Home Neuromodulation of the Neurogenic Bladder in Chronic Spinal Cord Injury With Transcutaneous Tibial Nerve Stimulation
Phase: NA
Conditions: Chronic Spinal Cord Injury, Neurogenic Bowel
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRB NPUagMeBE1Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
 
 
 
 
 
 
 
 
 
 
Home Neuromodulation of the Neurogenic Bladder in Chronic Spinal Cord Injury with 
Transcutaneous Tibial Nerve Stimulation 
 
NCT03458871 
 
Version Date: 08/31/2018 
 
 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRB NPUagMeBE2Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
STUDY PROTOCOL 
 
PROTOCOL NUMBER: 
HSC-MS-17-0423 
 
PROTOCOL TITLE: 
Home Neuromodulation of the Neurogenic Bladder in Chronic Spinal Cord Injury with 
Transcutaneous Tibial Nerve Stimulation 
VERSION: 
1 
DATE: 
4/28/2017 
 
CORRESPONDING PRINCIPAL INVESTIGATOR: 
Argyrios Stampas, MD; Assistant Professor Dept PM&R; TIRR Memorial Hermann 
The University of Texas Health Science Center at Houston 
 
 
 
SITE: 
TIRR Memorial Hermann 1333 Moursund St, Houston, TX 77030 
 
 
COLLABORATORS: 
 
- Christopher P. Smith, MD, MBA, MSS; Associate Professor, Scott Department of 
Urology, Baylor College of Medicine 
- Liang Zhu, PhD; Associate Professor, Division of Clinical and Translational 
Sciences, Department of Internal Medicine, The University of Texas Health Science 
Center at Houston 
- Radha Korupolu, MD, MS, Assistant Professor Dept PM&R; TIRR Memorial 
Hermann; The University of Texas Health Science Center at Houston 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRB NPUagMeBE3Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
GENERAL INFORMATION 
 
 
Name and address of the sponsor of the study: 
NA 
 
 
 
Name and address of the person authorized to sign the protocol and amendments: 
Argyrios Stampas, MD 
1333 Moursund St 
Houston, TX 77030 
 
 
Name and address of study monitor: 
No plan for study monitor 
 
 
 
 
Name, title, address and telephone number(s) of the medical expert for the trial 
Argyrios Stampas, MD  p: 713-797-5938 
 
 
 
Name and title of the investigator(s) and sub-investigators responsible for the trial 
with address and phone number(s) 
Argyrios Stampas, MD  p: 713-797-5938 
 
 
Name and addresses of the clinical laboratories and/or other institutions involved in 
the trial 
TIRR Memorial Hermann 
1333 Moursund St 
Houston, TX 77030 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRB NPUagMeBE4Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
TABLE OF CONTENTS 
1. 
BACKGROUND AND RATIONALE ............................................................................................... 5 
1.1. 
GENERAL INTRODUCTION ............................................................................................................ 6 
1.2. 
RATIONALE AND JUSTIFICATION FOR THE STUDY ....................................................................... 7 
A. 
RATIONALE FOR THE STUDY PURPOSE ........................................................................................... 7 
B. 
RATIONALE FOR DOSES SELECTED ................................................................................................. 7 
C. 
RATIONALE FOR STUDY POPULATION .............................................................................................. 7 
D. 
RATIONALE FOR STUDY DESIGN ...................................................................................................... 8 
2. 
HYPOTHESIS AND OBJECTIVES ................................................................................................. 8 
2.1. 
HYPOTHESIS ................................................................................................................................ 8 
2.4. 
POTENTIAL RISKS AND BENEFITS ................................................................................................ 9 
A. 
END POINTS - EFFICACY .................................................................................................................. 9 
B. 
END POINTS - SAFETY...................................................................................................................... 9 
3.1. 
LIST THE NUMBER OF SUBJECTS TO BE ENROLLED ....................................................................10 
3.2. 
CRITERIA FOR RECRUITMENT ....................................................................................................10 
3.3. 
INCLUSION CRITERIA ..................................................................................................................10 
3.4. 
EXCLUSION CRITERIA .................................................................................................................10 
3.5. 
WITHDRAWAL CRITERIA .............................................................................................................11 
3.6. 
SUBJECT REPLACEMENT ............................................................................................................11 
4. 
TRIAL SCHEDULE ...........................................................................................................................11 
5. 
STUDY DESIGN ...........................................................................................................................11 
5.1. 
SUMMARY OF STUDY DESIGN ....................................................................................................12 
6. 
METHODS AND ASSESSMENTS .................................................................................................13 
6.1. 
RANDOMIZATION AND BLINDING .................................................................................................13 
6.2. 
CONTRACEPTION AND PREGNANCY TESTING ............................................................................13 
6.3. 
STUDY VISITS AND PROCEDURES ..............................................................................................14 
7. 
TRIAL MATERIALS .........................................................................................................................15 
7.1. 
TRIAL PRODUCT (S) ....................................................................................................................15 
7.2. 
STORAGE AND DRUG ACCOUNTABILITY .....................................................................................15 
8. 
TREATMENT .....................................................................................................................................16 
8.1. 
RATIONALE FOR SELECTION OF DOSE .......................................................................................16 
8.2. 
STUDY DRUG FORMULATIONS ...................................................................................................16 
8.3. 
STUDY DRUG ADMINISTRATION .................................................................................................16 
8.4. 
SPECIFIC RESTRICTIONS / REQUIREMENTS ...............................................................................16 
8.5. 
BLINDING ....................................................................................................................................16 
8.6. 
CONCOMITANT THERAPY ............................................................................................................16 
9. 
SAFETY MEASUREMENTS ...........................................................................................................17 
9.1. 
DEFINITIONS ...............................................................................................................................17 
9.2. 
COLLECTING, RECORDING AND REPORTING OF ADVERSE EVENTS ..........................................17 
9.3. 
SAFETY MONITORING PLAN .......................................................................................................17 
10. 
DATA ANALYSIS ........................................................................................................................19 
10.1. 
DATA QUALITY ASSURANCE .......................................................................................................19 
10.2. 
DATA ENTRY AND STORAGE ......................................................................................................19 
11. 
SAMPLE SIZE AND STATISTICAL METHODS .....................................................................19 
11.1. 
DETERMINATION OF SAMPLE SIZE .............................................................................................19 
11.2. 
STATISTICAL AND ANALYTICAL PLANS .......................................................................................20 
12. 
ETHICAL CONSIDERATIONS ..................................................................................................20 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRB NPUagMeBE5Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
12.1. 
INFORMED CONSENT ................................................................................................................. 20 
12.2. 
IRB REVIEW ............................................................................................................................... 20 
12.3. 
CONFIDENTIALITY OF DATA AND PATIENT RECORDS ................................................................ 20 
13. 
PUBLICATIONS .......................................................................................................................... 21 
14. 
RETENTION OF TRIAL DOCUMENTS ................................................................................... 21 
15. 
REFERENCES ............................................................................................................................ 22 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRB NPUagMeBE6Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
STUDY PROTOCOL 
 
