Reducing Anticholinergic Bladder Medication Use in Spinal Cord Injury With Home Neuromodulation
Phase: NA
Conditions: Chronic Spinal Cord Injury, Neurogenic Bladder
Sponsor: The University of Texas Health Science Center, Houston

Protocol Number, Version No 1.134, SepOct. 0813, 2020 
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IRB NUMBER: HSC-MS-19-0518 
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Reducing anticholinergic bladder medication use in spinal cord injury with home neuromodulation 
 
NCT04074616 
 
Version Date: 10/20/2020 
 
 

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IRB NUMBER: HSC-MS-19-0518 
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STUDY PROTOCOL 
 
PROTOCOL NUMBER: 
HSC-MS-19-0518 
 
 
 
PROTOCOL TITLE: 
Reducing anticholinergic bladder medication use in spinal cord injury with home 
neuromodulation 
VERSION: 
1.143 
DATE: 
1009/0813/2020 
 
 
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 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 
 
 
 
 
 
COLLABORATORS: 
 
 
 
- Radha Korupolu, MD, MS, Assistant Professor Dept PM&R; TIRR Memorial 
Hermann; The University of Texas Health Science Center at Houston 
- Amanda Rounds, PhD; Clinical Research Coordinator II, MedStar NRH 

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GENERAL INFORMATION 
 
 
Name and address of the sponsor of the study: 
UTHealth KL2 award 
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Mission Connect [019-108] 
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Name and address of the person authorized to sign the protocol and amendments: 
Argyrios Stampas, MD 
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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 |||||||||||||||||||||||||||||| 
 
 
 
Name and title of the investigator(s) and sub-investigators responsible for the trial with 
address and phone number(s) 
Argyrios Stampas, MD |||||||||||||||||||||||||||||| 
 
 
Name and addresses of the clinical laboratories and/or other institutions involved in 
the trial 
TIRR Memorial Hermann 
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TABLE OF CONTENTS 
General Introduction 
6 
Rationale and justification for the Study 
7 
Rationale for the Study Purpose 
8 
Rationale for Doses Selected 
8 
Rationale for Study Population 
8 
Rationale for Study Design 
8 
Hypothesis 
9 
Potential Risks and Benefits: 
10 
End Points - Efficacy 
10 
End Points - Safety 
10 
List the number of subjects to be enrolled. 
11 
Criteria for Recruitment 
11 
Inclusion Criteria (table 1) 
11 
Exclusion Criteria (table 1) 
11 
Withdrawal Criteria 
12 
Subject Replacement 
12 
STUDY DESIGN 
13 
Summary of Study Design 
15 
Randomization and Blinding 
17 
Contraception and Pregnancy Testing 
17 
Study Visits and Procedures 
17 
Screening Visits and Procedures 
17 
Screening will be performed in the SCI clinic by the PI or co-I SCI attendings. 
17 
Study Visits and Procedures 
18 
Final Study Visit: 
18 
Post Study Follow up and Procedures 
18 
Discontinuation Visit and Procedures 
18 
Trial Product (s) 
19 

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Storage and Drug Accountability 
19 
Rationale for Selection of Dose 
20 
Study Drug Formulations 
20 
Study Drug Administration 
20 
Specific Restrictions / Requirements 
20 
Blinding 
20 
Concomitant therapy 
20 
Definitions 
21 
Collecting, Recording and Reporting of Adverse Events 
21 
Safety Monitoring Plan 
22 
Data Quality Assurance 
23 
Data Entry and Storage 
23 
Determination of Sample Size 
24 
Statistical and Analytical Plans 
24 
Informed Consent 
24 
IRB review 
24 
Confidentiality of Data and Patient Records 
25 

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STUDY PROTOCOL 
** please note, this protocol is the next step in studying home TTNS (HSC-MS-17-0423.) 
Since feasibility has been established, we are looking to study efficacy with this proposed 
randomized sham-control trial.** 
 
 
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.7-9 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 affect bladder function. We have tested this in 2 pilot trials and published the results 
of the first. 10 

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1. 
General Introduction 
 
The management of NLUTD in SCI includes: maintaining continence via timed voiding, 
catheterization (intermittent or indwelling), use of OAB medications, chemodenervation, and/or 
surgery. While these approaches have dramatically improved morbidity and mortality related to the 
upper urinary tracts, they are also associated with significant functional impairment11, challenges to 
community re-entry12-14, expense14 15, adverse effects 11 14, and ultimately QOL 11 (see Table 1). 
 
