an IC form and an Authorization to Use and Disclose Personal Health 
Information/Research Authorization as required by law that has been approved by the study site’s IRB 
and signed and dated by the subject. A subject may only consent after information has been given and 
explained to the subject on all aspects of the clinical investigation that are relevant to the subject’s 
decision to participate.  
Prior to enrolling subjects, the IC and the Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language as required by law must be approved by the 
IRB. The document(s) must be controlled (i.e., versioned and/or dated) to ensure it is clear which 
version(s) were approved by the IRB.  
The investigator must notify the subject of any significant new findings about the study that become 
available during the course of the study which are pertinent to the safety and well-being of the subject, 

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as this could impact a subject’s willingness to participate in the study. If relevant, consent may be 
requested from subjects to confirm their continued participation. 
Prior to initiation of any study-specific procedures, IC must be obtained from the subject. Likewise, 
privacy or health information protection regulation may require subjects to sign additional forms to 
authorize study sites to submit subject information to the study sponsor. The IC process must be 
conducted by the principal investigator or an authorized designee, and the IC Form and Authorization to 
Use and Disclose Personal Health Information/Research Authorization must be given to the subject in a 
language he/she is able to read and understand. The process of IC must be conducted without using 
coercion or undue improper influence on or inducement of the subject to participate by the investigator 
or other study site personnel. The IC process shall not waive or appear to waive subject’s legal rights. 
The language used shall be as non-technical as possible and must be understandable to the subject and 
the impartial witness, where applicable.  
The subject must have ample time and opportunity to read and understand the IC, to inquire about 
details of the study, and to decide whether or not to participate in the study. All questions about the 
study should be answered to the satisfaction of the subject. 
When the subject decides to participate in the study, the IC must be signed and personally dated by the 
subject and investigator or authorized designee, as required by the IC, and ensured by the principal 
investigator or his/her authorized designee. The investigator will clearly mark clinical records to indicate 
that the subject is enrolled in this clinical investigation. 
A copy of the IC and the Authorization to Use and Disclose Personal Health Information/Research 
Authorization, signed and dated as required by law, must be provided to the subject.  
If the IC is obtained the same day the subject begins participating in study-related procedures, it must 
be documented in the subject’s case history that consent was obtained prior to participation in any 
study-related procedures. It is best practice for the IC process to be documented in the subject’s case 
history, regardless of circumstance. 
The date the subject signed the IC and Authorization to Use and Disclose Personal Health 
Information/Research Authorization, as required by law, must be documented in the subject’s medical 
records. Once consent is obtained, report adverse events/deaths, study deviations and subject exits as 
they occur. All subjects who sign the IC will be considered enrolled for the study.   
For logistical and public safety issues (e.g., global pandemic), remote consenting and collection of 
baseline data will be allowed.  
The original of the signed IC must be filed in the hospital/clinical chart and/or with the subject’s study 
documents.  

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The IC and Authorization to Use and Disclose Personal Health Information/Research Authorization as 
required by law must be available for monitoring and auditing. Any Medtronic Field personnel 
supporting the implant procedure must be able to review the subject’s signed and dated IC and verify its 
completeness prior to proceeding with the implant/programming data download. In the event the 
Medtronic Field personnel identifies the IC as being incomplete, the implant procedure will not be 
allowed to occur until the consent of the subject can be adequately and appropriately obtained.  
Consistent with the DoH, vulnerable adults (i.e., those subjects mentally incapable of giving consent) are 
excluded from this protocol. Any subjects with mental incompetence (e.g., Alzheimer’s, dementia, 
psychiatric disorders, developmental disorders) should be assessed for vulnerable status. If the IC is 
signed by an individual other than the subject, the monitor may discuss whether the Investigator 
believes the subject meets the definition of a vulnerable adult. This protocol defines vulnerable adult as 
those subjects mentally incapable of giving consent, in the Investigator’s opinion. The Investigator 
should consider the definition of vulnerable adult per ISO 14155, which defines vulnerable adults as: 
“individuals who are unable to fully understand all aspects of the investigation that are relevant to the 
decision to participate, or who could be manipulated or unduly influenced as a result of a compromised 
position, expectation of benefits or fear of a retaliatory response. For example, this could include 
Individuals with loss of autonomy due to immaturity or through mental disability, persons in nursing 
homes, children, impoverished persons, subjects in emergency situations, ethnic minority groups, 
homeless persons, nomads, refugees, and those incapable of giving IC. Other vulnerable subjects could 
include, for example, members of a group with a hierarchical structure such as university students, 
subordinate hospital and laboratory personnel, employees of the sponsor, members of the armed 
forces, and persons kept in detention.    
10.7 Device Programming 
Subjects are recommended to be set to Therapy Schedule #1 (30 minutes of stimulation every other 
day) until the 6-month follow-up visit. Following the 6-month follow-up visit, any of the 9 preset Therapy 
Schedules may be set.   
For visits requiring the collection of programming and device data (e.g., Session Report, Usage Report) 
starting at the first visit following the device implant, data must be either transferred to Medtronic using 
the application on the handset and/or collected on the programming worksheet provided.   
10.8 Device Explants 
If the device is required to be explanted, a system modification visit will be completed. If the subject has 
the device explanted and a replacement is not anticipated to be implanted, the subject will complete a 
1-month phone call. Following the call, the subject will be exited from the study after all related AEs 
have been resolved or remain unresolved based on the Investigator’s determination with no further 
action planned.  

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It is recommended that all explanted devices be returned to Medtronic for analysis when permissible by 
local laws and regulations. See Section 7 for final product disposition details. 
In the event that a subject has a re-attempt after a previous unsuccessful system modification, the 
subsequent attempt(s) must be reported via eCRF as separate system modifications. 
10.9 Assessment of Efficacy 
Voiding Diaries should be completed prior to or directly after the follow-up visit when data are collected. 
Site personnel should review forms for completeness. 
Urinary Voiding Diary  
Symptoms related to OAB will be evaluated using paper voiding diaries. Subjects will be trained to 
complete the urinary voiding diaries for 3 days with diary details collected (such as date, time, type of 
episode, urgency using the IUSS scale17 nocturia, etc.) as part of the baseline procedures by 
appropriately trained, qualified and delegated site personnel. The urinary voiding diaries will be 
completed for 3 days prior to each subsequent follow-up visit starting at the 1-month follow-up visit (or 
immediately following if not completed prior). Every effort should be made to remind subjects of the 
importance of real-time diary completion. 
10.10 
Assessment of Quality of Life  
Subject assessments will be administered by appropriately trained, qualified, and delegated site 
personnel according to the usual practices of the site. Subjects will complete the study questionnaires 
confidentially on paper forms without site personnel consultation during the visit and these data will be 
entered into the EDC by site personnel.  
Overactive Bladder Quality of Life Questionnaire (OAB-q)  
The Overactive Bladder Quality of Life Questionnaire (OAB-q) is a 33-item validated questionnaire that 
was developed to assess symptom bother and the impact of overactive bladder (OAB) on health-related 
quality of life (HRQL)18. The questionnaire used in the current study includes a 4-week recall for 
symptom assessment. The questionnaire includes an HRQL Total score (comprised of the 4 domains: 
coping, concern, sleep, and social) and a symptom bother score.  
  
 
 
 
 
  
 
 

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Urgency Perception Scale (UPS) 
The Urgency Perception Scale (UPS) is a single item questionnaire measure of perceived urinary urgency 
with three response options22,23.  
10.11 
Assessment of Safety 
All adverse events and device deficiencies (see Section 12) will be collected throughout the study once 
the informed consent form is signed until the subject is exited from the study. 
10.12 
Recording Data 
Data entered must be traceable to source documents. Source documentation is defined as the first time 
data appear, and may include original documents, data, and records (e.g., hospital records, clinical and 
office charts, procedure reports, laboratory notes, memoranda, subjects’ diaries, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate copies, 
ultrasound images, subject files, device data and records kept at other departments involved in the 
study). 
In general, eCRFs (or paper copies) may not serve as source documents, unless specified below. Source 
documentation for data elements not routinely captured in medical records may vary from study site to 
study site; the study site may use source document worksheets. 
The investigator must ensure the availability of source documents from which the information on the 
eCRFs was derived. The type and location of source documents should be documented. Where printouts 
of electronic medical records are provided as source documents, or where copies of source documents 
are retained as source documents, they should be certified. Certification must contain (1) the signature 
of the individual making the copy, (2) the date the copy was made and (3) a statement attesting to the 
accuracy and completeness of the copy.  
The source documents must be made available for monitoring or auditing by Medtronic’s representative 
or representatives of the competent authorities and other applicable regulatory agencies. 
The CRF may be considered source for the following data collection elements: 
• 
Enrollment Notification: Study site assigned subject identifier 
• 
Baseline: Administrative information 
• 
Device Accountability eCRF: All device accountability data points 

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• 
AE eCRF: Date study site became aware of event, Relatedness of adverse event, System 
modification information, Common Terminology Criteria for Adverse Events 
Classification 
• 
DD eCRF: Date study site became aware of event 
• 
Deviations: Reason for deviation 
 
Electronic Data Capture (EDC) 
The Electronic system which is 21CFR§11 Part E compliant controls user access and ensures data 
integrity. This system is a fully validated system. The EDC system maintains an audit trail of entries, 
changes, or corrections in eCRFs. User access will be granted to each individual based on his or her 
delegation of authority and completion of required training. The system which allows the study centers 
to enter study data into the sponsor’s database over a secure internet connection, will be used to 
capture study required Case Report Form (CRF) information. Data reported on urinary voiding diaries 
and subject questionnaires will be entered into the database by site personnel.  
Electronic CRFs (eCRFs) will be provided by the sponsor; required data will be taken from source 
documents and directly entered into the study database via the eCRFs by the site personnel, in 
accordance with applicable regulations. 
The Principal Investigator, Sub-Investigator, or an individual delegated by the Principal Investigator on 
the Delegation of Authority and Signature Form, are responsible for documenting and entering data for 
the study on the eCRFs. The Principal Investigator or Sub-Investigator is required to approve all data on 
eCRFs via electronic signature. 
Programming and Device Data  
Programming and device data (e.g., Usage Report, Session Report) will be collected in accordance with 
instructions provided prior to the subject leaving the visit and transferred to Medtronic using the 
application on the handset and/or collected on the programming worksheet provided.  
Urinary Voiding Diaries  
Symptom data for this study will be collected using paper voiding diaries. 
The paper voiding diary collects details associated with symptoms for each episode. Diaries are to be 
completed only by the subject. The data will be entered to the EDC database by center personnel. 
Center personnel may not make entries to the diaries or questionnaires except for data fields confirmed 
by the subject as documented within source documentation. 
10.13 
Deviation Handling 
A study deviation is defined as an event within a study that did not occur according to the CIP. 

