The Effects Upon the Bladder of Transcutaneous Tibial Nerve Stimulation in Acute Traumatic Spinal Cord Injury
Phase: NA
Conditions: Spinal Cord Injury, Neurogenic Bladder
Sponsor: The University of Texas Health Science Center, Houston

IRB Page 1 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The Effects Upon the Bladder of Transcutaneous Tibial Nerve Stimulation 
in Acute Traumatic Spinal Cord Injury 
 
 
NCT02573402 
 
              Version Date: 10/04/2016 
 
 

IRB Page 2 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
STUDY PROTOCOL 
 
PROTOCOL NUMBER: 
HSC-MS-15-0806 
 
PROTOCOL TITLE: 
The Effects Upon the Bladder of Transcutaneous Tibial Nerve Stimulation in Acute 
Traumatic Spinal Cord Injury 
 
 
 
VERSION: 
6 
DATE: 
9/29/2016 
 
CORRESPONDING PRINCIPAL INVESTIGATOR: 
Argyrios Stampas, MD; Assistant Professor Dept PM&R; TIRR Memorial Hermann 
 
 
 
 
 
 
SITE: 
TIRR Memorial Hermann 133 Moursund St, Houston, TX 77030 
 
 
 
 
COLLABORATORS: 
-  Gerard Francisco, MD; Chair Dept. PM&R; UTHealth Health Science Center at 
Houston 
-  Christopher P. Smith, MD, MBA, MSS; Associate Professor, Scott Department of 
Urology, Baylor College of Medicine 
-  Kenneth Gustafson, PhD; Associate Professor of Biomedical Engineering, Case 
Western Reserve University 
- Yingchun Zhang, Ph. D, Assistant Professor at the University of Houston 
-  Liang Zhu, PhD; Assistant Professor, Division of Clinical and Translational Sciences, 
Department of Internal Medicine, The University of Texas Health Science Center at 
Houston 

IRB Page 3 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
GENERAL INFORMATION 
 
 
 
Name and address of the sponsor of the study: 
TIRR Rehab Innovations Grant Program 
TIRR Memorial Hermann 
1333 Moursund St 
Houston, TX 77030 
 
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 Page 4 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
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. ..................................................................11 
3.2. 
CRITERIA FOR RECRUITMENT ....................................................................................................11 
3.3. 
INCLUSION CRITERIA ..................................................................................................................11 
3.4. 
EXCLUSION CRITERIA.................................................................................................................11 
3.5. 
WITHDRAWAL CRITERIA .............................................................................................................12 
3.6. 
SUBJECT REPLACEMENT ...........................................................................................................12 
 
4. 
TRIAL SCHEDULE...........................................................................................................................12 
 
5. 
STUDY DESIGN ...........................................................................................................................12  
5.1. 
SUMMARY OF STUDY DESIGN ....................................................................................................12 
 
6. 
METHODS AND ASSESSMENTS.................................................................................................14 
 
6.1. 
RANDOMIZATION AND BLINDING.................................................................................................14 
6.2. 
CONTRACEPTION AND PREGNANCY TESTING ...........................................................................15 
6.3. 
STUDY VISITS AND PROCEDURES..............................................................................................15 
 
7. 
TRIAL MATERIALS .........................................................................................................................16 
 
7.1. 
TRIAL PRODUCT (S)....................................................................................................................16 
7.2. 
STORAGE AND DRUG ACCOUNTABILITY ....................................................................................17 
 
8. 
TREATMENT .....................................................................................................................................17 
 
8.1. 
RATIONALE FOR SELECTION OF DOSE ......................................................................................17 
8.2. 
STUDY DRUG FORMULATIONS ...................................................................................................17 
8.3. 
STUDY DRUG ADMINISTRATION .................................................................................................17 
8.4. 
SPECIFIC RESTRICTIONS / REQUIREMENTS ..............................................................................17 
8.5. 
BLINDING ....................................................................................................................................17 
8.6. 
CONCOMITANT THERAPY............................................................................................................18 
 
9. 
SAFETY MEASUREMENTS ...........................................................................................................18 
 
9.1. 
DEFINITIONS ...............................................................................................................................18 
9.2. 
COLLECTING, RECORDING AND REPORTING OF ADVERSE EVENTS .........................................18 
9.3. 
SAFETY MONITORING PLAN .......................................................................................................18 
 