We propose a non-invasive, readily-available, and inexpensive approach that can be used at 
home (and reduces reliance on the health care system) to improve bladder-related health and 
function, while overcoming existing barriers: TTNS (transcutaneous tibial nerve stimulation), 
the transcutaneous adaptation of PTNS (percutaneous TNS). PTNS has demonstrated equal 
efficacy to newer OAB medications in a randomized control trial of 100 SCI subjects, while 
boasting fewer adverse events. 6 Although a large study of this nature has not been performed 
with TTNS in SCI, in the population of people with NLUTD due to Multiple Sclerosis (MS), TTNS 
has been shown to improve urinary urgency in more than 80% of the subjects, reduce urinary 
frequency, and had a positive impact on QOL measures. 16 
 
 
Table 1. Limitations of current treatment approaches to NLUTD 
Pharmacologic 
Limitation 
Bladder 
Management 
OAB medications 
Chemo-denervation Neuromodulation 
(NM) 
Side Effects 
Functional 
limitations vary 
by bladder 
management 
method (i.e., 
incontinence 
between caths, 
supply 
management, 
hand function, 
etc.) 
Sedation, dry mouth, 
constipation, etc. Increased 
risk of dementia 
Interaction with other 
medications 
Urinary tract infectio 
Change in bladder 
management may be 
necessary 
Surgical 
complications with 
sacral NM 
Non-Compliance 
Higher doses required in SCI 
Requires urologic 
procedure every 3-6 
months 
PTNS> 55% non- 
compliance 
Access/ Expense 
Newer medications with 
decreased side effects are often
not covered by insurance or 
are too expensive 
Largely unavailable, 
very expensive, 
involves invasive 
procedure. 
Both PTNS and 
sacral NM largely 
unavailable and 
very expensive 
 
 
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 have used the proposed TTNS protocol for research purposes 
(HSC-MS-15-0806, HSC-MS-17-0423). Based on the pilot safety data, we believe we should test 
the efficacy of the protocol for home use in a randomized control trial. 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.” 
 
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 

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and strengthening. We propose the development of a protocol that uses the same equipment in a 
novel way to effect bladder function. 

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2. 
Rationale and justification for the Study 
 
We have selected a neuromodulation technique, TTNS, which we have used safely with 
evidence of efficacy. 
 
Pilot Data: The leading theory for the mechanism of bladder neuromodulation by TNS is 
that stimulation of the tibial nerve sensory afferents block the visceral bladder afferents at the 
level of the spinal cord.17 This leads to a disruption of the bladder reflex arc, thereby 
decreasing motor efferent activity and subsequent pathologic reflex bladder contractions. This 
reflex arc is intact in people with thoracic level 9 (T9) injury and above (rostral). This 
hypothesis has been tested in a pilot trial of TTNS in acute SCI.10 
 
Pilot Trial I, Safety and Bladder Capacity: TTNS in acute SCI was performed in a 
randomized sham-control trial of TTNS for 30 minutes x 10 days using a commercially/readily 
available neuromuscular electric stimulation (NMES) device. In this trial, there were no safety 
events, compliance was 100%, and hospital staff noted ease of use. Decrease in bladder 
capacity and detrusor-sphincter dyssynergia (DSD) events were both mitigated in the TTNS 
group (Fig. 1). Also, evidence of the proposed mechanism was seen with significantly 
increased volumes to sensation in the TTNS group compared to the controls post-trial. These 
findings suggest that TTNS has the potential to mitigate the development of morbid 
neurogenic bladder in acute SCI. We also provided evidence of altering the nervous system 
response to bladder filling in a cohort of these subjects, suggesting the ability of reducing AD.18 
We then investigated home use of TTNS as the next phase of study. 
 
 
 
Fig. 1: Bladder sensation, detrusor-sphincter dyssynergia (DSD) frequency and bladder capacity changes in control 
and TTNS group over time. € between group difference p=0.01; *change from baseline p<0.02; 
 
Pilot Trial II, Effect on Voiding Program and QOL: TTNS in the home setting was tested in a 
single-arm pre-post pilot trial in subjects with chronic SCI performing intermittent 
catheterization (IC) with complaints of incontinence. There was 100% (16/16) completion of 
trial, no complications, TTNS was found to be easy to use, 86% (12/14) reduced their OAB 
medication dosage and anticholinergic side effects, and QOL scores improved (Fig. 2). This 
pilot trial suggests TTNS is feasible and safe to be performed at home. A randomized sham- 
control trial is needed to determine if TTNS can be used at home to manage NGB symptoms, 
as proposed in this study. 