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Prior approval is not required when a deviation is necessary to protect the safety, rights, or well-being of 
a subject in an emergency or in unforeseen situations beyond the investigator’s control (e.g., subject 
failure to attend scheduled follow-up visits, inadvertent loss of data due to computer malfunction, 
inability to perform required procedures due to subject illness). 
For medically justifiable conditions which preempt a subject’s ability to complete a study-required 
procedure, it may be permitted to report only one deviation which will apply to all visits going forward. 
This may also apply for other unforeseen situations (e.g., the subject permanently refuses to complete a 
study required procedure and the data will not contribute to the primary end point analysis). However, 
prior approval from Medtronic is required for such situations.  
All study deviations must be reported on the eCRF regardless of whether medically justifiable, pre-
approved by Medtronic, an inadvertent occurrence, or taken to protect the subject in an emergency. 
Multiple deviations of the same type at the same visit may be reported on a single form in the database. 
In the event the deviation involves a failure to obtain a subject’s consent or is made to protect the life or 
physical well-being of a subject in an emergency, the deviation must be reported to the IRB as well as 
Medtronic within five (5) working days. Reporting of all other study deviations should comply with IRB 
policies and/or local laws and must be reported to Medtronic as soon as possible upon the study site 
becoming aware of the deviation. Reporting of deviations must comply with IRB policies, local laws, 
and/or Regulatory Authority requirements. Refer to Table 11: Investigator reports applicable per 
Medtronic requirements for deviation reporting requirements and timeframes for reporting to 
Medtronic and/or FDA.  
Medtronic is responsible for analyzing deviations, assessing their significance, and identifying any 
additional corrective and/or preventive actions (e.g., amend the CIP, conduct additional training, 
terminate the investigation). Repetitive or serious investigator compliance issues may result in initiation 
of a corrective action plan with the investigator and study site, and in some cases, may necessitate 
suspending enrollment until the problem is resolved or ultimately terminating the investigator's 
participation in the study.  
Examples of study deviations include but are not limited to: 
• 
Failure to obtain proper IC 
• 
Failure to collect required study data (e.g., required study diary) 
• 
Inclusion/exclusion criteria not met 
10.14 
Subject Exit, Withdrawal or Discontinuation 
Subjects are free to voluntarily withdraw from the study at any time and for any reason. All implanted 
subjects will be followed until the 24-month follow-up visit, unless withdrawn from the study. 
Withdrawn or exited subjects will be followed by the Investigator (if still implanted with the study 

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device) or any physician in accordance with standard of care if the subject has been explanted and is 
seeking other treatments for OAB. 
Examples of reasons for study discontinuation include, but are not limited to, those listed below: 
• 
Subject death  
• 
Subject lost to follow-up  
• 
Subject voluntarily withdraws from the study  
• 
Investigator terminates the subject’s participation in the study due to lack of compliance, 
violation of/change in eligibility criteria  
• 
Any clinical laboratory abnormality, current illness, or other medical condition or situation 
occurs such that continued study participation would not be in the best interest of the subject.  
• 
Normal study completion 
Prior to deeming a subject lost to follow-up, telephone calls must be documented in the subject’s 
medical record. When subjects are lost to follow-up the investigator will make efforts to confirm the 
vital status of the subject. If a minimum of three attempts to contact the subject have failed (e.g., phone 
and mailed letter), and no response is received, the site should exit the subject and complete the Study 
Exit eCRF.  When subjects are lost to follow-up the investigator will make efforts to confirm the vital 
status/health status of the subject as described in the informed consent 
When a subject is withdrawn (exited) from the study, the Study Exit eCRF is to be completed and should 
include detailed notes as to why the subject was withdrawn from the study (e.g., discomfort, lack of 
efficacy, diary too burdensome).  
If the subject has the device explanted and a replacement is not implanted, the subject must be exited 
from the study after all related AEs have resolved. Withdrawn subjects will not be replaced. All 
components of the investigational system should be returned unless instructed by Medtronic to dispose 
of product at the institution.  
Once a subject completes participation in the study, the subject will be given guidelines for continued 
therapy use. Any device, procedure and/or therapy related adverse events and all product complaints 
should continue to be reported until the product is explanted.  
10.14.1 
Study Exit 
A Study Exit eCRF is required for all subjects. Prior to exiting a subject from the study, it is recommended 
to follow the subject until all ongoing related AEs are resolved or unresolved with no further actions 
planned. Upon exiting from the study, no further study data will be collected, or study visits will occur 
for the subject. All data available through the time of the subject’s exit will be used for analysis.  
Subjects are urged to remain in the study as long as possible but may be exited from the study for any of 
the following situations: 

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• 
Subject lost to follow-up 
• 
Subject death 
• 
Subject did not meet inclusion/exclusion criteria  
• 
Subject was not implanted with an investigational device 
• 
Subject did not provide consent or data use protection authorization 
• 
Subject chose to withdraw (e.g., consent withdrawal, relocation to another geographic 
location)  
• 
Investigator deemed withdrawal necessary (e.g., medically justified, failure of subject to 
maintain adequate study compliance)  
• 
Device explant with no planned replacement.  
The following information should be collected at study exit: 
• 
Date of exit  
• 
Reason for exit 
10.14.2 
Study Completed 
At the completion of the 24-month follow-up visit, subjects will be exited from the study. The 24-month 
follow-up visit and exit visit should be combined, and both a 24-month follow-up visit eCRF and a Study 
Exit eCRF need to be completed.   
11. Risks and Benefits 
11.1 Potential Risks 
The Clinical Study Risk Management process for the TITAN 2 Study is being performed in accordance 
with the Code of Federal Regulations for Investigational Device Exemptions (IDE) (21 CFR 812), FDA 
guidance, and elements of ISO 14971 applicable to clinical research studies to ensure that the level of 
risk is acceptable prior to starting the study. 
The Medtronic TNM Clinician Guide and MRI Guidelines for the TNM Neurostimulator and associated 
TNM system labeling include system contraindications, precautions, warnings, adverse events, 
directions for use and other system specific details. In addition to the risks normally associated with a 
procedure, the following adverse events may occur with the use of an implantable neurostimulation 
system for tibial neuromodulation. Certain adverse events may necessitate surgical intervention.  
Risks (potential adverse events) related to the tibial neurostimulator implant or explant procedure: 
- Implant site pain  
- Infection  

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- Reaction to local anesthetic (e.g., redness, irritation at the injection site) 
- Wound complications (e.g., swelling, hematoma, bruising, bleeding, seroma)  
Risks (potential adverse events) after implantation of the tibial neurostimulator: 
- Adverse change in bowel and/or urinary function 
- Allergic or immune system response to the implanted materials 
- Device site pain 
- Infection 
- Neurostimulator migration or erosion  
- Uncomfortable stimulation sensations  
There may be technical device problems with the investigational system which could impact therapy 
delivery. 
There is a possibility of risks to an unborn child. These risks are unknown. Women who are pregnant or 
expect to become pregnant during the course of the study are excluded from participating. 
The clinical investigation has been designed to involve as little pain, discomfort, fear, and any other 
foreseeable risk as possible for the subjects, and both the risk threshold and the degree of distress are 
specifically defined in the clinical investigation plan and constantly monitored. 
11.2 General Study Risk/Inconveniences  
Subjects may find completing the urinary voiding diary and questionnaire embarrassing and/or an 
inconvenience.   
As with all clinical research, there may be additional risks related to this study that are not yet known. 
11.3 Risk Minimization 
The potential risks associated with the TNM system and tibial neuromodulation were identified and 
have been successfully mitigated which include mitigations of selecting qualified investigators, training 
study personnel on the CIP and providing adequate instructions and labeling.  
In addition, investigators will be actively involved in the implantation and follow-up of the subjects 
implanted with the TNM device. Risks will be minimized by careful assessment of each subject prior to, 
during, and after implant of the TNM system.  
The subject will be informed of any potential study risks.  
After implantation, subjects in the TITAN 2 Pivotal study will be followed at regular intervals to monitor 
the condition of the implanted device.  

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The Clinical Events Committee and Sponsor will review all related and serious adverse events and/or 
implantation at any time, if necessary, to protect the safety and well-being of subjects. The study will 
pause enrollment and implantation after 7 study subjects experience device migration that results in a 
device explant. This criterion corresponds to a rate of 6% (7/121) of the total planned implanted 
subjects and ensures that the final 90% confidence interval lower bound (2.7%) for the observed rate 
exceeds the previously reported rate of adverse events related to migration that led to device explant 
(2.2%)14.  
Due to lack of reported data regarding adverse events related to erosion in this therapy space, a similar 
pausing criterion will also be applied for erosion that results in a device explant. That is, the study will 
pause enrollment and implantation after 7 study subjects experience device erosion that results in a 
device explant. 
Should enrollment and/or implantation pause due to either of these rules (for device migration or 
erosion), the FDA will be notified. The study will not continue implanting until approval is obtained from 
the FDA. 
11.4 Potential Benefits 
The TNM system may offer no medical benefit. The potential benefits of having the TNM system may 
include an improvement in overactive bladder symptoms. Additionally, information collected from this 
study may assist in the design of new product(s)/therapy(ies), future clinical studies, and/or product 
labeling. 
11.5 Risk-Benefit Rationale 
Residual risks of the TNM system have been characterized as acceptable per Medtronic clinical procedure 
for risk management. No further risk mitigation is required at this time. Medtronic will continue to 
evaluate the risk/benefit profile, safety, and performance of the product as data becomes available. 
The following measures will also be taken to minimize risk to participants as part of this clinical 
investigation plan: 
1. Physicians and staff will receive appropriate training prior to using the study devices. Training 
will include instruction on the implant and explant procedure, TNM system and protocol 
requirements 
2. Instructions are provided with the TNM device and study aids to ensure consistent use of the 
device within pre-tested parameters. 
3. Subjects will be closely monitored by appropriately trained personnel during the procedure 
and at regularly scheduled intervals for the duration of the study where their comfort, any 
potential adverse events and satisfaction will be assessed. 
4. Physicians will employ usual and customary clinical technique (e.g., sterile technique during 
implant use and aseptic wound care procedures).  