1. 
BACKGROUND AND RATIONALE 
 
There are over 1 million people living with spinal cord injury (SCI) with devastating functional 
impairments including paralysis and bowel/bladder dysfunction.1 Nearly every person with SCI 
develops neurogenic bladder.2 The gold-standard treatment of neurogenic bladder involves the 
use of anticholinergic bladder medications, which suffers from non-compliance and adverse 
medication effects.3 Improving bowel and bladder function is the number one priority that people 
living with SCI wish to achieve.4 Treatments such as bladder neuromodulation with tibial nerve 
stimulation (TNS), have been shown to improve bladder function in SCI without adverse 
effects.5,6 Percutaneous TNS (PTNS) is performed using a needle inserted into the skin to direct 
the electric current, provided by trained healthcare workers in the clinic setting under physician 
supervision. This requires frequent visits in a population with known accessibility challenges. 
Transcutaneous TNS (TTNS) accomplishes the same goal, but uses non-invasive surface 
electrodes. However, this modality has only been performed in the clinic setting. There is 
currently a gap in our knowledge about the safety and feasibility of TTNS at home for bladder 
neuromodulation in SCI. The proposed research is innovative, in our opinion, because it 
represents a substantive departure from the status quo by using TTNS at home to replace 
anticholinergic medications and provide a dignified treatment that can improve quality of life. 
 
Electric stimulation is routinely being used in neurorehabilitation. The PI has published reviews 
on the current state of rehabilitation in SCI, describing the use of FES and NMES in SCI for 
motor/sensory recovery, decreasing spasticity, and improving neuropathic pain.9, 10 Patients are 
routinely prescribed electric stimulation units for home use to help with motor recovery and 
strengthening. We propose the development of a protocol that uses the same equipment in a 
novel way to effect bladder function. 
 
We are currently using the proposed TTNS protocol for research purposes (HSC-MS-15-0806) 
at TIRR for acute SCI during their inpatient rehabilitation admission (Table 1). Based on the 
preliminary safety data, we believe we can develop this protocol for home use (Table 2). 
 
Table 1. Preliminary data demographics of subjects inpatient TTNS protocol 
Subject # Group 
Gender 
Age 
Etiology 
SCI 
Days 
from 
injury to 
protocol 
start 
Neurologic 
Level 
ASIA 
injury 
severity 
1 
Exp 
M 
27 
Motorcycle 22 
T4 
B 
2 
Exp 
F 
24 
MVA 
18 
T1 
A 
3 
Exp 
F 
48 
MVA 
23 
C4 
A 
4 
Exp 
F 
27 
MVA 
12 
C5 
B 
5 
? 
M 
29 
MVA 
38 
T3 
A 
6 
? 
M 
28 
Motorcycle 11 
C6 
C 
7 
? 
M 
45 
Motorcycle 18 
C6 
A 
8 
? 
M 
47 
MVA 
11 
T6 
C 
9 
? 
F 
55 
Fall 
12 
C4 
C 
10 
? 
F 
36 
MVA 
6 
T4 
A 
11 
? 
M 
48 
Motorcycle 7 
T3 
A 
12 
/ 
M 
61 
MVA 
14 
C1 
B 
Exp= experimental group; ?= blinded to group allocation; MVA= motor vehicle accident; ASIA= 
American Spinal Cord Injury Association 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRB NPUagMeBE7Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
 