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Post-Trial 
15 
10 
Dry mou 
5 
Constipat 
Hard stool 
0 
Sleepy/ tired * 
Decreased Thought Pr 
Decreased Libido 
Baseline 
15 
10 
5 
0 
Baseline and Post-Trial I-QOL scores 
75 
70 
∆= 2.9 
 
65 
∆= 3.5 
∆= 3 
∆= 6.2 
60 
 
 
55 
50 
 
45 
I-QOL Total 
I-QOL A&L 
I-QOL PS 
I-QOL SE 
 
Baseline 
Post-Trial 
B. 
Anticholinergic Side Effect Questionnaire 
 
 
 
 
 
th 
ion 
 
 
ocess 
 
 
Number of subjects: 
0-5 
5-10 
10-15 
 
 
5-10 
10-15 
Fig 2. Incontinence QOL (I-QOL) and Anti-cholinergic Side Effect Questionnaire 
results. A. Baseline and Post-Trial Results of I-QOL total and subscores: A&L= 
avoidance and limitation; PS= psychosocial; SE= social embarrassment. ∆= change 
in scores from baseline to post-trial. B. Baseline and Post-Trial responses to 
anticholinergic side effects presented as color contours. Post-Trial, most subjects 
had none/mild side effects, with dry mouth and sleepy/tired symptoms significantly 
less post-trial, *p<0.03. 
Percentile 
* 
A. 

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a. 
Rationale for the Study Purpose 
 
The status quo for NB management in SCI is catheterization for safely emptying the bladder and 
anticholinergic medications once symptoms of DH or DSD occur.3 This does not address the 
pathologic reflexes that lead to morbidity, including AD. Neuromodulation via TTNS may be able to 
address DH and DSD and alter the course of NB and prevent the morbidity arising from pathologic 
reflexes secondary to SCI. Pilot trial have tested the safety and feasibility of TTNS in acute SCI 
and have generated evidence of efficacy, including mitigating the loss in bladder capacity seen in 
chronic SCI. Preliminary data of TTNS performed at home provides evidence of high compliance, 
feasibility, and efficacy. Unlike the clinic-based treatment required for PTNS, compliance for the 
home-based treatment with TTNS is nearly double that of PTNS based on pilot data.13 
 
 
 
b. 
Rationale for Doses Selected 
 
Based on our pilot trials, tibial nerve stimulation protocols use submotor current intensity with a 
duration of 200 µs and frequency of 10Hz. 10 TTNS will be used 5 days weekly. 
 
c. 
Rationale for Study Population 
 
Participants: Participants will include SCI performing intermittent catheterization (IC) and using 
OAB medications, ages 18-75. Adults over 75 years old are excluded as age-related changes may 
influence bladder function.19 Although NLUTD managed with an indwelling catheter could also 
benefit, the outcome measures in this study reflect areas of importance for those performing IC. 
 
 
 
d. 
Rationale for Study Design 
 
Based on our experience with TTNS, we believe this protocol can be used to help with neurogenic 
bladder management. Subjects who perform intermittent catheterization are being selected 
because they more likely to have incontinence 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 2 weeks 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 
possible incontinence. The outcome measures are measure of bladder medication doses and 
surveys. The Incontinence Quality of Life (I-QOL) survey reflects the quality of life related to 
incontinence. 20 The Neurogenic Bladder Symptom Score (NBSS) measures and scores 
symptoms related to NGB. 21 Both will be conducted at baseline and at 3-months post-discharge. 
The medication + TTNS adherence survey and Medication + TTNS % survey. Adherence scales 
will measure adherence to medication and transcutaneous tibial nerve stimulation. Will be 
conducted at baseline, then every 4 weeks. The Connor-Davidson Resilience Scale (CD-RISC-25) 
will measure resilience. Conducted at baseline, week 6 and at the end of trial. The PROMIS 
General Self-Efficacy (GSE) will measure self-efficacy. (There is no validated Spanish version. 
Therefore, a conclusion cannot be made.) Conducted at baseline, week 6 and at the end of trial. 