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5. Stimulation will be set in clinic with feedback from the study subject 
6. All subjects will have the ability to turn off or adjust stimulation at any time using the provided 
handset and communicator.  
 
In addition to the potential benefits to the subjects of the study in terms of an improvement in 
overactive bladder symptoms, the benefit of the study also lies in the knowledge to be gained from the 
TITAN 2 results and the potential to improve future TNM therapies. Based on the risk acceptance criteria 
for the TITAN 2 study outlined in the risk management documentation, the study-specific residual risk is 
determined to be acceptable given the expected benefits. 
11.6 Risk Determination 
The TNM system used in the TITAN 2 Pivotal study meets the definition for a significant risk (SR) 
investigational device exemption (IDE) study in 21CFR§812.3(m), because it is an implanted device and 
presents a potential for serious risk to the health, safety, or welfare of a subject.   
12. Adverse Events and Device Deficiencies 
12.1 Adverse Events 
All adverse events as well as all device deficiencies will be considered reportable for this study and will 
be collected after the subject is consented to participate in the study through study exit. The term 
“investigational device” is part of ISO 14155:2020 definitions. The term “investigational device” refers to 
any device used in the study including market released devices.  
Adverse event terms are defined as follows: 
• 
Device Related: An adverse event that results from the presence or performance (intended or 
otherwise) of any component of the TNM system 
• 
Procedure Related: An adverse event that occurs due to any procedure related to the 
implantation or explant of the TNM system. The procedure is defined as the neurostimulator 
implant and/or explant procedures  
• 
Study Aids Related: An adverse event that results from the presence or performance (intended 
or otherwise) of any study aids related to the TNM system 
• 
Therapy Related: An adverse event related to therapy delivery by device e.g., device stimulation 
issue (normally therapy-related events resolve when the device is turned off or reprogrammed). 
Adverse events that are classified as possible, probable, or causal are considered to be related for 
analysis purposes. Reporting of adverse events to Medtronic will occur on an AE eCRF. Each event must 
be reported separately. For AEs that require immediate reporting (see Table 10: Reporting 
Requirements), initial reporting may be done by phone or on the eCRF completing as much information 
as possible. The completed AE eCRF must be submitted to Medtronic as soon as possible.   

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Any medication/treatment associated with the treatment of an AE must be reported.  
Subject deaths are also required to be reported in accordance with Table 10: Reporting Requirements.  
All non-subject AEs (users or other persons as defined in Table 6) will be collected throughout the study 
duration. 
Special considerations for adverse events and device deficiencies reporting: 
• 
Normal expected complaints or symptoms reported during or following the procedure which are 
related to ordinary procedure or post-procedure care will be reported as adverse events; 
however, they will not be analyzed as device, procedure, therapy, or study aid-related adverse 
events unless there is a clinically significant change in severity or duration of symptoms, or the 
event requires clinical intervention that is different from ordinary procedure or post-procedure 
care.   
• 
Includes headache, incisional pain, nausea, vomiting, low grade fever, oozing at dressing, 
dizziness, irritability, sleepiness, nervousness, insomnia, constipation, confusion, skin 
irritation/redness, and similar events. 
• 
The Clinical Events Committee will review these events to confirm agreement with the 
decision made by the study investigator. 
• 
Any non-clinically significant stimulation-related effects that occur during the implant 
procedure, programming, and follow-up period will not be considered a reportable adverse 
event. 
• 
Worsening of OAB symptoms (including questionnaire outcomes) will be collected as part of the 
efficacy objectives and will not be considered a reportable adverse event.  
• 
Device movement should be assessed and reported as an adverse event if there is clinically 
significant pain, loss of nerve capture resulting in loss of efficacy, or device explant 
• 
Documented pre-existing conditions are not considered AEs unless the nature or severity of the 
condition has worsened.  
• 
It is recommended that additional diagnostic information be collected to evaluate reported 
adverse events, such as suspected infections. It is recommended that cultures are obtained prior 
to antibiotic treatment for any suspected infections with discharge or that result in device 
explant procedures. Additional diagnostic information should be reported on the Adverse Event 
eCRF.   
12.2 Device Deficiency 
The Device Deficiency (DD) definition is provided in Table 6: Adverse Event and Device Deficiency 
Definitions. DD information will be collected throughout the study and reported to Medtronic. Note that 
DD that result in an AE to the subject should be captured as an AE only. 

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DD that did not lead to an AE but could have led to a SADE (i.e., if suitable action had not been taken, if 
intervention had not been made, or if the circumstances had been less fortunate) require immediate 
reporting (see Table 10: Reporting Requirements). 
12.3 Processing Updates and Resolution 
For any changes in status of a previously reported adverse event or DD (i.e., change in actions taken, 
change in outcome, change in relatedness), information needs to be updated on, or added to the 
original AE or DD eCRF. All AEs must be followed until the AE has been resolved, is unresolved with no 
further actions planned, the subject dies or exits the study, or until study closure, whichever occurs first.  
In the event that a subject is exited from the study prior to their completion in the study, it is 
recommended to continue following the subject until all unresolved related AEs, are resolved or 
unresolved with no further actions planned 
At the time of study exit, all collected adverse events that are unresolved must be reviewed and an 
update to the original AE must be reported. 
12.4 Definitions/Classifications 
Where the definition indicates “device”, it refers to any investigational device or system component 
used in the study. Table 6: Adverse Event and Device Deficiency Definitions contains adverse event and 
device deficiency definitions.  

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Unanticipated Serious Adverse 
Device Effect (USADE)  
(ISO 14155:2020, 3.51) 
Serious adverse device effect which by its nature, incidence, severity, or 
outcome has not been identified in the current risk assessment 
 
NOTE 1: Anticipated serious adverse device effect (ASADE) is an effect 
which by its nature, incidence, severity, or outcome has been identified in 
the risk assessment.  
 
 
 
Serious Health Threat 
(ISO 14155:2020, 3.46) 
Signal from any adverse event or device deficiency that indicates an 
imminent risk of death or a serious deterioration in the health in subjects, 
users, or other persons, and that requires prompt remedial action for other 
subjects, users, or other persons 
 
NOTE 1: This would include events that are of significant and unexpected 
nature such that they become alarming as a potential serious health hazard 
or possibility of multiple deaths occurring at short intervals.  
 
 
 
 

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updated. If the death occurs at a location remote from the study site, it is the study site’s responsibility 
to make every attempt to retrieve all pertinent information related to the subject’s death and submit 
the investigator’s death summary of the known events surrounding the death to Medtronic or its 
designee. The Investigator should also attempt to determine, as conclusively as possible, whether such 
deaths are related to the device system, therapy, and/or procedure. In addition, the principal 
investigator should follow commercial medical device reporting requirements. The principal investigator 
should provide as much of the following supporting documentation as possible for deaths: 
• Death certificate 
• Death summary/hospital records, if allowed by state/local law 
• Autopsy report, if allowed by state/local law 
All device system components that were being used at the time of the death should be returned to 
Medtronic for analysis, if applicable. Any subject death will be reported on the Adverse Event and Study 
Exit eCRFs. 
Regulatory reporting of Subject Deaths will be completed in accordance with FDA requirements. 
12.7 Product Complaint Reporting 
It is the responsibility of the investigator to report all product complaint(s) associated with a medical 
device distributed by Medtronic, regardless of whether they are related to intended use, misuse, or 
abuse of the product. Reporting must be done immediately and via the regular channels for market-
released products. The reporting of product complaints by the clinical team must be done according to 
the local Standard Operating Procedures.  Medtronic will notify FDA of events as determined to be 
reportable based on FDA requirements outlined in 21 CFR 812.150(b).   
13. Data Review Committees 
13.1 Clinical Events Committee Review 
At regular intervals, an independent CEC will conduct a medical review of all reported related and/or 
serious adverse events for subjects participating in the study.  
The CEC will consist of a minimum of three (3) non-Medtronic employed physicians that are not 
participating investigators for the study, including a CEC chairperson. At least three CEC members must 
adjudicate, at a minimum, all deaths and serious AEs related to any component of the system under 
investigation. All other AEs must be adjudicated by at least one physician member of the CEC.  
In addition, the CEC will periodically review trending of reported adverse events to make 
recommendations to the Sponsor whether to continue, modify or stop the study based on pre-specified 
pausing rules defined in the clinical investigational plan.   

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The CEC Charter will define the CEC processes for member selection, meeting frequency, roles and 
responsibilities, procedures, and record keeping. 
Medtronic personnel may facilitate and participate in an CEC meeting but will be non-voting members. 
If the CEC disagrees with the investigator’s classification of the event, the rationale will be provided to 
the investigator. If the investigator agrees with the CEC’s adjudication, the CRF documenting the AE will 
be updated accordingly. 
If the investigator does not agree with the CEC’s adjudication classification, both determinations will be 
provided within the final report; however, the CEC’s adjudication will be used for data analysis. The 
disagreement will also be included in reporting to IRBs and regulatory authorities, if required. 
13.2 CRO 
No CRO(s) will be used in the TITAN 2 Pivotal study. 
14. Statistical Design and Methods 
This section presents statistical considerations for the study design and provides a high-level description 
of planned analysis and reporting. More details will be given in a separate Statistical Analysis Plan that 
will be approved before data freeze or lock. Any deviation to the pre-specified statistical analyses will be 
noted in the study report.  
14.1 General Aspects of Analysis 
The study will be considered successful when the primary objective is met. 
For each of the objectives, the available data will be summarized, and missing data will be discussed. 
The main analysis of the study objectives will be intention-to-treat, meaning that the analysis will use 
the Full Analysis Set (FAS). The FAS includes all subjects, using the intention-to-treat (ITT) principle, who 
have an attempted device implant. Additional information on missing data plans are found in section 
14.1.2. 
Analyses of all data will be summarized with standard descriptive summary statistics, including counts 
and percentages for categorical variables, and mean, standard deviation, median, minimum, and 
maximum for continuous variables. The primary objective will be tested as described in section 14.4.1. If 
the primary objective is passed, the secondary objectives will each be tested as described in section 14.5 
following the Hochberg multiple testing strategy. All p-values will be reported as 2-sided tests. 
Additionally, 95% Confidence intervals will be supplied for selected measures. 
Safety data will be summarized as the count of events, count of subjects, and percentage of subjects 
who experienced the event. Subject disposition will be illustrated in a flow diagram. Subject visits will be 