 
Table 2. Adverse events monitored in subjects recruited. 
Subject 
# 
NPS 
change 
mean 
(range) 
DVT/PE 
UTI 
Resp 
Infection 
Cellulitis 
Skin 
Irritation 
Other 
Infection 
Pressure 
Injury 
Unexpected 
Discharge 
1 
-0.1 
(0-1) 
N 
N 
N 
N 
N 
N 
N 
N 
2 
0 
N 
N 
N 
N 
N 
N 
N 
N 
3 
0 
N 
Y* 
N 
N 
N 
N 
N 
N 
4 
0 
N 
Y^ 
N 
N 
N 
N 
N 
N 
5 
-0.5 
(-5-0) 
N 
N 
N 
N 
N 
N 
N 
N 
6 
0.5 
(0-5) 
N 
N 
N 
N 
N 
N 
N 
N 
7 
0 
Y # 
N 
N 
N 
N 
N 
Y% 
N 
8 
0 
N 
N 
N 
N 
N 
N 
N 
N 
9 
? 
N 
Y* 
N 
N 
N 
N 
N 
N 
10 
? 
N 
Y$ 
N 
N 
N 
N 
N 
N 
11 
? 
N 
Y$ 
N 
N 
N 
N 
N 
N 
12 
? 
N 
Y$ 
N 
N 
N 
N 
Y$ 
N 
* UTI 6 days after completion of protocol, unrelated 
^ UTI 7 days after completion of protocol, unrelated 
# PE discovered due to complaints of shortness of breath, unrelated to protocol. 
% Sacral skin injury 7 days after completion of protocol, unrelated 
$ prior to subject recruitment 
?- have not completed study, blinded to stimulation pain scores 
 
There have been 12 subjects recruited to the inpatient TTNS protocol with a variety of cervical 
and thoracic injuries, with subsequent complete and incomplete paraplegia and tetraplegia. 
Consecutive inpatients were screened and approached for the study. To date (7/12/2017), 
11/12 patients that consented to the study completed the TTNS protocol and 1 (subject 12) has 
ongoing stimulation. There were no reported complaints about the TTNS. There were no 
adverse events directly related to the TTNS protocol, including worsening pain (numeric pain 
scale (NPS)), skin irritation, and bladder complaints (urinary tract infections, leaking, 
incontinence, etc). 
 
Please note, the above subjects have all been acutely injured and are at higher risk for morbidity 
compared to chronic SCI subjects.  Half of the UTIs occurred before subject recruitment, and 
half of the UTIs occurred about 1 week after completion of the stimulation protocol. None 
occurred during the TTNS protocol. Based on our inpatient experience with this TTNS protocol, 
the high compliance, lack of adverse events, and feasibility, we believe this protocol can be 
translated to the outpatient setting and performed by the subjects themselves and/or their 
caregivers. 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRB NPUagMeBE8Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
1.1. 
General Introduction 
 
The Stamobil + is an electric stimulation unit used for the rehabilitation of those with paralysis. It 
is currently used at TIRR Memorial Hermann on nearly every patient with paralysis for the 
purposes of motor and sensory recovery.  We are currently using the proposed TTNS protocol 
for research purposes (HSC-MS-15-0806) at TIRR for acute SCI during their inpatient 
rehabilitation admission. Based on the preliminary safety data, we believe we can develop this 
protocol for home use. The proposed protocol is using the device in a new way, to stimulate the 
nerves of the legs which is known to effect the bladder in a process described as 
“neuromodulation.” 
 
The status quo as it pertains to the management of neurogenic bladder in SCI is anticholinergic 
medications to inhibit bladder activity, increase bladder capacity, and decrease detrusor 
pressures.4 However, management of neurogenic bladder requires further improvement, with an 
estimated 50% developing serious urologic complications.2 Ongoing research regarding the 
neuromodulation of chronic neurogenic bladder is promising, demonstrating equal efficacy to 
current management without non-compliance and adverse medication side effects, with 
improved quality of life.5-8 Although neuro-modulation techniques are currently used for chronic 
neurogenic bladder, its use is limited to frequent clinic visits, imposing a barrier to a population 
known to have challenges accessing medical care. The proposed research is innovative, in our 
opinion, because it represents a substantive departure from the status quo by using 
transcutaneous tibial nerve stimulation in the home setting to improve bladder function. 
Rehabilitation horizons for neurogenic bladder management which have previously been 
unattainable through current efforts including the prevention of detrusor sphincter dyssynergia 
and related autonomic dysreflexia, maintenance of bladder capacity and compliance, and 
reduction in oral medication use with improved quality of life are also likely to become attainable. 
 
Electric stimulation is currently being used in neurorehabilitation. The candidate has published 
reviews on the current state of rehabilitation in SCI, describing the use of FES and NMES in 
acute SCI for motor/sensory recovery, decreasing spasticity, and improving neuropathic pain.9, 10 
Patients are routinely prescribed electric stimulation units for home use to help with motor 
recovery and strengthening. We propose the development of a protocol that uses the same 
equipment in a novel way to effect bladder function. 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRB NPUagMeBE9Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
1.2. 
Rationale and justification for the Study 
 
We have selected a neuromodulation technique, TTNS, that has been used safely in chronic SCI 
with good results for improving quality of life and bladder parameters and have developed a 
protocol for home use. 
Specific Aim 1: Determine the safety, feasibility, and compliance of a daily home TTNS 
protocol in chronic SCI provided by self or caregiver for 4 weeks. 
Hypothesis 1.1:  TTNS at home is safe and feasible with high compliance. 
Hypothesis 1.2: TTNS protocol will demonstrate overall satisfaction as a neurogenic bladder 
treatment option based on survey questionnaire. 
 