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2. 
HYPOTHESIS AND OBJECTIVES 
 
 
1. 
Hypothesis 
 
Specific Aim 1. In a randomized sham-control trial (n=60), determine the efficacy of home TTNS 
in SCI. 
Hypothesis 1.1: Those in the TTNS group will be able to reduce their OAB medication dosages 
while maintaining continence compared to controls over a period of 3 months. 
Hypothesis 1.2: Symptoms of NGB measured by the Neurogenic Bladder Symptom Score 
(NBSS) and a voiding diary (VD) will be reduced in the TTNS group compared to controls. 
 
Specific Aim 2. Determine the impact on quality of life using TTNS at home. 
Hypothesis 2.1: Incontinence-related QOL (I-QOL) will be increased in the TTNS group compared 
to the controls and from baseline. 
Hypothesis 2.2: Anticholinergic side effects will be decreased in the TTNS group at 3-months 
compared to the controls and from baseline. 
 
2. 
Primary Objectives 
 
OBJECTIVE: to advance the science and care around bladder function and management among 
people with spinal cord injury/disease (SCI/D) and NLUTD with TTNS (and if so, we anticipate 
translating this research to other populations with NLUTD). Specifically, we seek to demonstrate 
that TTNS will improve NLUTD in SCI/D by: 
 
1. 
intervening acutely with neuromodulation of the neurogenic bladder via TTNS to maintain 
bladder capacity by reducing pathologic reflexes, DH and DSD; 
 
2. 
altering pathologic autonomic nervous system (ANS) responses and reducing autonomic 
dysreflexia (AD). 
 
3. 
improving the quality of life (QOL) of those living with SCI/D by providing a feasible, non- 
pharmacologic, and dignified intervention for NLUTD that can be performed at home; 
 
In this proposed study, we seek to provide evidence for overall objective #3 using home TTNS. We 
hypothesize that TTNS can be used in the home setting to maintain continence while reducing 
OAB medication dosages and improve quality of life. 
 
Primary Objective 1: Evidence of TTNS efficacy with reduced OAB medication dosage 
Primary Objective 2: Evidence of TTNS efficacy with reduced NGB symptoms as measured by 
the NBSS and the Voiding Diary 
 
 
3. 
Secondary Objectives 

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Secondary Objective 1: I-QOL scores will be increased in the TTNS group compared to the 
controls 
 
Secondary Objective 2: Anticholinergic side effects will be reduced in the TTNS group compared 
to the controls. 
 
4. 
Potential Risks and Benefits: 
 
a. 
End Points - Efficacy 
Primary Objective 1: Evidence of TTNS efficacy with a greater proportion of bladder medication 
reduction in the TTNS group compared to the control group. Time to achieve this endpoint will be 
approximately 3 months after subject recruitment, anticipated 1 year to complete all subject 
recruitment. 
 
Priamry Objective 2: Evidence of TTNS efficacy with reduced NGB symptoms as measured by 
the NBSS and the Voiding Diary. Time to achieve this endpoint will be approximately 3 months 
after subject recruitment, anticipated 1 year to complete all subject recruitment. 
 
b. 
End Points- Quality of Life 
 
Secondary Objective 1: Improved QOL in the TTNS group compared to the controls at the end of 
the 3-month trial, based on I-QOL scores. Time to achieve this endpoint will be approximately 3 
months after subject recruitment, anticipated 1 year to complete all subject recruitment. 
 
Secondary Objective 2: Decreased anticholinergic side effects in the TTNS group compared to 
the controls at the end of the 3-month trial, based on an anticholinergic side effect survey. Time to 
achieve this endpoint will be approximately 3 months after subject recruitment, anticipated 1 year 
to complete all subject recruitment. 

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c. 
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 0.6 episodes per patient during the 3-month 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 
 
1. 
List the number of subjects to be enrolled. 
60 subjects. Consecutive SCI clinic encounters meeting the inclusion/exclusion criteria will be 
asked to enroll. Children and pregnant women will be excluded. 
 
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 criteria. 
- 
Flyers will be posted and distributed in the outpatient clinic to increase study awareness. 