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 Page 5 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
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 Page 6 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
STUDY PROTOCOL 
 
 
1. 
BACKGROUND AND RATIONALE 
 
There are over 1 million people living in the United States with spinal cord injury (SCI) with 
devastating functional impairments including paralysis and bowel/bladder dysfunction.1   Over 
time after SCI, reorganization of the spinal reflexes occurs and it is suspected that these 
synaptic alterations cause detrusor sphincter dyssynergia (DSD). It is estimated that DSD 
occurs in 75% of suprasacral spinal cord injuries with up to 50% developing serious urologic 
complications with current management strategies.2   Neuromodulation techniques, such as 
transcutaneous tibial nerve stimulation (TTNS), currently improve bladder function and reduce 
DSD in chronic SCI, but little is known about their efficacy in acute spinal cord injury.3   There is 
currently a gap in our knowledge about the effects of TTNS on the bladder in acute spinal cord 
injury. We hypothesize that TTNS can improve neurogenic bladder parameters during acute 
SCI and that development of a feasible protocol during acute rehabilitation will maintain these 
results and decrease the incidence of DSD. 
 
We believe we can use existing TTNS technology to help neurogenic bladder in SCI.  First, we 
need to determine the safety and feasibility of a 2-week TTNS protocol in acute SCI during 
inpatient rehabilitation. Second, we will examine the effects on the bladder of this protocol as 
seen on urodynamic studies (USD) before and after the protocol, as well as on 2-month follow- 
up. We will perform an observational study of TTNS and UDS on all 4 common neurologic 
categories of acute SCI admitted to TIRR Memorial Hermann and consenting to the study. 
Patients enrolled in the study will have baseline urodynamics performed, and then randomized 
to a control trial (RCT) of a 2-week protocol of TTNS to test for safety and efficacy during 
inpatient rehabilitation to evaluate bladder changes based upon pre- and post- urodynamic 
testing, as well as 2-month follow-up.  A subset of those in the experimental TTNS group will 
also have a 1-month follow-up in which they will have a maintenance session of TTNS in clinic. 
 
We will concurrently test novel high density (hd) surface electrodes during the urodynamic 
studies to see if there is correlation between the electrical activity seen by the hd surface 
electrodes and the pressure recordings of the bladder. We believe this has the potential to 
develop into a non-invasive outcome measure in neurogenic bladder. We will be recording 
bladder activity with high density EMG surface electrodes during session 1, session 5, and 
session 10. These are the same types of electrodes used in the UDS.  Surface electrodes will 
adhere to the skin and placed above and below the pubic bone, placed by the research 
assistant.  Recordings will last the entire stimulation session. 
 
We will be looking at urine growth factors and inflammatory markers.  These markers have 
been investigated in patients with SCI in the past, however due to technical errors, the 
conclusions have been withdrawn.  These technical errors have since been corrected and the 
biomarkers are being utilized to characterize other bladder pathologies, including returning to 
look at neurogenic bladder in SCI.  They are currently being used to explore the treatment 
efficacy of BOTOX in the neurogenic bladder in SCI at TIRR, in which I am involved as a co- 
investigator. 

IRB Page 7 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
1.1. 
General Introduction 
 
The EMPI 300 PV and the newer model, the EMPI Continuum, are electric stimulation units 
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. 
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 75% of suprasacral SCIs developing DSD and up to 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, little is little 
known about the effects of neuromodulation of the bladder in the acute phase of SCI recovery. 
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 acutely 
injured 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 acute neurorehabilitation. The candidate has 
published reviews on the current state of acute 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   There has been little published regarding the effects of electric stimulation 
upon the bladder in acute SCI.  Sievert et al. performed invasive sacral neuromodulation in 
acute SCI in spinal shock (atonic bladder seen on UDS, but time from injury was not reported), 
with the hypothesis that early intervention would prevent the development of pathologic reflexes 
leading to DSD.11   Unlike the controls that experienced the typical sequelae of SCI neurogenic 
bladder over time, including decreased bladder capacity and frequent UTIs complicated by 
sepsis and hospitalizations, the group receiving the implanted neuromodulation device 
maintained normal bladder capacity, reported improved quality of life scores, and the detrusor 
did not develop hyperactivity.11   Although the mechanism of action is unclear, it appears to be 
afferently mediated, requiring electrically induced nerve conduction to prevent the abhorrent 
reflexes from forming which cause detrusor overactivity and DSD.12   Less invasive, 
transcutaneous electric stimulation performed directly over the bladder for 30 sessions over a 5 
week period in acute SCI (as early as 2 months) produced continued beneficial results based 
on UDS after 2 years.7   Based upon an extensive review of the literature on neuromodulation of 
neurogenic bladder and the clinical experience of our research team, we believe a TTNS 
protocol over a 2 week period will show significant improvements in UDS outcomes. 
 