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tabulated and compliance to the visit schedule and visit windows will be summarized. Attrition will be 
identified and summarized.  
Data analysis will be performed by Medtronic-employed statisticians or designees. A validated statistical 
software package (e.g., SAS version 9.4 or higher) will be used to analyze the study results. PASS 2019 
sample size calculation software was utilized for determination of sample sizes and associated statistical 
power calculations. 
14.1.1 
Analysis Sets 
All Enrolled analysis set: Includes subjects who completed the informed consent process.  
Full Analysis Set (FAS): Includes subjects with an attempted implant. If all implant procedures are 
successful, this will be equivalent to the All Implanted Analysis set. 
All Implanted Analysis set: Includes subjects who are implanted. 
Complete Case analysis sets: Includes subjects who are implanted and provide outcome measures at 
both baseline and follow-up visits. This set is defined for each outcome measure at each follow-up visit. 
The study requires subjects to have UUI to be implanted. UUI subjects are those who have ≥1 urinary 
urge incontinence episode per day at baseline. For analysis purposes, Urinary Frequency (UF) subjects 
are those who have ≥10 urinary frequency episodes per day at baseline and all subjects will be 
considered to have urinary urgency since all eligible subjects have UUI. Some supportive, secondary 
objective, and additional measure analyses may use different definitions or subsets of the analysis sets 
listed above (e.g., changed assumptions for those subjects considered to have either UUI or UF).  
14.1.2 
Handling Missing Data 
Primary and secondary objectives will be analyzed using the FAS. The FAS includes all subjects, using the 
intention-to-treat principle, who have an attempted device implant. All attempts will be made to 
minimize missing data. For diary-based metrics, missing is defined as any diary which has a total length 
of less than 48 hours, as defined in section 14.1.5. The OAB-q may be missing if the HRQL Total cannot 
be calculated; scoring details are found in section 14.5.4. If 5% of the data or fewer are missing for the 
analysis, no imputation will be used and the data will be analyzed using the Complete Case analysis 
set25. Otherwise, if missing data are observed, imputation will be used for the primary and secondary 
objectives.  
The primary objective imputation will be done using multiple imputation (MI). Predictive mean matching 
multiple imputation will be used for each variable. First, multiple imputation will be applied to impute 
missing values in average daily UUI episodes. Unless model errors dictate otherwise, each model will 
consider Baseline and Month 1, Month 2, Month 3, and Month 6 variables for the UUI episodes variable 
and demographic variables of age, gender, history of pregnancy, and BMI. The fully conditional 
specification (FCS) method within SAS (version 9.4 or higher) with 30 repetitions and 100 burn-in 

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iterations will be used for imputation. No limits will be defined for imputed values. Following 
imputation, the 6-month outcome data will be converted to the appropriate endpoint (i.e., change from 
baseline/UUI responder). The estimate and variance of the mean proportion of subjects considered a 
UUI responder will be determined for each imputation dataset. For the primary objective, the mean and 
variance for the proportion will be determined using MI analysis methods and the objective will be 
tested using a Z-test comparing the observed responder rate to the primary objective performance goal 
of 40%. 
For the secondary objectives, the following imputation steps will be taken: 
o For secondary objectives related to UUI episodes, the imputation datasets created for the 
primary objective will be used. For OAB-q HRQL, UF episodes, and urgency, a new set of 
imputation datasets will be created following the same methods as the primary objective 
but replacing UUI episodes with OAB-q HRQL, UF episodes, or urgency score. 
o After imputation, the normality for the outcome metric will be checked through Shapiro-
Wilk test for each imputation dataset. If p-value>0.05 for at least 15 imputed datasets (half 
of the total), it will be considered that the data are normally distributed. In this case, the 
mean and standard error of the outcome metric will be calculated within each imputed 
dataset, and then combined using MI analysis methods. The mean and standard error of the 
outcome metric will be reported, and the objective will be tested with a t-test. 
o If the distribution of outcome metric is non-normal (p-values ≤0.05 in more than 15 of the 
imputed datasets), MI will not be used. Instead, last observations carried forward (LOCF) will 
be applied, with the imputed dataset tested using the Wilcoxon signed-rank test. 
Sensitivity analyses will be completed for the primary and secondary objectives including subjects who 
received a TNM implant (“All Implanted Analysis”), using only subjects with outcome data at baseline 
and follow-up (“Complete Case Analysis”), and using only those complete case subjects who received 
stimulation (“As Treated Analysis”). 
 
 Comprehensive descriptions of subject 
accountability and missing data will be provided. 
14.1.3 
Multiplicity Adjustments 
The primary objective is the percentage of subjects considered a UUI responder at 6 months. Four 
secondary objectives will also be assessed, all of which will be assessed 6 months after implantation of 
tibial neuromodulation.  
To support an indication for OAB, device effectiveness will be demonstrated for the symptoms 
associated with OAB, including UUI, UF, and urgency. UUI therapy effectiveness will be demonstrated if 
the primary objective proportion of subjects with UUI response is greater than the performance goal 
(40%).  UF therapy effectiveness will be demonstrated if the secondary UF objective demonstrates an 

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improvement from baseline to 6 months in number of UF episodes. Urgency therapy effectiveness will 
be demonstrated if the secondary urgency objective demonstrates an improvement from baseline to 6 
months in urinary urgency. 
The p-values for the primary and secondary objectives will be calculated according to the methods 
outlined in their respective analysis sections. The p-values will be reported unadjusted and two-sided; 
however, declarations of statistical significance will follow the procedures laid out in this section. 
The primary objective will be tested separately from the secondary objectives. If the one-sided primary 
objective p-value is <0.025, then the null hypothesis will be rejected, and the test will be declared 
statistically significant. 
The Hochberg method for the multiplicity adjustment will be used to test the four secondary objective 
hypotheses, thereby maintaining an overall two-sided type I error rate at 0.05 for these objectives. Each 
p-value for the four secondary objectives will be calculated. If all p-values are less than 0.05 (two sided), 
all will be declared significant. If not, the p-values will be ordered from largest to smallest (identified as 
p1-p4 in this section).  If p1 is greater than 0.05, the remaining p-values (p2, p3, p4) will be compared 
against an alpha of 0.025 (0.05/2). If the three remaining p-values are all less than 0.025, they will all be 
declared significant. If p2 is greater than 0.025, the remaining p-values (p3, p4) will be compared against 
an alpha of 0.017 (0.05/3). If p3 and p4 are both less than 0.017, they will both be declared significant. If 
p3 is greater than 0.017, p4 will be compared against an alpha of 0.013 (0.05/4). If p4 is less than 0.013, 
it will be declared significant. 
The multiplicity adjustment will be performed for evaluations of the secondary endpoints only. No 
multiplicity adjustment will be performed for supporting, sensitivity, or subset analyses or for 
evaluations of the additional study measures. 
14.1.4 
Study Site Pooling 
The investigators of this study will conduct the study according to this protocol and use the study-
specific eCRFs to collect study data. The study site personnel will be trained prior to the study initiation 
at each study site. Periodic study monitoring by Medtronic will ensure compliance with protocol 
requirements. Therefore, there is no a priori provision to exclude any study sites from the analysis. The 
data from all study sites will be pooled for analysis. To reduce the possibility of atypical results from a 
study site overly influencing the combined results, no more than 24 subjects will be implanted at each 
study site. The per-study site enrollment cap may be increased upon Sponsor approval. 
As an exploratory analysis to assess if treatment effect differs by study center, Freeman and Halton’s 
extension of Fisher’s exact test will be conducted using UUI responder as the response variable. This 
analysis will be based on the Complete Case analysis set for the primary objective. If the p-value 
approaches statistical significance (defined as ≤0.15), the percentage of subjects who are considered a 
UUI responder will be presented by site. If center(s) causing the significance are identified, variables 

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relating to patient characteristics and other factors will be analyzed to try to identify why this center is 
showing a different treatment effect.  
To increase the power of the test for treatment-by-center interaction, all study centers that are too 
small (fewer than four implanted subjects) to be reliably analyzed alone or to have a noticeable impact 
on overall study results will be combined into one “virtual” study center. All other study centers with 
four or more implanted subjects will stand alone in the analysis. If the virtual study center is larger than 
30 implanted subjects (~25% of the required sample size), the virtual study center will be split into 2 
virtual study centers defined by ordering the study centers alphabetically and splitting the study centers 
as near the midpoint as possible. In the case that the midpoint is within an individual study center, that 
study center will be included with the study centers from earlier in the alphabet.  
14.1.5 
Diary Data Analysis 
The primary and several other objectives and additional measures are based on the analysis of voiding 
diary data. The diary will be collected for 3 days prior to or after each study visit. The site will assign 
each diary to the corresponding visit in the eCRF. In some cases, the diary might be completed for 
slightly less or more than 3 days (e.g., for 68 or 75 rather than the expected 72 hours). All diaries which 
are greater than 48 hours will be used for analysis. For UI, UUI, and UF, the total number of episodes will 
be determined for each subject’s diary collection period at each visit. The actual total length of the diary 
for each visit will be determined by using the subject-specific diary start and end time reported by the 
site. The number of episodes will be divided by the total length of the diary for that subject at the visit 
and reported as a daily (24 hour) rate (i.e., ‘per day’). The change will be determined by subtracting the 
baseline value per day from the follow-up value per day. Percentage change will be determined by 
dividing the change in episodes per day by the baseline value. Negative values for change and 
percentage change represent an improvement.  Responder rate for UUI is defined as the proportion of 
TNM subjects experiencing a reduction of 50% or more in daily urinary urge incontinence (UUI) 
episodes. Responder rate for UF is defined as the proportion of TNM subjects experiencing a reduction 
of 50% or more in daily urinary frequency (UF) episodes or a return of voiding to <8 voids per day. 
Responder rate for UI is defined as the proportion of TNM subjects experiencing a reduction of 50% or 
more in daily urinary incontinence (UI) episodes. Responder rate for urinary urgency (UU) is defined as 
the proportion of TNM subjects with an improvement of at least 1 point on the UPS. OAB responder rate 
is defined as the proportion of TNM subjects who are considered either a UUI, UF, or UU responder. 
 