Specific Aim 2. Determine the efficacy of a 4 week TTNS protocol. 
Hypothesis 2.1: Incontinence quality of life scores and frequency of incontinence will improve 
with TTNS compared to their baseline. 
Hypothesis 2.2: Frequency of catheterization and volumes voided will improve with TTNS 
compared to baseline measurements. 
Hypothesis 2.3: Anticholinergic-related side effects will improve with TTNS after discontinuation 
of bladder medications 
 
a. 
Rationale for the Study Purpose 
 
Neuromodulation techniques have been safely used for improving neurogenic bladder in chronic 
SCI for many years. However, bladder neuromodulation is only being performed in the clinic 
setting requiring frequent visits, limiting its use in a population known to have high healthcare 
costs and barriers to accessing medical care. Based on our experience, we believe we can 
develop a home-based protocol. 
 
Gaps in the knowledge which we intend to fill are: 
1) Safety, feasibility, and compliance of a home TTNS protocol in chronic SCI. 
2) Efficacy of a 4-week TTNS protocol in SCI based on the Incontinence Quality of Life (I-QOL), 
which will provide effect size to power future studies. 
 
b. 
Rationale for Doses Selected 
 
Based upon an extensive review of the literature on neuromodulation of neurogenic bladder and 
the clinical experience of the mentorship team, we believe a TTNS protocol over a 4 week period 
will improve continence. Tibial nerve stimulation protocols use submotor current intensity with a 
duration of 200 μs and frequency of 10Hz.13,14 Increasing the treatment frequency dramatically 
shortens the time required for response while maintaining efficacy, varying from 6-12 sessions.14 
 
c. 
Rationale for Study Population 
 
Participants will include consecutive SCI subjects at the SCI clinic who meet the I/E criteria 
(Table 1) and consent to the protocol. 
 
 
d. 
Rationale for Study Design 
 
Based on our current inpatient experience, we believe this protocol can be performed safely at 
home by subjects and/or their caregivers if given detailed instructions. Subjects who perform 
intermittent catheterization are being selected because they more likely to have incontinence 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRB NPUagMeBE10Ro:fH2S3C-MS-17-
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
than those with an indwelling catheter. If patients are interested, we will trial stimulation in clinic. 
We will exclude those who we cannot produce toe flexion with posterior tibial nerve stimulation. 
After 1 week of home stimulation, those that are on bladder medicine will discontinue the 
medication. There is no other harm from rapid discontinuation of bladder medication, except for 
incontinence. We expect that incontinence will be reduced from this first week of TTNS. 
The I-QOL questionnaire is administered at baseline, and at the end of 2 and 4 weeks to 
determine when best effects of TTNS are achieved. 
 
2. 
HYPOTHESIS AND OBJECTIVES 
 
 
2.1. 
Hypothesis 
 
Specific Aim 1: Determine the safety, feasibility, and compliance of a daily home TTNS 
protocol in chronic SCI provided by self or caregiver for 4 weeks. 
Hypothesis 1.1:  TTNS at home is safe and feasible with high compliance. 
Hypothesis 1.2: TTNS protocol will demonstrate overall satisfaction as a neurogenic bladder 
treatment option based on survey questionnaire. 
 
Specific Aim 2. Determine the efficacy of a 4 week TTNS protocol. 
Hypothesis 2.1: Incontinence quality of life scores and frequency of incontinence will improve 
with TTNS compared to their baseline. 
Hypothesis 2.2: Frequency of catheterization and volumes voided will improve with TTNS 
compared to baseline measurements. 
Hypothesis 2.3: Anticholinergic-related side effects will improve with TTNS after discontinuation 
of bladder medications 
 
2.2. 
Primary Objectives 
 
Primary Objective 1:  Safety, feasibility, and compliance of TTNS at home. 
Primary Objective 2:  Overall satisfaction with TTNS based on survey. 
 
2.3. 
Secondary Objectives 
 
Secondary Objective 1: I-QOL scores will improve and incontinence episodes will reduce after 
TTNS compared to baseline. 
 
Secondary Objective 2: The frequency of catheterization and the volumes voided will improve 
with TTNS compared to baseline based on bladder diary. 
 
Secondary Objective 3: Anticholinergic side effects will be reduced based on survey after 
TTNS protocol. 
 
2.4. 
Potential Risks and Benefits: 
 
a. 
End Points - Efficacy 
Specific Aim 1: No efficacy requirement for the safety and feasibility studied in specific aim 1. 
 
Specific Aim 2: We expect improved I-QOL scores compared to baseline. As a pilot trial, we 
have not powered the study for this measure. Results from this study will provide effect size to 
power a larger study. 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRBPNaUgM
e B1E0Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
b. 
End Points - Safety 
Urinary Tract Infection (UTI) risk: 
We expect the rates of morbidity to be the same between those who participate and those who 
do not. However, because UTI is directly related to the bladder, we will focus on the occurrence 
of UTI. Based on literature, the overall rate of UTI in SCI is about 2.5 episodes per patient per 
year. As a result, we expect to see 0.2 episodes per patient during the 4-week study period. 
Based on that, we construct the stopping rules to stop at 20% UTI rate using lower 90% exact 
Blyth-Still-Casella confidence bounds. If the number of patients with UTI exceed 3 in the first 5 
patients, 4 in the first 10 patients, or 5 in the 14 patients, then patient accrual will be paused 
pending a review by a medical advisory board comprised of SCI experts. 
 