Concurrently, we will be testing new hd surface electrodes and correlate the electrical activity 
found to the pressure recordings during UDS. This harmless, non-invasive technology may 
provide a useful, quick, feasible, outcome measure in neurogenic bladder. 
 
We will be looking at urine growth factors and inflammatory markers to characterize neurogenic 
bladder in SCI. They are currently being used to explore the treatment efficacy of BOTOX in 
the neurogenic bladder in SCI at TIRR. 

IRB Page 8 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
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 as seen on UDS, 
specifically cystometry, and we are applying it during the acute period during inpatient 
rehabilitation. The hypotheses are 1) TTNS will be a safe and feasible modality that can be 
used during acute rehabilitation and 2) a 2-week protocol of TTNS will be an effective protocol 
to improve bladder parameters, reduce oral bladder medication usage, and reduce the 
frequency of DSD and detrusor hyperreflexia (DH) at 2-month follow-up UDS. 
 
High density surface electrodes are currently being studied in the bladder of animal models. 
There is a wealth of data recorded from the electrical activity of the bladder and the pelvic 
muscles. The hypothesis is that there will be a correlation between UDS outcomes and the 
high definition surface electrode recordings that may allow its use as a non-invasive, novel, and 
feasible outcome measure. 
 
Studies have shown that cytokines and chemokines responsible for autocrine, paracrine and 
endocrine signalling are also released by non-immune cells in the bladder such as urothelium 
and detrusor cells. [Bouchelouche et al, 2004; Bouchelouche et al, 2006a; Bouchelouche et al, 
2006b] The urinary bladder relies on a broad array of cytokines, chemokines and growth 
factors to effect biochemical changes within its organ in response to disease and therapeutic 
intervention.  But not all these chemokines/cytokines and growth factors can serve as urinary 
biomarkers or surrogates of treatment response as they have to fulfil the key requirement of 
being present in detectable amounts in urine that can be assayed using standard methods. 
 
The detectable amount of nerve growth factor (NGF) in the NGB patients combined with its 
known role in neuroimmune interactions makes NGF an ideal candidate for a urinary biomarker. 
It has been proposed that after neurologic injury, the bladder releases NGF into the urine in 
response to the injury.  NGF and its receptors may also amplify other immunoinflammatory and 
neuronal pathways contributing to bladder inflammation and symptoms associated with UTI. 
 
Other proteins have been consistently detected in the urine of subjects with SCI or other 
neurological diseases like MS or impairments like diabetes. The chemokines and cytokines 
include: interleukin IL-5, IL-6, IL-1Ra, sIL-2R, CC chemokines including MCP-1, MIP-1 β, 
RANTES(Regulated upon Activation, Normal T Expressed and Secreted), CXC chemokines 
including GRO-α/ CXCL1, IL-8,  and IP-10 and growth factors including vascular endothelial 
growth factor (VEGF), epidermal growth factor (EGF), platelet derived growth factor (PDGF- 
AA), VEGF, and PDGF. 

IRB Page 9 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
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 rarely performed in acute 
SCI, and it is not common in acute rehabilitation. There has been little published regarding the 
effects of electric stimulation upon the bladder in acute SCI.  Sievert et al. performed invasive 
sacral neuromodulation in acute SCI in spinal shock (atonic bladder seen on UDS, but time 
from injury was not reported), with the hypothesis that early intervention would prevent the 
development of pathologic reflexes leading to DSD.11   Unlike the controls that experienced the 
typical sequelae of SCI neurogenic bladder over time, including decreased bladder capacity 
and frequent UTIs complicated by sepsis and hospitalizations, the group receiving the 
implanted neuromodulation device maintained normal bladder capacity, reported improved 
quality of life scores, and the detrusor did not develop hyperactivity.11   Although the mechanism 
of action is unclear, it appears to be afferently mediated, requiring electrically induced nerve 
conduction to prevent the abhorrent reflexes from forming which cause DH and DSD.14   Less 
invasive, transcutaneous electric stimulation performed directly over the bladder for 30 sessions 
over a 5 week period in acute SCI (as early as 2 months) produced continued beneficial results 
based on UDS after 2 years.7 
 