 
 
 
 
 
 

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14.2 Analysis Execution 
Study progress reports will be submitted annually. Analysis for the purposes of supporting pre-market 
approval applications will occur once all subjects have completed the 6-month follow-up visit and will 
include the primary and secondary objectives and detailed safety summaries. Additional measures will 
be addressed based on available data at time of the pre-market approval application. A final report will 
be prepared once all data collection has ended and all subjects have completed the 24-month follow-up 
visit or have been exited. The inferential analysis for the primary and secondary objectives will not be 
updated for the final report.  
14.3 Interim Analysis 
No interim analyses are planned for this study.  
14.4 Primary Objective 
14.4.1 
Primary Objective – UUI Responder Rate 
To demonstrate that the percentage of subjects who are considered a UUI responder after 6 months of 
tibial neuromodulation exceeds a performance goal of 40%.  
Hypothesis: The percentage of subjects who are considered an UUI responder 6 months after tibial 
neuromodulation implantation is greater than 40%.  
H0: p ≤ 40% 
HA: p > 40% 
Where p = the percentage of subjects who are UUI responders 
Endpoint Definition and Derivation: A 3-day urinary voiding diary be used to collect bladder symptoms, 
including UUI episodes. The primary objective endpoint is the proportion of tibial neuromodulation 
subjects considered a UUI responder at 6 months after device implant. A subject is considered a UUI 
responder if they meet the UUI responder criteria as defined in the voiding diary analysis section 14.1.5.  
Performance Requirements: The null hypothesis will be rejected if the two-sided p-value is less than 
0.05. 
Rationale for Performance Criteria: The proposed study design includes a primary objective 
performance goal of 40%. The performance goal defines an active historical control for this study and 

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was defined to position the outcome between the expected performance for medications and the more 
complex SNM treatment.  
Sample Size Justification: The sample size justification for the primary objective is provided in section 
14.7. 
Analysis Methods: The analysis for UUI responder rate will be summarized at 6 months after implant. If 
5% of the data or fewer are missing for the primary analysis, no imputation will be used and the 
objective will be tested using a binomial test for the Complete Case analysis set. Otherwise, missing data 
will be imputed for the Full Analysis Set as specified in section 14.1.2, and the objective will be tested 
using a Z-test. The two-sided 95% confidence interval will also be provided.  
Determination of Subjects/Data for Analysis: The primary objective analysis will include all subjects 
from the Full Analysis Set (i.e., all implant attempted subjects) as defined in section 14.1.1.  
Supportive and Sensitivity Analyses: There are no requirements or expectations for the results of the 
supporting and sensitivity analyses. They are meant to investigate the robustness of the study results 
and/or to provide further details on the therapy effects.  
Additional supporting analyses to further understand the primary objective will be completed through 
analyses of the change in UUI (secondary objective) and percentage change in UUI (additional measure). 
To assess the robustness of the primary objective results under the influence of missing data, sensitivity 
and subgroup analyses will be conducted using alternative missing data methods and by including 
different subsets of subjects. The first sensitivity analysis will be completed including subjects from the 
Primary Objective Complete Case analysis set. This analysis set will be used for a second sensitivity 
analysis which will be completed including only subjects who received stimulation (‘As treated analysis’) 
at the 6-month follow-up visit. An analysis will also be completed to evaluate UUI responder rate 
differences between different programs. A tipping point sensitivity analysis will also be completed. A 
final sensitivity analysis will be conducted on the Primary Objective Complete Case analysis set assigning 
response failure for all subjects who took OAB medication or received an advanced therapy from 
implant to the 6-month follow-up visit. 
Complete Case analysis set subgroup analyses will be done for the following subject groups: sex, age 
(divided by median age; divided by age 65), race, and ethnicity. Subjects on the demographic cut point 
will be added to the adjacent group containing fewer subjects. Any subgroup with less than 10 subjects 
will not be reported. 
As an exploratory analysis to assess if treatment effect differs by study center, a supporting analysis will 
be completed, as described in 14.1.4. This analysis will test whether the treatment effect is 
homogeneous between study centers for the UUI responder rate at 6 months. 

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UUI responder rate will be assessed over time through 24 months as part of the additional measures. 
14.5 Secondary Objective(s) 
The following secondary objectives have specific hypotheses to be tested.  After the primary objective is 
met, these four secondary objectives will be tested as described in 14.1.3. 
14.5.1 
Secondary Objective – UUI Change 
To demonstrate an improvement from baseline to 6 months in number of UUI episodes in subjects with 
UUI at baseline 
Hypothesis: The change from baseline in UUI episodes is not 0. 
H0: µ = 0 
HA: µ ≠ 0 
Where µ = the change in UUI episodes 
Endpoint Definition and Derivation: A 3-day urinary voiding diary will be used to collect bladder 
symptoms, including UUI episodes. Calculation of change in UUI is defined in the voiding diary analysis 
section 14.1.5. A negative change in UUI episodes represents an improvement. 
Performance Requirements: The null hypothesis will be rejected if the two-sided p-value is determined 
to be significant, as described in section 14.1.3. 
Sample Size Justification: Data from published studies or studies presented at conferences on TNM 
outcomes at 3, 6, and 9 months were used as starting points to estimate expected reduction in UUI 
episodes as well as expected patient-to-patient variability. Assumption on the expected mean difference 
(-2.0 episodes per day) and standard deviation (3.5 episodes per day) was used to assess statistical 
power. Presuming a two-sided, one-sample t-test with alphas ranging from 0.013 to 0.05, power is 
calculated to be no less than 99% for any of the scenarios examined with a sample size of 121 subjects. 
Additionally, the minimum detectable change in mean episodes was calculated to be as low as -1.0. 
Analysis Methods: The analysis for change in UUI will be summarized for baseline, at 6 months after 
implant, and for the change from baseline. If 5% of the data or fewer are missing for the analysis, no 
imputation will be used, and the objective will be tested using a paired t-test following the multiple 
testing strategy described in section 14.1.3. If more than 5% of the data are missing, missing  data will be 
imputed as specified in section 14.1.2. If non-normality of the data is detected via a significant (p<0.05) 
Shapiro-Wilk test, a Wilcoxon signed-rank test will replace the t-test.  
Determination of Subjects/Data for Analysis: The change in UUI analysis will include all subjects from 
the Full Analysis Set (i.e., all implant attempted subjects) as defined in section 14.1.1. 

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Supportive and Sensitivity Analyses: There are no requirements or expectations for the results of the 
supporting and sensitivity analyses.  
Additional supporting analyses to further understand the UUI secondary objective will be completed 
through analyses of the percentage change in UUI (additional measure). 
To assess the robustness of the objective results under the influence of missing data, sensitivity analyses 
will be conducted using alternative missing data methods. The first sensitivity analysis will be completed 
including subjects from the Secondary Objective (UUI Change) Complete Case analysis set. This analysis 
set will be used for a second sensitivity analysis which will be completed including only subjects who 
received stimulation (‘As treated analysis’) at the 6-month follow-up visit. A final complete case 
sensitivity analysis will be performed comparing the change in UUI episodes to a performance goal of 1 
episode/day. 
UUI change from baseline will be assessed over time through 24-months as part of the additional 
measures. 
14.5.2 
Secondary Objective – UF Change 
To demonstrate an improvement from baseline to 6 months in number of UF episodes in subjects with 
UF at baseline 
Hypothesis: The change from baseline in UF episodes is not 0. 
H0: µ = 0 
HA: µ ≠ 0 
Where µ = the change in UF episodes 
Endpoint Definition and Derivation: A 3-day urinary voiding diary will be used to collect bladder 
symptoms, including UF episodes. UF episodes include all urinary voids. Calculation of change in UF is 
defined in the voiding diary analysis section 14.1.5. A negative change in UF episodes represents an 
improvement. 
Performance Requirements: The null hypothesis will be rejected if the two-sided p-value is less than 
0.05.  
Sample Size Justification: Data from published studies on TNM outcomes at 6 months were used as a 
starting point to estimate expected reduction in UF episodes as well as expected patient-to-patient 
variability. Assumption on the expected mean difference (-2.0 episodes per day) and standard deviations 
(3.0 episodes per day) were used to assess statistical power. Presuming a two-sided, one-sample t-test 
with alphas ranging from 0.013 to 0.05, power is calculated to be no less than 98% for any of the 
scenarios examined with a sample size of 51 subjects (as only 42% of the total 121 subjects in the study 
are expected to have UF with 10 episodes per day at baseline). Additionally, the minimum detectable 
difference in mean daily episodes was calculated to be as low as 1.4. 