Bladder medication discontinuation risk: 
- 
Worsened incontinence 
 
Electric Stimulation Risks: 
Electric stimulation is commonly performed on the extremities of those with spinal cord injury at 
the study institution. There are few adverse reactions to electric stimulation. The common ones 
include: 
- 
Pain with electric stimulation: in these cases, the intensity is reduced until it is 
comfortable. 
- 
Skin irritation: it is common for redness to occur on the skin at the site of the surface 
electrode. This typically dissipates within an hour of removing the electrode. In some 
cases, the redness remains the next day. In these cases, they are likely sensitive to the 
adhesive used and a hypoallergenic skin electrode will be provided. 
 
3. 
STUDY POPULATION 
 
3.1. 
List the number of subjects to be enrolled. 
Consecutive SCI clinic encounters meeting the inclusion/exclusion criteria will be asked to enroll. 
Children and pregnant women will be excluded. 
 
3.2. 
Criteria for Recruitment 
 
- 
Initial screening will be performed in the clinic with the subject and PI 
- 
In those interested, they will be given an IRB-approved consent form to review and to sign. 
- 
Those with tetraplegia will unlikely have the ability to sign and we will have a 3rd party attest 
to the consent. 
- 
Patients will ideally decide to participate in clinic, but can always decide at a later date and 
return to clinic to trial the TTNS as part of the I/E critreria. 
 
3.3. 
Inclusion Criteria (table 1) 
 
Table 1. Inclusion/ Exclusion Criteria 
 
Inclusion 
Exclusion 
18-65 years old 
Multiple medications for the 
Cancer in the tibial nerve 
bladder 
path and/or bladder. 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRBPNaUgM
e B1E1Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
Neurologically stable SCI 
for ≥ 6 months 
Other diagnoses to explain 
incontinence (ex: UTI, 
bladder stones, multiple 
sclerosis, etc.) 
Inability to elicit toe/plantar 
flexion with electric 
stimulation during clinic 
visit. 
 
Intermittent catheterization 
to empty bladder 
2+ pitting edema that does 
not resolve 
Inability to understand 
directions 
 
Stable bladder 
medications for ≥ 3 
months 
Known peripheral 
neuropathy or injury to the 
path of the tibial nerve 
Non-English speaking 
 
Demand-type cardiac pacemaker or implanted 
defibrillator 
3.4. 
Exclusion Criteria (table 1) 
 
Patients on multiple bladder medications will be excluded for the rationale that they have a 
severely dysfunctional bladder that requires multiple bladder medications, likely having 
developed over many years. It is unlikely that TTNS alone can benefit this population and it 
would skew the results for efficacy. 
 
Patients with known etiologies of incontinence other than SCI will be excluded. 
 
Those patients with severe lower leg edema will be excluded because in our current trial, we 
have found that the electric current does not elicit toe flexion in those with extensive leg edema. 
 
For electric stimulation, we exclude those that have an implanted cardiac device, cancer at the 
stimulation site, and those that we cannot elicit toe flexion in clinic. 
 
3.5. 
Withdrawal Criteria 
 
Possible reasons for discontinuation of study intervention: 
- 
Intolerable incontinence after discontinuation of bladder medications 
- 
Intolerant to electric stimulation 
- 
Non-compliance 
3.6. 
Subject Replacement 
Subjects who drop out will be replaced by recruitment from the SCI clinic and asking for informed 
consent from those who meet the I/E criteria. 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRBPNaUgM
e B1E2Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
4. 
TRIAL SCHEDULE 
 
Table 2. Timeline of protocol per subject 
Weeks in Study Protocol 
 
Activities 
0 
W1 
W2 
W3 
W4 
Clinic Enrolment: 
Eligibility screen 
X 
Informed Consent 
X 
Incontinence Questionnaire (I-QOL) 
X 
Side effect questionnaire 
X 
TTNS demonstration 
X 
Home 
Bladder diary 
□----------------------------------------------------□ 
I-QOL 
X 
X 
TTNS 
□----------------------------------------------------□ 
Discontinue bladder medication 
X 
Side effect questionnaire/ TTNS survey 
X 
 
5. 
STUDY DESIGN (Table 2) 
 
Anticipated number of patients to screen: 40 
 
Anticipated number of patient to enrol: 20 
 
Anticipated drop out or loss to follow-up: 4 
 
Approximate time to complete study recruitment: 1 year 
Expected duration of subject participation: 4 weeks 
 
TTNS protocol: (please refer to protocol HSC-MS-15-0806) electrodes 2 inch by 2 inch will 
be placed according to anatomic landmarks, with the negative electrode behind the internal 
malleolus and the positive electrode 10cm superior to the negative electrode, verified with 
rhythmic flexion of the toes secondary to stimulation of the flexor digitorum and hallicus 
brevis. The intensity level will be set to the amperage immediately under the threshold for 
motor contraction. If there is not contraction seen, maximal tolerable intensity will be used. 
In addition, if the patient perceives pain, the intensity will be lowered until comfortable. 
Stimulation frequency of 10 Hz and pulse width of 200ms in continuous mode will be 
used.13, 14 
 
 Information gathered: 
o Clinical demographics, morbidity, and Neurologic Exam findings from interview with 
subjects, exam, and EMR review. 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRBPNaUgM
e B1E3Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
o Bladder diary will include: 
• 
use of TTNS with amperage and presence of toe flexion, and pain score 0-10 
• 
log of catheterization, volumes 
• 
log of incontinence episodes 
• 
Description of other observed changes, including but not limited to: fatigue, 
vision changes, mental status, bowel program changes, and sexual function 
changes. 
o Information will be tabulated on an Excel spreadsheet on my personal work desktop, 
password protected.  Any paper data (bladder diary) will be de-identified and 
retained in a locked drawer in the locked office of the PI. 
 