Gaps in the knowledge which we intend to fill are: 
1) Safety and feasibility of TTNS in acute SCI during inpatient rehabilitation 
2) Efficacy of a 2-week TTNS protocol in SCI based on UDS findings on 2-month follow-up. 
3) Analysis of bladder medication usage in those with and without TTNS, frequency of DSD, 
and evaluation of morbidity at 2-month follow-up 
 
The rationale for the use of the hdEMG electrodes is to attempt to develop a novel outcome 
measure for neurogenic bladder that is practical, feasible, and non-invasive. 
 
 
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 2 week 
period will show significant improvements in UDS outcomes. 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 4 groups of acute tSCI ages 18-65, 10 in each group, based on the 
common neurologic categories of spinal cord injury: 
- 
Tetraplegia, complete 
- 
Tetraplegia, incomplete 
- 
Paraplegia, complete 
- 
Paraplegia, incomplete 
 
The age range for this study was selected because age-related changes that may alter the 
urodynamic studies in adults increases over the age of 65.15 Consecutive patients meeting the 
inclusion/exclusion criteria admitted to inpatient rehabilitation for tSCI will be asked to enroll. 
There are approximately 200 acute tSCI patients admitted to our institution annually, the 
majority of which satisfy the inclusion criteria. The distribution of the 4 neurologic classifications 
required is similar to the published data from the Model Systems.16   Inclusion criteria include 

IRB Page 10 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
ages 18-65 years old admitted to inpatient rehabilitation within 6 weeks of injury with a 
neurologic level of injury rostral to T10 (T9 and above).  This is a significant neurologic level 
because the bladder remains innervated at these levels, without damage to the spinal cord 
neurons innervating the bladder. The RCT is 10 sessions over 2 weeks, thus discharge within 
2 weeks is undesirable. Because our institution serves a large geographic region, routinely 
providing care to five different states, the ability to return to outpatient clinic for follow-up is 
considered inclusion criteria. Although there is no clear definition of “acute” SCI, most studies 
range from 2- 14 weeks post injury.15-19   The European Multicenter Study about Spinal Cord 
Injury has published a time schedule for the stages of SCI, in which our time frame would be 
considered acute.17   The 6 week time period was chosen as the upper limit to ensure 
recruitment of patients within the time frame of the grant period. We anticipate most subject 
recruitment within 4 weeks of injury given current admission trends. 
 
d. 
Rationale for Study Design 
 
Specific Aim 1:  Safety and feasibility of TTNS in acute SCI during acute rehabilitation.  This 
has been demonstrated in chronic SCI. 
Specific Aim 2.1:  2-week RCT of TTNS to compare UDS outcomes to controls on 2-month 
follow-up. 
Specific Aim 2.2:  Those that receive a TTNS maintenance dose 1 month after discharge will 
have better urodynamic outcomes than both the control and those in the TTNS that did not 
receive the maintenance dose. 
 
 
2. 
HYPOTHESIS AND OBJECTIVES 
 
 
 
2.1. 
Hypothesis 
 
Hypothesis 1: TTNS will be a safe and feasible modality that can be used in acute tSCI 
patients during inpatient rehabilitation. They will have non-significant differences in morbidity, 
mortality, and functional outcome measures during their admission compared to controls. 
 
Hypothesis 2.1: Those that receive TTNS will show significant improvements in bladder 
parameters on post-UDS compared to both baseline UDS and the control group. 
Improvements may be seen in the following UDS parameters: 
- 
volume at first involuntary detrusor contraction 
- 
maximum detrusor pressure (cmH20) 
- 
bladder capacity (maximum volume infused) 
- 
frequency of detrusor sphincter dyssynergia 
 
Hypothesis 2.2:  On 2-month follow-up, those that received TTNS will have sustained bladder 
improvements compared to control with less occurrence of DSD on UDS.  Those that receive a 
maintenance dose of TTNS will have better urodynamics than those that did not. 
 