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3. 
Inclusion Criteria (table 1) 
 
Inclusion criteria: 1) ages 18-75 years; 2) SCI performing IC; 3) up to 2 anticholinergic OAB 
medications; 4) stable OAB medications in the past 2 months; 5) SCI neurologic level above T10; 
6) English and Spanish speaking. Subjects that satisfy initial screening and willing to participate in 
the trial will have electric stimulation placed to attempt toe flexion as a check of the tibial nerve 
integrity. Those who cannot achieve toe flexion will be excluded. 
 
 
Table 2. Inclusion and Exclusion Criteria 
 
Inclusion Criteria 
Exclusion Criteria 
18-75 years old 
Traumatic and Non-traumatic SCI performing 
IC 
Past history of genitourinary diagnoses or 
surgeries 
History of CNS disorders and/or peripheral 
neuropathy 
Up to 2 anticholinergic OAB medications 
Pregnancy 
No changes in OAB medications 
Lower motor neuron bladder 
Neurologic level of injury above T10 
Concern for tibial nerve pathway injury 
English and Spanish speaking 
Absence of toe flexion or AD with electric 
stimulation 
 
Bladder chemodenervation in past 6 months 
 
Potential for progressive SCI including 
neurodegenerative SCI, ALS, cancer myelopathy, 
Multiple sclerosis, transverse myelitis 
SCI= spinal cord injury; IC= intermittent catheterization; OAB= overactive 
bladder; T10= thoracic level 10; CNS= central nervous system; AD= autonomic 
dysrelflexia 

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4. 
Exclusion Criteria (table 1) 
 
Subjects meeting any of the exclusion criteria at baseline will be excluded from participation: 
- 
 - History of genitourinary diagnoses (i.e. prostate hypertrophy, overactive bladder, cancer, 
etc.) 
- 
Potential for progressive SCI including neurodegenerative SCI, ALS, cancer myelopathy, 
Multiple sclerosis, transverse myelitis 
- 
- History of central nervous system disorder (i.e. prior SCI, stroke, brain injury, Parkinson’s 
disease, MS, etc.) 
- 
- History of peripheral neuropathy 
- 
- pre-SCI symptoms of peripheral neuropathy (numbness and/or tingling in feet, 
sharp/jabbing/burning pain in feet, sensitivity to touch, lack of coordination, muscle 
weakness, etc.) 
- 
- Pregnancy 
- 
- Known injury to the lumbosacral spinal cord or plexus, or pelvis with associated neuropathy 
- 
- concern for tibial nerve pathway injury 
- 
- absence of toe flexion or autonomic dysreflexia during electric stimulation test 
- 
- bladder chemodenervation in prior 6 months 
5. 
Withdrawal Criteria 
 
Possible reasons for discontinuation of study intervention: 
- 
Intolerable incontinence after discontinuation of bladder medications 
- 
Intolerant to electric stimulation 
- 
Non-compliance 
 
To mitigate non-compliance, a stipend for effort in completing voiding diary will be provided at 
$10 per day (2 days per month). An additional $20 will be provided for logging bladder 
medication use and TTNS use/settings monthly. If both voiding diary and TTNS diary are 
reported, a $10 bonus will be provided, therefore $70 month 1, and $50 for each months 2 and 
3. At most per subject= $170 for the 3-month trial per subject. Subjects will also receive 
reimbursement for travel for the urodynamic studies up to $200 per trip (two urodynamic studies 
= up to $400 per subject) and if medication reduction requires new prescriptions to cover co- 
payments when applicable up to $50 total per subject. 
 
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. 

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4. 
TRIAL SCHEDULE 
 
 

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5. 
STUDY DESIGN 

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Anticipated number of patients to screen: 80 
● Anticipated number of patients to enroll: 60 
● Anticipated drop out or loss to follow-up: 6 
 
Approximate time to complete study recruitment: 1 year 
Expected duration of subject participation: 3-months. 3-months was selected as a fair 
assessment of efficacy. Clinically, medications are determined efficacious based on 1-month or 
less of use. 
 