5.1. 
Summary of Study Design 
 
In Specific Aim 1, we will monitor for safety, feasibility, and compliance of a home TTNS 
program for bladder management. In Specific Aim 2, the efficacy of home TTNS will be 
compared to baseline Incontinence- Quality of Life questionnaire. A bladder diary will also 
capture important information such as frequency and volume of catheterization, incontinence 
episodes, and other related observations. 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRBPNaUgM
e B1E4Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
6. 
METHODS AND ASSESSMENTS 
 
a. 
Physical exam will be performed per usual care at TIRR, by the attending SCI 
physicians. Data will be retrieved from the electronic medical record and placed into the 
data spreadsheet.  Missing data will be requested from the attending physician or 
directly from the patient. 
b. 
Transcutaneous Tibial Nerve Stimulation (TTNS) will be placed daily by trained research 
assistants in the clinic to determine if the subject meets I/E criteria. Skin inspection will 
be performed before and after the trial stimulation session at the electrode sites. 
c. 
The Bladder diary will be used to collect data use of TTNS with amperage and presence 
of toe flexion, pain score 0-10, as well as incontinence episodes and volumes. The 
research assistant will call weekly to capture the written data and monitor progress with 
the protocol. 
 
 
6.2. 
Randomization and Blinding 
 
a. 
Not Applicable. 
 
6.3. 
Contraception and Pregnancy Testing 
 
For females of childbearing age included in the trial, sexually active women with male partners 
will be excluded. 
 
Females of childbearing age will have to adhere to medically recommended contraception if 
sexually active, such as condoms and/or birth control pills. 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRBPNaUgM
e B1E5Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
6.4. 
Study Visits and Procedures 
 
- 
Screening Visits and Procedures 
 
Screening will be performed in the SCI clinic by the PI and co-I SCI attendings. 
 
Those that meet the I/E criteria will be approached for the study by the PI and co-I attendings. 
They have until the study period is complete to decide whether they want to participate. 
However, they will have to return to clinic to have the TTNS trial performed and the directions 
for home use. 
 
- 
Study Visits and Procedures 
 
Subjects will have their first study visit after their normal clinic visit. Once consented, we will trial 
TTNS for a response of toe flexion. If they have a response, they will be included in the study. 
If no response or not tolerating electric stimulation, they will not be included in the study. 
 
Participants will have direction in clinic on the use of the Stamobil+, including written, oral, and 
smartphone images/video if they have access. 
 
The electric stimulation protocol will use stimulation frequency of 10 Hz and pulse width of 
200ms in continuous mode for 30 minutes daily, beginning as soon as possible. For sexually 
active women of child-bearing age, the home use will begin after the results of a pregnancy test 
are provided.  The goal is daily use of TTNS for 4 weeks. 
 
Subjects will be called weekly to capture the information from the bladder diary log and to 
monitor progress of protocol. They will also be reminded to change electrodes weekly. 
 
- 
Final Study Visit: 
 
Upon completion of the 4-week protocol, subjects will return with the stimulator and the bladder 
diary. 
 
- 
Post Study Follow up and Procedures 
 
The data will be statistically analysed in the post-study follow up. Subject participation is not 
required. 
 
- 
Discontinuation Visit and Procedures 
 
If withdrawal occurs, no evaluation will be required for the final study visit, regardless of the 
withdrawal reason. There are no safety risks in withdrawing from this study at any point. 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRBPNaUgM
e B1E6Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
7. 
TRIAL MATERIALS 
 
The electric stimulation device used for TTNS is the Stamobil +. 
 
7.1. 
Trial Product (s) 
 
The Stamobil + is a class II medical device that requires a prescription for use. It is a 
multifunction electrotherapy device currently used at TIRR Memorial Hermann for the purpose 
of motor and sensory recovery in people with paralysis. It has the ability to provide conventional 
neuromuscular electric stimulation (NMES), transcutaneous electric nerve stimulation (TENS) 
and Pulsed Galvanic Stimulation electrotherapy. The device has wide-ranging capability and 
programmability, with stimulation and wave parameters adjusted for the proposed study 
purpose.  The FDA Approved indications for the Empi Continuum are: 
 
As an NMES device, indications are for the following conditions: 
• Retarding or preventing disuse atrophy 
• Maintaining or increasing range of motion 
• Re-educating muscles 
• Relaxation of muscle spasms 
• Increasing local blood circulation 
• Prevention of venous thrombosis of the calf muscles immediately after 
surgery 
 
As a TENS device, indications are for the following conditions: 
• Symptomatic relief and management of chronic, intractable pain 
• Adjunctive treatment for post-surgical and post-trauma acute pain 
• Relief of pain associated with arthritis 
 
As a Pulsed Current device, indications are for the following conditions: 
• Reduction of edema (under negative electrode) 
• Reduction of muscle spasm 
• Influencing local blood circulation (under negative electrode) 
• Retardation or prevention of disuse atrophy 
• Facilitation of voluntary motor function 
• Maintenance of increase of range of motion 
 
As a functional electrical stimulation (FES) device, the indications for the 
following condition: 
• Stimulation of the leg and ankle muscles of partially paralyzed patients 
to provide flexion of the foot, thus improving the patient’s gait 
 