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Rationale for Clinical Relevance: No published data are available defining minimum clinically meaningful 
improvement for the change in UF episodes. In the absence of published definitions, assessment of 
effect size can be used to determine the level of effect. As published by Cohen (1988)27, an effect size of 
0.2 indicates a small effect, 0.5 a modest effect, and 0.8 a large effect. A modest effect size would 
correspond to a change of -1.5 episodes per day. The assumed mean ± standard deviation difference of 
2.0 ± 3.0 UF episodes per day (i.e., an effect size = 0.67) for implantable tibial therapy is considered a 
medium to large effect.  
Analysis Methods: The analysis for change in UF will be summarized for baseline, at 6 months after 
implant, and for the change from baseline. If 5% of the data or fewer are missing for the analysis, no 
imputation will be used, and the objective will be tested using a paired t-test following the multiple 
testing strategy described in section 14.1.3. If more than 5% of the data are missing, missing data will be 
imputed as specified in section 14.1.2. If non-normality of the data is detected via a significant (p<0.05) 
Shapiro-Wilk test, a Wilcoxon signed-rank test will replace the t-test.  
Determination of Subjects/Data for Analysis: The change in UF analysis will include all subjects from the 
Full Analysis Set (i.e., all implant attempted subjects) who have UF as defined in section 14.1.1. 
Supportive and Sensitivity Analyses: There are no requirements or expectations for the results of the 
supporting and sensitivity analyses.  
To assess the robustness of the objective results under the influence of missing data, sensitivity analyses 
will be conducted using alternative missing data methods. The first sensitivity analysis will be completed 
including subjects from the Secondary Objective (UF Change) Complete Case analysis set. This analysis 
set will be used for a second sensitivity analysis which will be completed including only subjects who 
received stimulation (‘As treated analysis’) at the 6-month follow-up visit. A final complete case 
sensitivity analysis will be performed comparing the change in UF episodes to a performance goal of 1 
episode/day. A Complete Case supporting analysis will be provided assessing the UF change from 
baseline using different definitions of UF (UF defined as ≥8 and UF defined as ≥12). 
UF change from baseline will be assessed over time through 24 months as part of the additional 
measures. 
14.5.3 
Secondary Objective – UPS Change 
To demonstrate an improvement from baseline to 6 months in urgency using the Urgency Perception 
Scale (UPS) 
Hypothesis: The change from baseline in UPS is not 0.  
H0: µ = 0 
HA: µ ≠ 0 
Where µ = the change in UPS score 

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Endpoint Definition and Derivation: The UPS will be used to collect OAB urgency. The UPS was 
developed to assess urgency associated with overactive bladder (OAB). The UPS is a single question 
assessed at each visit and has 3 options for responses: 1, ‘I am usually not able to hold urine’; 2, ‘I am 
usually able to hold urine until I reach the toilet if I go immediately’; and 3, ‘I am usually able to finish 
what I am doing before going to the toilet’. Change from baseline is calculated by subtracting the 
baseline value from the follow-up value. Therefore, the change can range from -2 to 2 (with positive 
change indicating an improvement)23. 
Performance Requirements: The null hypothesis will be rejected if the two-sided p-value is determined 
to be significant, as described in section 14.1.3. 
Sample Size Justification: Internal data from TNM outcomes were used as a starting point to estimate 
expected change in UPS as well as patient-to-patient variability in that change. Assumptions on the 
expected mean difference (0.50) and standard deviation (0.80) were used to assess statistical power. 
Presuming a two-sided, one-sample t-test with alphas ranging from 0.013 to 0.05, power is calculated to 
be at least 99% for any of the scenarios examined with a sample size of 121 subjects. Additionally, the 
minimum detectable change in UPS was calculated to be as low as 0.24 points.  
Rationale for Clinical Relevance: No published data are available defining minimum clinically meaningful 
improvement for UPS. In the absence of published definitions, assessment of effect size can be used to 
determine the level of effect. As published by Cohen (1988)27, an effect size of 0.2 indicates a small 
effect, 0.5 a modest effect, and 0.8 a large effect. A modest effect size would correspond to a change of 
0.4 in the mean UPS. The assumed mean ± standard deviation change of 0.5 ± 0.8 in the UPS (i.e., an 
effect size = 0.63) for tibial therapy is considered a medium to large effect.  
Analysis Methods: The analysis for UPS will be summarized for baseline, at 6 months after implant, and 
for the change from baseline. If 5% of the data or fewer are missing for the analysis, no imputation will 
be used, and the objective will be tested using a paired t-test following the multiple testing strategy 
described in section 14.1.3. If more than 5% of the data are missing, missing data will be imputed as 
specified in section 14.1.2. If non-normality of the data is detected via a significant (p<0.05) Shapiro-Wilk 
test, a Wilcoxon signed-rank test will replace the t-test. 
Determination of Subjects/Data for Analysis: The UPS analysis will include all subjects from the Full 
Analysis Set (i.e., all implant attempted subjects) as defined in section 14.1.1 as all subjects are expected 
to have urgency. 
Supportive and Sensitivity Analyses: There are no requirements or expectations for the results of the 
supporting and sensitivity analyses. 
To assess the robustness of the objective results under the influence of missing data, sensitivity analyses 
will be conducted using alternative missing data methods. The first sensitivity analysis will be completed 

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including subjects from the Secondary Objective (UPS) Complete Case analysis set. This analysis set will 
be used for a second sensitivity analysis which will be completed including only subjects who received 
stimulation (‘As treated analysis’) at the 6-month follow-up visit. A third sensitivity analysis will be 
performed excluding those subjects who report limited problems with urgency, as reported by a 
baseline score of 3 on the UPS. A final complete case sensitivity analysis will be performed comparing 
the change in urgency to a performance goal of 0.4. 
A supportive analysis will be completed summarizing the percentage of subjects in each category at 
each visit. 
UPS change from baseline will be assessed over time through 24 months as part of the additional 
measures.  
14.5.4 
Secondary Objective – OAB-q Change 
To demonstrate an improvement from baseline to 6 months in quality of life (QoL) using the Overactive 
Bladder Symptom Quality of Life Questionnaire (OAB-q) 
Hypothesis: The change from baseline in OAB-q HRQL is not 0.  
H0: µ = 0 
HA: µ ≠ 0 
Where µ = the change in OAB-q HRQL total score 
Endpoint Definition and Derivation: The OAB-q will be used to collect quality of life. The OAB-q was 
developed to assess symptom bother and the impact of overactive bladder (OAB) on health-related 
quality of life (HRQL). The Health-Related Quality of Life (HRQL) total score is calculated by summing the 
four subscale scores (coping, concern, sleep, social). For each subscale, if <50% of the items are missing, 
the subscale is retained with the mean of the items present used to impute the missing items in that 
subscale. If ≥50% of items in any subscale are missing, the HRQL Total will be missing. A positive change 
in OAB-q HRQL score represents an improvement. 
Performance Requirements: The null hypothesis will be rejected if the two-sided p-value is determined 
to be significant, as described in section 14.1.3. 
Sample Size Justification:  
Data from a published study on TNM outcomes at 6 months were used as a starting point to estimate 
expected change in OAB-q HRQL score as well as patient-to-patient variability in that change.   
Assumptions on the expected mean change (20 points) and standard deviation (30 points) were used to 
assess statistical power. Presuming a two-sided, one-sample t-test with alphas ranging from 0.013 to 
0.05, power is calculated to be no less than 99% for any of the scenarios examined with a sample size of 

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14.7 Sample Size Determination 
The sample size for the primary objective was estimated using a binomial distribution for a one-sided 
alpha=0.025 test to show a 15% increase for the proportion compared to a performance goal of 40%. 
Assuming the alternative hypothesis of ≥55% of subjects who are considered an UUI responder, a 
minimum of 121 implant attempted subjects achieves at least 90% power to reject a performance goal 
of 40%. The primary objective will have at least 88% power for any alternative hypothesis that is at least 
15% larger than a performance goal. Secondary objectives are also expected to be adequately powered 
based on this sample size. 
Assuming a ~40% attrition rate before implant, up to 200 subjects will be consented to achieve at least 
121 subjects with implant attempted. Enrollment will be closed once the number of completed implants 
reaches 121; all enrolled subjects who meet eligibility criteria may be implanted (not to exceed 130 total 
implants). Implant attempted subjects who exit from the study will not be replaced. 
14.8 Minimization of Bias 
Potential sources of bias that may be encountered in this study have been considered and minimized by 
careful study design. Methods incorporated in the study design to minimize potential bias include (but 
are not limited to): 
• 
To ensure a widespread distribution of data and minimize site bias in study results, the 
maximum number of subjects to be implanted at a single study site shall not exceed 20% (24 
subjects) of the total implanted subjects 
• 
A statistical analysis plan will be developed prior to analyzing data which will document all 
prespecified analyses and analysis methods 
• 
Well justified performance goals, defined based on historical controls from multiple sources, are 
applied for each objective 
• 
All study investigators will be trained on and required to follow the CIP 
• 
All study investigators and Medtronic personnel will be trained on their respective aspects of 
the study using standardized training materials 
• 
All sites will use the same version of the CIP and standardized case report forms 
• 
All study investigators will be required to meet 21 CFR Part 54, Financial Disclosure by Clinical 
Investigators 
• 
Monitoring will be conducted to verify adherence to the CIP 
 
In summary, potential sources of bias that may be encountered in this study have been considered and 
minimized by careful study design. 

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14.9 Safety Evaluation 
All AEs and DDs will be collected throughout the study once the informed consent form is signed. AEs 
and DDs will be coded and summarized using the most recent version of Medical Dictionary for 
Regulatory Affairs (MedDRA). Severity will be assessed by the Investigator. Relatedness and seriousness 
of the events will be classified by the Investigator, CEC, and the Sponsor. Cases where the Investigator’s 
classification does not match the CEC’s classification will be displayed within the final report; however, 
the CEC’s adjudication will be used for data analysis. 
Adverse events and DDs that occur prior to implant will be summarized. Adverse events and DDs that 
occur on or after tibial neuromodulation implant date through study discontinuation will also be 
summarized; summaries specific to the timeframe from implant to the 6-month follow-up visit will be 
included. The denominator will be the number of subjects in the All Implanted analysis set. Adverse 
events in subjects with implant attempted but without full implant will also be summarized. Events that 
occur in subjects with an unsuccessful implant procedure will be included in the summaries. AEs and 
DDs will be summarized with number of events, number of subjects who experienced the event, and 
percentage of subjects who experienced one or more events. 
15. Ethics 
15.1 Statement(s) of Compliance 
This study will be conducted in compliance with this clinical investigation plan (CIP) and good clinical 
practice (GCP) according to the US CFR on Electronic records (21 CFR§11), Protection of human subjects 
(21 CFR§50), Financial disclosure by clinical investigators (21 CFR§54), Institutional review boards (21 
CFR §56), Medical Device Reporting (21CFR§803), Investigational Device Exemptions (21CFR§812), the 
ethical principles that originate from the Declaration of Helsinki, and applicable local regulatory 
requirements and laws in the states in which the study will be conducted. 
The TITAN 2 Study was designed to reflect the GCP principles outlined in ISO 14155:2020 and other 
international clinical requirements outlined below, except no coordinator principal investigator or 
institution will be identified for the study. These include the protection of the rights, safety and well-
being of human subjects, controls to ensure the scientific conduct and credibility of the clinical 
investigation and the definition of responsibilities of the sponsor and investigators. In accordance with 
ISO 14155:2020, the sponsor shall avoid improper influence on, or inducement of, the subject, monitor, 
any investigator(s) or other parties participating in, or contributing to, the clinical investigation. All 
investigators shall avoid improper influence on or inducement of the subject, sponsor, monitor, other 
investigator(s) or other parties participating in or contributing to the clinical investigation. AE and DD 
handling in the TITAN 2 Study is ISO 14155:2020 compliant for all participating geographies. 