TTNS protocol: Same TTNS setting will be used as protocols HSC-MS-15-0806 and HSC-MS- 
17-0423. 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, 
patients will be excluded. 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 
 
Sham protocol and rationale: Toe flexion will be attempted, as in the TTNS protocol. Then the 
stimulation will be reduced to 1 mA for 30 minutes. Rationale: In order to make this a 
convincing blind, the TTNS protocol must be simulated closely as subjects may interact and 
discuss. Rather than turning the device off, they will be instructed that the stimulation required 
is below motor threshold, at 1 mA. Based on the knowledge of the pilot trial requiring about 
40mA for TTNS, and the amperage for needle-driven PTNS adjacent to the tibial nerve at 0.5 
– 1mA, it is unrealistic that 1mA via surface electrodes is sufficient to activate the tibial nerve. 
Both TTNS and sham participants will be instructed to use the device for 30 minutes, 5 days 
per week. 
 
Medication reduction protocol: Subjects will be using up to 2 anticholinergic OAB 
medications. Subjects generally use similar medications with a common approach- maximize 
one medication before adding a second medication. The PI will provide a weekly weaning 
schedule, individualized for each subject. No changes will occur during the first 2 weeks of 
TTNS. Starting week 3, the secondary OAB medication will be halved if possible, otherwise 
discontinued. Should the subject tolerate this, weaning will continue until one medication is 
discontinued, then the other. If the subject does not tolerate weaning, they will remain on the 
lowest, tolerable dose and we will attempt weaning the following week. 
 
 
− 
Information gathered: 
o Clinical demographics, morbidity, and Neurologic Exam findings from interview with 
subjects, exam, and EMR review. 
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 I-QOL at baseline initial visit and then at 3-month follow-up. Can be conducted over 
phone. 

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o NBSS at baseline and every 4 weeks (monthly) and at the 3-month follow-up. Can be 
conducted over phone. 
o Anticholinergic survey at baseline and then at 3-month follow-up. Can be conducted 
over phone. 
o TTNS satisfaction survey at 3-month follow-up. Can be conducted over the phone. 
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. 
o General self-efficacy at baseline, week 6 and at the end of the trial. Can be conducted over the 
phone. 
o CD-RISC at baseline, week 6 and at the end of the trial. Can be conducted over the phone. 
o The medication and TTNS adherence survey at baseline then every 4 weeks. Can be conducted 
over the phone. 
o The medication and TTNS % survey at baseline then every 4 weeks. Can be conducted over 
the phone. 

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1. 
Summary of Study Design 
 
A randomized control trial of TTNS v sham-control in chronic SCI (n=60) performing intermittent 
catheterization on OAB medications will be performed to address the following Specific Aims: 
 
In Specific Aim 1, we will assess the efficacy of TTNS based on reduced OAB medication use 
over 3 months while maintaining stable NGB symptoms based on NBSS score. A bladder diary 
will also capture important information such as frequency and volume of catheterization, 
incontinence episodes, and other related observations. 
 
In Specific Aim 2, we will assess whether TTNS improves incontinence-related QOL based on I- 
QOL survey scores. 

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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 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. Blood 
pressure will also be monitored during this trial for an additional safety measure to 
ensure autonomic dysreflexia is not occurring. 
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 (RA) will call weekly to capture the written data and monitor progress 
with the protocol. 
d. 
The RA will also perform the survey outcome measures (NBSS, I-QOL,CD-RISC, GSE, 
Medication adherence surveys and anticholinergic side effect questionnaire) at baseline 
every 4 weeks, 6 weeks and at 3-months. Surveys can be conducted over the 
telephone. 
 
2. 
Randomization and Blinding 
 
Subjects will be randomized to either TTNS or sham control (1:1) using a block 
size of 4 and stratified based on complete/incomplete SCI to ensure the equal 
allocation of the most severely injured in the two groups. The PI will be blinded to 
randomization and treatment allocation, managed by the research assistant. 
 
3. 
Contraception and Pregnancy Testing 
 
Females of childbearing age will have to adhere to medically recommended contraception if 
sexually active with men, such as condoms and/or birth control pills. 

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4. 
Study Visits and Procedures 
 
- 
Screening Visits and Procedures 
 
Screening will be performed in the SCI clinic by the PI or co-I SCI attendings. 
 
Those that meet the I/E criteria will be approached for the study by the PI or 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. The goal is 5 
days per week of TTNS use for 3-monhts. 
 
Subjects will be called weekly to capture the information of the TTNS log and to monitor 
progress of protocol. They will also be reminded to change electrodes weekly. 3 days prior to 
the NBSS call, the RA will contact the subjects to remind them to begin recording in their voiding 
diary for 2 days. 
 