7.2. 
Storage and Drug Accountability 
 
There are no special storage needs for the device. They will be stored in the locked office of the 
PI in a dry, dedicated place. 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRBPNaUgM
e B1E7Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
8. 
TREATMENT 
8.1. 
Rationale for Selection of Dose 
 
Neuromodulation of the bladder is currently available with percutaneous TNS in the clinic 
setting, for a variety of patient populations. Stimulation frequency of 10 Hz and pulse width of 
200ms in continuous mode will be used.13,14 
 
Neuromodulation of the bladder has been shown to be effective after 6-8 sessions, with 
sessions performed once weekly over 12 weeks or 3 times weekly. The 30 minute stimulation 
session is commonly used for bladder neuromodulation.23, 24 
 
 
8.2. 
Study Drug Formulations 
 
NA 
8.3. 
Study Drug Administration 
 
NA 
 
8.4. 
Specific Restrictions / Requirements 
 
NA 
 
8.5. 
Blinding 
 
NA 
 
8.6. 
Concomitant therapy 
 
Medications that may have an effect upon the bladder will be recorded. The medication classes 
include: 1) bladder medications, 2)anti-spasm medications, 3) anti-depressants/anxiolytics; 4) 
neuropathic pain medications. 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRBPNaUgM
e B1E8Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
9. 
SAFETY MEASUREMENTS 
9.1. 
Definitions 
An adverse event is any unfavourable and unintended sign, symptom, or disease temporally 
associated with the use of a medical treatment or procedure that may or may not be considered 
related to the medical treatment or procedure. 
 
The FDA definition of unanticipated adverse device effect will be used, as followed: An 
unanticipated adverse device effect as defined by FDA regulations at 2CFR 812.3(s) – Any 
serious adverse effect on health or safety or any life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem, or death was not previously identified in 
nature, severity, or degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem associated with 
a device that relates to the rights, safety, or welfare of subjects. 
 
Skin irritation, inflammation, and electrode burn beneath the electrodes are potential adverse 
events directly related to the use of electric stimulation. 
 
 
9.2. 
Collecting, Recording and Reporting of Adverse Events 
 
The Investigator will be responsible for collecting and reporting adverse events during the UDS. 
The research assistant and the PI will collect adverse events related to the randomized control 
trial. 
 
Grading of the severity of the adverse events will be made by the PI, using the Common 
Terminology Criteria for Adverse Events v4.0 developed by the National Cancer Institute. The 
relevant “Burn” category is included below. 
 
Reporting procedures for: 
 Deaths and life threatening events 
 other SAEs 
 Other adverse events 
 
The PI will report problems according to the UTHSC-Houston IRB policy, specifically in the 
event which in the opinion of the PI is both unexpected and related and places subjects or 
others at risk of harm. 
 
The PI will report the reportable events to CPHS via iRIS within 7 days, unless the report 
involves the death of a participant, in which case the report needs to be provided to CPHS 
within 24 hours. 
 
9.3. 
Safety Monitoring Plan 
 
The Data Safety Monitoring Plan (DSMP) for the research study includes periodic statistical 
analysis on rates of morbidity of study participants compared to controls by the PI and the 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRBPNaUgM
e B1E9Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
statistician. Because of the rolling recruitment in the proposed protocol, we anticipate the 
number of recruited individuals will be sufficient for morbidity review quarterly. 
 
Specifically, we will focus on the occurrence of UTI. We hypothesize that the rate of UTIs in 
TTNS group will be similar to the SCI population. Based on literature, the overall rate of UTI in 
SCI is about 2.5 episodes per patient per year. As a result, we expect to see 0.2 episodes per 
patient during the 4-week study period. Based on that, we construct the stopping rules to stop 
at 20% UTI rate using lower 90% exact Blyth-Still-Casella confidence bounds. If the number of 
patients with UTI exceed 3 in the first 5 patients, 4 in the first 10 patients, or 5 in the 14 patients, 
then patient accrual will be paused pending a review by a medical advisory board comprised of 
SCI experts. 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRBPNaUgM
e B2E0Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
10. 
DATA ANALYSIS 
10.1. Data Quality Assurance 
 
The PI will be solely responsible for the accuracy of the data.  Single data entry will be 
performed with plans to check 10% of primary variables as a quality control. Single data entry 
error rates are slightly higher than 0.5% when performed by trained staff and the minimally 
improved error rate through double data entry is outweighed by substantial cost savings for 
single data entry.25 Data anomalies will be reviewed by the PI and clarification and/or correction 
will be performed. Incomplete entries will be reviewed and corrected if information is available. 
 
10.2. Data Entry and Storage 
 
Data will be entered on a spreadsheet file located on the TIRR Memorial Hermann password- 
protected desktop computer of the PI located in a locked office in TIRR Memorial Hermann. 
After data from reports generated from the UDS are entered into the spreadsheet, they will be 
filed in a study binder in a locked drawer in the office of the PI with HIPPA information removed. 
 
5 years after manuscript publication, the paper reports will be placed into the shredder bins for 
destruction. 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRBPNaUgM
e B2E1Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
11. 
SAMPLE SIZE AND STATISTICAL METHODS 
 
11.1. Determination of Sample Size 
 
For SA 1, safety, feasibility, compliance, we use as a convenient sample size. The preliminary 
data with 12 subjects have shown high compliance, lack of adverse events, and feasibility. So 
we believe 14 is sufficient and we will enrol 20 patients to account for non-compliance in the 
outpatient setting. This study will help us to determine effect size for future studies. 
 