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The study will be conducted in accordance with this protocol, the ethical principles that have their origin 
in the Declaration of Helsinki have been implemented in this clinical study by means of the informed 
consent process, IRB approval, regulatory authority approval, study training, and risk benefit 
assessment.  
The study will be publicly registered prior to the first enrollment in accordance with the 2007 FDAAA 
and DoH on http://clinicaltrials.gov (PL 110-85, section 810(a)).  
Study investigators will be required to sign and date an investigator agreement stating their intent to 
adhere to applicable regulations. 
Prior to consenting any subjects in this clinical study, FDA approval and each investigation center’s IRB 
will be required to approve the current CIP, the subject ICF, including any other written information to 
be provided to the subjects and, if applicable, the materials used to recruit subjects. The IRB approval of 
the clinical study must be received in the form of a letter and provided to Medtronic. The approval letter 
must contain enough information to identify the version or date of the documents approved. If this 
information is not contained in the approval letter, it must be retrievable from the corresponding 
submission letter. Sponsor written approval is required prior to the initiation of subject activities. 
Investigators and their delegated staff are required to be adequately trained and delegated prior to 
being activated on the study. If action is taken by an IRB with respect to the investigation, the 
investigator must ensure this information is forwarded to the sponsor. 
Medtronic contracts with participating institutions/investigators through a Clinical Trial Agreement that 
defines the scope and responsibilities and associated compensation related to carrying out the 
obligations under a clinical study sponsored by Medtronic. Medtronic will provide funding for the study 
and will be funding all study procedures costs.  
16. Study Administration 
16.1 Monitoring 
It is the responsibility of Medtronic to ensure proper monitoring of this study. Trained Medtronic 
personnel or delegates appointed by Medtronic may perform study monitoring either onsite or 
remotely in order to ensure that the study is conducted in accordance with the CIP, the CTA, and the 
applicable regulatory and local requirements. Medtronic, or delegates, must therefore be allowed direct 
access to the subjects’ case histories (clinic and hospital records, and other source data/documentation) 
upon request as per the IC, Research Authorization (where applicable) and CTA. The principal 
investigator must make every effort to meet with the monitor during or at the end of each monitoring 
visit. 

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16.1.1 
Monitoring Visits 
Frequency of monitoring visits may be based upon subject enrollment, study compliance, number of 
adverse events, number of deviations, observations from previous monitoring visits and any suspected 
inconsistency in data that requires investigation. Monitoring for the study, including site initiation visits, 
interim monitoring visits, and closeout visits, will be done in accordance with the study-specific 
monitoring plan. 
Monitoring visits may be conducted periodically to assess study site progress, the investigator’s 
adherence to the CIP, regulatory compliance including but not limited to IRB approval and review of the 
study, maintenance of records and reports, and review of source documents against subject eCRFs in 
accordance with the study-specific monitoring plan. Monitors review study site regulatory and study 
compliance by identifying observations of non-compliance and communicating those observations along 
with recommendations for preventative/corrective actions to study site personnel. Monitors may work 
with study personnel to determine appropriate corrective action recommendations and to identify 
trends within the study or at a particular study site. 
Contact information for the study monitoring: 
Medtronic Core Clinical Solutions Monitor Group 
8200 Coral Sea Street, N.E., MVS33 
Mounds View, MN 55112 
16.2 Data Management 
Medtronic personnel will perform routine edit and consistency checks for items such as missing data or 
inconsistent data. Identified data inconsistencies will be resolved by use of data discrepancies; 
investigators and site personnel will review data discrepancies and respond to the discrepancies in a 
timely manner. The resolved discrepancy will become a part of the eCRF record for the subject. 
The EDC system which is 21CFR§11 Part E compliant controls user access and ensures data integrity. This 
system is a fully validated system. The RDC system maintains an audit trail of entries, changes, or 
corrections in eCRFs. User access will be granted to each individual based on his or her delegation of 
authority and completion of required training. If a person only authorized to complete eCRFs makes 
changes to an already signed eCRF, the system will require the Principal Investigator, or authorized 
delegate, to re-sign the eCRF. 
The data reported on the eCRFs shall be derived from source documents and be consistent with these 
source documents, and any discrepancies shall be explained in writing.  
Device data from transmissions will be uploaded to secure servers. Upon receipt, device data will be 
maintained with databases and retrieved for analysis and reporting. 

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Ultrasound images are to be retained by the site with a deidentified copy submitted to Medtronic via a 
secure file transfer method (e.g., Box, encrypted USB) and stored at Medtronic in a secured access 
location. 
The Principal Investigator, or delegated personnel, is responsible for the data submitted and must 
review all data for accuracy and provide his/her approval of the eCRF and sign each form with an 
electronic signature. 
16.3 Direct Access to Source Data/Documents 
The Principal Investigator and center personnel will provide the Medtronic monitor(s) with complete 
access to primary source data (e.g., paper, and electronic hospital/clinical charts, appointment books, 
laboratory records) that support the data on the eCRFs as well as other documentation supporting the 
conduct of the study. The monitor will perform source data verification and routine reviews of study-
related regulatory documents during scheduled monitoring visits and work to secure compliance should 
any deficiencies be observed. The monitoring plan contains the strategy for frequency of monitoring 
visits and source data verification to be performed for this study. 
Source data is all information, original records (or certified copies) of clinical findings, observations, or 
other activities in a study necessary for the reconstruction and evaluation of the study. Examples of 
these original documents and records include, but are not limited to: hospital/clinic records, phone 
records, study specific source worksheets, laboratory reports, etc. Site personnel should clearly indicate 
the subjects participate in the study within the medical records. 
Medtronic may conduct audits at participating study sites. The purpose of an audit is to verify the 
performance of the monitoring process and the study conduct, independently of the personnel directly 
involved in the study. RAs, such as the FDA, may also perform inspections at participating study sites. 
The investigator and/or institution shall permit Medtronic, IRBs and RAs direct access to source data and 
documents during monitoring, audits, and regulatory inspections. 
In accordance with GCP and regulatory requirements, Medtronic will investigate suspected cases of 
fraud. 
16.4 Confidentiality 
Subject confidentiality is assured through the use of subject identification (SID) numbers, and the de-
identifying of photocopied or records obtained by the Sponsor with the exception of data reviewed 
during remote monitoring visits conducted through a secure system (e.g., BOX). In addition to the 
review of records on site, release of de-identified records to Medtronic may be necessary, such as in the 
evaluation of adverse events. 
All information and data sent to parties involved in study conduct concerning subjects or their 
participation in this study will be considered confidential. Study sites will assign a unique SID to each 

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subject. Records of the subject/SID relationship will be maintained by the study site. The SID number is 
to be recorded on all study documents to link them to the subject’s medical records at the study site.  
Confidentiality of data will be observed by all parties involved at all times throughout the clinical 
investigation. All data shall be secured against unauthorized access. The privacy of each subject and 
confidentiality of his/her information shall be preserved in reports and when publishing any data.  In the 
US, “Protected Health Information” (PHI) will be maintained in compliance with the Health Insurance 
Portability and Accountability Act of 1996 along with any regional requirements. To maintain 
confidentiality, the subject’s name or any other PHI should not be recorded on any study document 
other than the IC and Subject Identification & Enrollment Log. This scenario will be covered in the IC. In 
the event a subject’s name/PHI is included for any reason, it will be blinded as applicable. In the event of 
inability to blind the identification (e.g., digital media), it will be handled in a confidential manner by the 
authorized personnel. Data relating to the study might be made available to third parties (for example in 
case of an audit performed by RA), provided the data are treated as confidential and that the subject’s 
privacy is guaranteed. No identifiable subject information will be published. 
16.5 Liability 
Medtronic, Inc. (including all wholly owned subsidiaries) maintains appropriate clinical study liability 
insurance coverage as required under applicable laws and regulations and will comply with applicable 
laws and customs concerning specific insurance coverage.  
16.6 CIP Amendments 
Any revisions or amendments to the CIP or IC document, along with a statement of justification for the 
changes, will be submitted to FDA and governing IRBs, according to applicable regulations. Approval by 
FDA (as applicable) and IRB must be obtained prior to implementing a CIP revision at the study site. 
16.7 Record Retention 
The principal investigator is responsible for ensuring that all essential study documentation is retained 
and accessible for a minimum of 2 years after the date the investigation is completed or terminated or 
the records are no longer required to support a pre-market approval application, whichever date is later. 
Medtronic will inform the investigator/study site when these documents are no longer required to be 
retained. 
No study document or image will be destroyed without prior written agreement between Medtronic 
and the investigator. The investigator should take measures to prevent accidental or premature 
destruction of documents. Should the investigator wish to assign the study records to another party or 
move them to another location, advance written notice must be given to Medtronic. 
Medtronic will retain the study records according to Medtronic corporate policy and record retention 
schedule. 