- 
Final Study Visit: 
 
Upon completion of the 3-month study period, final voiding diary information will be collected and 
the post-trial questionnaires will be conducted. 
 
- 
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. OAB 
medications can be resumed at the prior efficacious dose. 

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7. 
TRIAL MATERIALS 
 
The electric stimulation device used for TTNS is the Stamobil +. 
 
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 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 
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. 

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8. 
TREATMENT 
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 
 
 
2. 
Study Drug Formulations 
 
NA 
3. 
Study Drug Administration 
 
NA 
 
4. 
Specific Restrictions / Requirements 
 
NA 
 
5. 
Blinding 
 
NA 
 
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. 

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9. 
SAFETY MEASUREMENTS 
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. 
 
 
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. 

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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 
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 0.6 episodes per 
patient during the 3-month 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. 

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10. 
DATA ANALYSIS 
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. 
 
 
2. 
Data Entry and Storage 
 
Data will be entered on a UTH google drive spreadsheet file, with permission to access 
controlled by the PI. Data collected by the RA from the voiding diary and survey outcome 
measures will be entered into the spreadsheet. Data will be coded by subject ID. 
 
The RA will have the linking log of the patients to their subject ID in her password-protected 
desktop in the TIRR Memorial Hermann Research building. 
 
 
5 years after manuscript publication, the paper reports will be placed into the shredder bins for 
destruction. 

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11. 
SAMPLE SIZE AND STATISTICAL METHODS 
 
1. 
Determination of Sample Size 
 
Sample size will be determined from Aim 1.1. Assuming that 40% of the subjects in the control 
group are able to reduce their bladder medications (placebo effect), the study would require a 
sample size of 21 for each group (i.e. a total sample size of 42), to achieve a power of 80% for 
detecting a difference in proportions of 43% between the two groups (83% in TTNS group – 40% 
in control group) at a two sided p-value of 0.05. Accounting for 40% dropout, we will recruit 30 
subjects in each arm for a total of 60 subjects. In Aim 1.2, the NBSS has demonstrated 
responsiveness to change after bladder chemodenervation with a mean difference of 11.8 
(11),22 which would require a sample size of 20. For Aim 2.1, a 7±17 point improvement in the I- 
QOL score was observed after 4 weeks of TTNS use in our pilot study. We expect the control 
group to have minimal improvement in I-QOL scores due to placebo effect, estimated as 3 
points. With power of 80% and a more conservative standard deviation of 4 points, we need a 
sample size of 22 in total by two-sample two-sided t-test at a type I error rate of 0.05. The 
sample size determined by Aim 1.1 is sufficient for this aim. 
 
2. 
Statistical and Analytical Plans 
Patients will be randomized to control and TTNS at a 1:1 ratio by computer-generated 
sequences, with stratified allocation in blocks of 4 controlling for complete SCI, with the 
investigator blinded to the treatment allocation. Changes in outcomes listed in Aim 1 and 2 will 
be compared between groups by two-sample two-sided t-test or Wilcoxon rank-sum test. 
Descriptive statistics and mean plots will be provided for the longitudinal measurements. 
Multilevel mixed-effects regression models will be used for longitudinal analyses of treatment 
effects, controlling for confounding variables including age, sex, severity of SCI, compliance 
(number of sessions), and OAB medication dosages. Multiple testing will be adjusted by 
Bonferroni correction if necessary. Non-random missing data will be analyzed using the 
method in Ibrahim and Molenberghs.23 Considering the unknown long-term effects of TTNS, we 
may not see significant treatment effect on some outcomes by conventional (frequentist) 
analyses. We plan a Bayesian analysis (with either skeptical or neutral priors) to estimate the 
probability (with 95% credible intervals) of treatment effect. Conventional analysis will be 
performed in SAS 9.4 (SAS Institute, Cary NC) and Bayesian analysis will be performed in R 
3.5.0 using packages like R2WinBUGS. 
 
12. 
ETHICAL CONSIDERATIONS 
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. 

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2. 
IRB review 
 
This protocol and the associated informed consent documents have been submitted to the IRB 
for review and approval, pending. 
 
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 controlled by the RA on her password-protected desktop computer at TIRR 
Memorial Hermann. 
 
 
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 
Case Report Form 
Appendix 2 
Sample Voiding Diary Log 
Appendix 3 
Informed Consent Form 

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