11.2. Statistical and Analytical Plans 
This pilot study will serve as an earlier-phase developmental function that will enhance the 
probability of success in a larger subsequent randomization intervention trial. 
In Aim 1, for safety, we hypothesize that there will be no unusual adverse events. However, 
because UTI is directly related to the bladder, we will focus on the occurrence of UTI.  Based 
on literature, the overall rate of UTI in SCI is about 2.5 episodes per patient per year.18 As a 
result, we expect to see .2 episodes per patient during the 4-week study period. Based on that, 
we construct the stopping rules to stop at 20% UTI rate using lower 90% exact Blyth-Still- 
Casella confidence bounds. If the number of patients with UTI exceed 3 in the first 5 patients, 4 
in the first 10 patients, or 5 in the 14 patients, then patient accrual will be paused pending a 
review by a medical advisory board comprised of SCI experts. 
For feasibility and compliance, we will calculate descriptive statistics to determine the dropout 
rate and percent of adherence to the prescribed regimen as well as program satisfaction. If the 
dropout rate is less than 25%, and if subjects complete greater than 70% of daily TTNS use in 
the 4-week period, we will consider the study has high feasibility/adherence. If more than 80% 
of subjects report that they were satisfied with the program, then we will consider the study has 
high satisfaction. 
 
In Aim 2, descriptive statistics will be provided for incontinence episodes, catheterization 
frequency, volumes voided, and anticholinergic-related side effects after the TTNS. The results 
along the time will be compared to baseline by paired t test, signed t test, or repeated measure 
methods when appropriate. Since this is an exploratory study and the efficacy of TTNS in this 
study will be further studied in future larger studies, Bonferroni correction will not be necessary. 
TTNS satisfaction will be based on the scores of a TTNS survey and descriptive analysis will 
be provided as well. We will also check the association between these changes from baseline, 
as well as bladder medication associations. 
 
12. 
ETHICAL CONSIDERATIONS 
12.1. Informed Consent 
 
The PI will obtain informed consent from subjects meeting I/E criteria after screening in their 
SCI clinic visit. Ideally they can decide that day, but can have until study completion to decide. 
Likely 1 year. 
IRB-approved study participation material will be provided to the subjects. 
Non-English speakers will be excluded. 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRBPNaUgM
e B2E2Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
12.2. IRB review 
 
This protocol and the associated informed consent documents have been submitted to the IRB 
for review and approval, pending. 
 
12.3. Confidentiality of Data and Patient Records 
 
All patient records will remain confidential. Data with Protected health Information (PHI) will be 
de-identified and given a number assignment found on the Linking Log. The Linking Log is a 
separate file in a separate folder found on the PI’s desktop computer. 
 
13. 
PUBLICATIONS 
 
We anticipate publication in a peer-reviewed journal within 2 years of beginning this study 
describing the effects of home TTNS in SCI. 
 
14. 
RETENTION OF TRIAL DOCUMENTS 
 
All records for all participants including CRFs and source documentation will be retained by the 
PI in a binder locked in his office, and on his desktop computer locked in his office. IRB and 
regulatory records will be placed in a binder along with the mentioned documents and will be 
retained by the PI in his office at TIRR Memorial Hermann, locked in a cabinet. 
 
List of Attachments 
 
Appendix 1 
Study Schedule and Study Design 
Appendix 2 
Case Report Form 
Appendix 3 
Sample Voiding Diary Log 
Appendix 4 
Informed Consent Form 

IRB NUMBER: HSC-MS-17-0423 
  
IRB APPROVAL DATE: 08/31/2018 
IRBPNaUgM
e B2E3Ro:fH2S3C-MS-17-0423 
Protocol Number, Version No and Date 
IRB APPROVAL DATE: 08/31/2018 
 
REFERENCES: 
 
1. Ackery A, Tator C, Krassioukov A. A global perspective on spinal cord injury 
epidemiology. Journal of Neurotrauma. October 2004, 21(10): 1355-1370. 
2. Weld KJ, Dmochowski RR. Association of level of injury and bladder behavior in 
patients with post-traumatic spinal cord injury. Urology. 2000 Apr;55(4):490-4. 
3. Stöhrer M, Blok B, Castro-Diaz D, Chartier-Kastler E, Del Popolo G, Kramer G, 
Pannek J, Radziszewski P, Wyndaele JJ. EAU guidelines on neurogenic lower 
urinary tract dysfunction. Eur Urol. 2009 Jul;56(1):81-8. 
4. Anderson KD. Targeting recovery: priorities of the spinal cord-injured population. J 
Neurotrauma. 2004 Oct;21(10):1371-83. 
5. Chaabane W, Guillotreau J, Castel-Lacanal E, Abu-Anz S, De Boissezon X, 
Malavaud B, Marque P, Sarramon JP, Rischmann P, Game X. Sacral 
neuromodulation for treating neurogenic bladder dysfunction: clinical and urodynamic 
study. Neurourol Urodyn. 2011 Apr;30(4):547-50. 
6. Chen G, Liao L, Li Y. The possible role of percutaneous tibial nerve stimulation using 
adhesive skin surface electrodes in patients with neurogenic detrusor overactivity 
secondary to spinal cord injury. Int Urol Nephrol. 2015 Mar;47(3):451-5.