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16.7.1 
Investigator Records 
The investigator is responsible for the preparation and retention of the records cited below. All of the 
below records, with the exception of case history records and case report forms, should be kept in the 
Investigator Site File (i.e., the study binder provided to the investigator) or Subject Study Binder. 
Electronic CRFs must be maintained and signed electronically within the electronic data capture system 
during the study. The following records are subject to inspection and must be retained for a period of 
two years (or longer as local law or hospital administration requires) after the date the investigation is 
completed or terminated or the records are no longer required to support a pre-market approval 
application, whichever date is later. 
• 
All correspondence between the IRB, sponsor, monitor, FDA, and the investigator that 
pertains to the investigation, including required reports.  
• 
Subject’s case history records, including:  
 
Signed and dated IC signed by subject 
 
Observations of AEs/ADEs/DDs 
 
Medical history 
 
Implant and follow-up data (if applicable) 
 
Documentation of the dates and rationale for any deviation from the protocol 
• 
List of investigation study sites 
• 
Financial Disclosure  
• 
Subject Identification & Enrollment Log 
• 
Device Disposition Logs containing information similar to model and serial numbers of 
devices delivered to the study site, subject IDs of the subjects implanted, received dates 
of devices, implant/used dates, explant dates, returned-to-sponsor dates and reasons, 
initials of all persons who received, used, or disposed each device, and method of 
disposal/destruction   
• 
All approved versions of the CIP, IC, Report of Prior Investigation Summary  
• 
Signed and dated CTA 
• 
CV of principal investigators and key members of investigation study site team  
• 
Documentation of delegated tasks 
• 
IRB approval documentation. Written information that the investigator or other study 
staff, when member of the IRB, did not participate in the approval process.  
• 
FDA notification, correspondence, and approval 
• 
Study training records for study site staff 

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• 
Any other records that FDA requires to be maintained 
• 
Final Study Report including the statistical analysis 
16.7.2 
Sponsor Records 
Medtronic shall maintain the following accurate, complete, and current records: 
• 
All correspondence which pertains to the investigation 
• 
Investigational device traceability record containing information similar to model and 
serial numbers of devices, shipping date and name and address of person that received 
shipped device, location (if different than person shipped to), transfer and receipt by 
Medtronic dates  
• 
Sample of label attached to investigational device 
• 
Signed Investigator Trial Agreements, Financial Disclosure and current signed and dated 
CV of principal investigator and key members of the investigation study site, delegated 
task list 
• 
All approved IC templates, and other information provided to the subjects and 
advertisements, including translations 
• 
Copies of all IRB approval letters and relevant IRB correspondence and IRB voting 
list/roster/letter of assurance 
• 
Names of the institutions in which the study will be conducted 
• 
FDA correspondence, notification and approval as required by national legislation 
• 
Names/contact addresses of monitors 
• 
Monitoring visit reports 
• 
Statistical analyses and underlying supporting data 
• 
Final report of the study 
• 
The CIP, Report of Prior Investigations summary and study related reports, and revisions 
• 
Study training records for study site personnel and Medtronic personnel involved in the 
study 
• 
Any other records that local regulatory agencies require to be maintained.  
Medtronic records and reports will be maintained in a password-protected document management 
system, and paper documents (where applicable) will be stored in stored in secured file cabinets at 
Medtronic during the course of this study.  
After closure of the study Medtronic will archive records and reports indefinitely. 

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• 
Insufficient enrollment to complete the study within the expected timeframe 
• 
Identification of unacceptable safety profile; suspicion of an unacceptable risk will result in a 
suspension, confirmation of an unacceptable risk will result in termination 
• 
Inadequate subject adherence to follow-up requirements 
• 
Product performance/product supply issues 
Medtronic reserves the right to suspend or terminate the study at an individual site. Reasons may 
include, but are not limited to, the following:  
• 
Noncompliance with the protocol, including inadequate subject adherence to follow-up 
requirements  
• 
Serious or repeated deviations at the site  
• 
Failure to implement required corrective and preventive actions  
• 
Insufficient enrollment to complete the study within the expected timeframe  
• 
Loss of appropriately trained site personnel  
Investigators are required to notify the IRB and FDA (as applicable) of study suspension/termination. In 
addition, Investigators should assess whether or not to continue the study based on reasons above. 
Subjects will be notified by the investigator of suspension/termination due to unacceptable risk or of 
termination due to any other cause. 
17. References 
 
1.  
Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract 
function: Report from the standardisation sub-committee of the international continence 
society. Neurourol Urodyn. 2002;21(2):167-178. doi:10.1002/nau.10052 
2.  
Kowalik CG, Cohn JA, Delpe S, et al. Nocturia: Evaluation and Current Management Strategies. 
Rev Urol. 2018;20(1):1-6. doi:10.3909/riu0797 
3.  
Van Kerrebroeck P, Abrams P, Chaikin D, et al. The standardization of terminology in nocturia: 
report from the standardization subcommittee of the International Continence Society. BJU Int. 
2002;90 Suppl 3:11-15. doi:10.1046/j.1464-410x.90.s3.3.x 
4.  
Lightner DJ, Gomelsky A, Souter L, Vasavada SP. Diagnosis and Treatment of Overactive Bladder 
(Non-Neurogenic) in Adults: AUA/SUFU Guideline Amendment 2019. J Urol. 2019;202(3):558-
563. doi:10.1097/JU.0000000000000309 
5.  
Lucas MG, Bosch RJL, Burkhard FC, et al. EAU guidelines on assessment and nonsurgical 
management of urinary incontinence. Eur Urol. 2012;62(6):1130-1142. 
doi:10.1016/j.eururo.2012.08.047 

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6.  
Syan R, Brucker BM. Guideline of guidelines: Urinary incontinence. BJU Int. 2016;117(1):20-33. 
doi:10.1111/bju.13187 
7.  
Revicky V, Tincello DG. New surgical approaches for urinary incontinence in women. Maturitas. 
2014;77(3):239-242. doi:10.1016/j.maturitas.2013.12.008 
8.  
Longworth M-C, Fowler GE. Modern management of overactive bladder syndrome. Obstet 
Gynaecol Reprod Med. 2016;26(6):184-187. doi:10.1016/j.ogrm.2016.03.003 
9.  
Longworth M-C, Fowler GE. Modern management of overactive bladder syndrome. Obstet 
Gynaecol Reprod Med. 2013;23(9):259-262. doi:10.1016/j.ogrm.2013.06.008 
10.  
Gaziev G, Topazio L, Iacovelli V, et al. Percutaneous Tibial Nerve Stimulation (PTNS) efficacy in 
the treatment of lower urinary tract dysfunctions: a systematic review. BMC Urol. 2013;13:61. 
doi:10.1186/1471-2490-13-61 
11.  
Peters KM, Carrico DJ, Perez-Marrero RA, et al. Randomized trial of percutaneous tibial nerve 
stimulation versus Sham efficacy in the treatment of overactive bladder syndrome: results from 
the SUmiT trial. J Urol. 2010;183(4):1438-1443. doi:10.1016/j.juro.2009.12.036 
12.  
Peters KM, Macdiarmid SA, Wooldridge LS, et al. Randomized Trial of Percutaneous Tibial Nerve 
Stimulation Versus Extended-Release Tolterodine: Results From the Overactive Bladder 
Innovative Therapy Trial. J Urol. 2009;182(3):1055-1061. doi:10.1016/j.juro.2009.05.045 
13.  
Gordon T, Merchant M, Ramm O, Patel M. Factors Associated With Long-Term Use of 
Percutaneous Tibial Nerve Stimulation for Management of Overactive Bladder Syndrome. 
Female Pelvic Med Reconstr Surg. July 2020. doi:10.1097/SPV.0000000000000911 
14.  
MacDiarmid S, Staskin DR, Lucente V, et al. Feasibility of a Fully Implanted, Nickel Sized and 
Shaped Tibial Nerve Stimulator for the Treatment of Overactive Bladder Syndrome with Urgency 
Urinary Incontinence. J Urol. 2019;201(5):967-972. doi:10.1016/j.juro.2018.10.017 
15.  
Rogers A, Bragg S, Ferrante K, Thenuwara C, Peterson DKL. Pivotal Study of Leadless Tibial Nerve 
Stimulation with eCoin((R)) for Urgency Urinary Incontinence: An Open-Label, Single Arm Trial. J 
Urol. April 2021:101097JU0000000000001733. doi:10.1097/JU.0000000000001733 
16.  
Heesakkers JPFA, Digesu GA, van Breda J, Van Kerrebroeck P, Elneil S. A novel leadless, miniature 
implantable Tibial Nerve Neuromodulation System for the management of overactive bladder 
complaints. Neurourol Urodyn. 2018;37(3):1060-1067. doi:10.1002/nau.23401 
17.  
Nixon A, Colman S, Sabounjian L, et al. A validated patient reported measure of urinary urgency 
severity in overactive bladder for use in clinical trials. J Urol. 2005;174(2):604-607. 
doi:10.1097/01.ju.0000165461.38088.7b 
18.  
Coyne KS, Gelhorn H, Thompson C, Kopp ZS, Guan Z. The psychometric validation of a 1-week 
recall period for the OAB-q. Int Urogynecol J Pelvic Floor Dysfunct. 2011;22(12):1555-1563. 
doi:10.1007/s00192-011-1486-0 
19.  
 
 
20.  
Yalcin I, Bump RC. Validation of two global impression questionnaires for incontinence. Am J 
Obstet Gynecol. 2003;189(1):98-101. doi:10.1067/mob.2003.379 
21.  
Tincello DG, Owen RK, Slack MC, Abrams KR. Validation of the Patient Global Impression scales 
for use in detrusor overactivity: Secondary analysis of the RELAX study. BJOG Int J Obstet 
Gynaecol. 2013;120(2):212-216. doi:10.1111/1471-0528.12069 

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22.  
Freeman R, Hill S, Millard R, Slack M, Sutherst J. Reduced perception of urgency in treatment of 
overactive bladder with extended-release tolterodine. Obstet Gynecol. 2003;102(3):605-611. 
doi:10.1016/s0029-7844(03)00623-9 
23.  
Cardozo L, Coyne KS, Versi E. Validation of the urgency perception scale. BJU Int. 
2005;95(4):591-596. doi:10.1111/j.1464-410X.2005.05345.x  
24.  
Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Publish Date: November 27, 
2017. 
25.  
Buhi ER, Goodson P, Neilands TB. Out of sight, not out of mind: strategies for handling missing 
data. Am J Health Behav. 2008;32(1):83-92. doi:10.5555/ajhb.2008.32.1.83 
26.  
Haylen BT, de Ridder D, Freeman RM, et al. An International Urogynecological Association 
(IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic 
floor dysfunction. Neurourol Urodyn. 2010;29(1):4-20. doi:10.1002/nau.20798 
27.  
Cohen J. Statistical Power Analysis for the Behavioural Sciences, 2nd edn. Hillsdale, NJ: Lawrence 
Erlbaum Associates. 1988. 
 
18. Appendices 
18.1 Informed Consent Materials 
Copies of all informed consent materials will be provided to the site under a separate cover. 
18.2 Participating Investigators, Institutions & Institutional 
Review Boards 
At the time of completion of the Clinical Investigation Plan, site selection is not yet complete. Therefore, 
a complete list of names and addresses of the clinical investigators and institutions will be distributed 
within the Current List of Investigators Report.  The complete list of Institutional Review Boards will be 
provided with the Annual Progress Report.  
18.3 Labeling 
Copies of the TNM system labeling will be provided to the site under a separate cover.