 
 
2.2. 
Primary Objectives 
 
Primary Objective 1:  Monitor for safety of a 2 week TTNS protocol in acute SCI. 
Primary Objective 2:  Compare the effects upon the bladder of a 2-week TTNS protocol in 
acute SCI versus control group upon completion of the TTNS protocol with UDS as well as on 
2-month follow-up UDS. 

IRB Page 11 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
2.3. 
Secondary Objectives 
 
Secondary Objective 1:  Identify the neurologic bladder category of acute SCI based on 
baseline UDS in which TTNS is effective.  Subjects will be stratified into the randomized trial 
based on areflexic bladder versus not-areflexic bladder. 
 
Secondary Objective 2: Identify the effects of a maintenance dose of TTNS one month after 
completion of the 2 week trial. 
 
Secondary Objective 3: Compare the findings of hdEMG surface electrodes above the pubic 
bone to the urodynamic study findings of the detrusor. 
 
Secondary Objective 4: Characterize other bladder pathologies, including neurogenic bladder 
in SCI, by analysing urine growth factors and inflammatory markers. 
 
 
 
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:  Upon completion of the randomized control trial, we expect to observe 
significant improvements in UDS measures comparing baseline to post- UDS in the TTNS 
group and at the 2-month follow-up.  The UDS outcome measures we expect to improve are: 
 
- 
Increase in bladder capacity by 50% or 100ml 13 
- 
Increase in volume at first detrusor contraction by 50% or 100ml 13 
- 
Decrease in maximum detrusor pressure by 25% 18 
 
We also expect to see decreased frequency of DSD in those that received TTNS compared to 
the Control group. We do not expect beneficial UDS changes in the Control group 
 
Anticipated benefits include improved bladder capacity, decreased detrusor pressure, 
decreased detrusor-sphincter dyssynergia, improved morbidity, and decreased bladder 
medication usage. 
 
b. 
End Points - Safety 
 
We expect the rates of morbidity to be the same between those who participate and those who 
do not in both Aims of the research. Risks can be divided into the risks involved in having 
urodynamic studies and the risk of having electric stimulation. 
 
Urodynamic Study Risks: 
Some complications of urodynamic cystometry may include, but are not limited to, the following: 
- 
Urinary Tract infections (UTIs) 
- 
Autonomic Dysreflexia (symptoms of increased adrenaline response which may 
include increase blood pressure, headache, sweating, and flushing). 
 
UTIs are a risk any time a foreign object is introduced into the urethra and or bladder. To 
mitigate this risk, skilled urology nurses will be using sterile technique to insert the catheters. 
 
Autonomic Dysreflexia (AD) is a unique phenomenon which occurs when there is an injury or 

IRB Page 12 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
lesion between the sacrum (bottom) and the pons (top) within the spinal cord. It may occur in 
any SCI with a neurologic level of T6 (middle spine) and above.  It occurs whenever there is a 
noxious stimulus below the neurologic level of injury, with a mounting stress response that may 
cause elevated blood pressures, sweating, flushing, and/or headaches. In this setting, the 
distention of the bladder during the study and/or the catheter insertion/placement may be the 
noxious factor. To mitigate AD: 
- 
Filling rate will be 40ml/min, rather than 50ml/min. 
- 
Blood pressure will be monitored every 3-5 minutes.  An elevated SBP >20mmgHG 
from baseline indicates AD. 
- 
Staff will be monitoring for sweating, flushing, and asking about headaches during 
the study. 
- 
Should the patient have AD, we will stop filling for 5 minutes, reposition the patient 
and/or catheter as needed, and examine for any other noxious stimuli. 
- 
After 5 minutes, we will resume the filling at 20ml/min. 
- 
Should the AD persist, the study will stop and we will follow the AD protocol, which 
includes checking BP every 3-5 minutes, loosening clothes, sitting the patient up, 
emptying the bladder, examining the patient for impacted bowel, and examining the skin 
for lesions.  Should the protocol fail in lowering the BP and the patient requires 
medication management to lower the BP, a code will be called to better address the 
situation. 
 
It is not routine to perform UDS acutely due to evolving bladder reflexes. However, it is 
possible to perform UDS during the acute phase of injury.  Bellucci et al. successfully performed 
UDS on 60 acute SCI patients with injuries less than 40 days prior to the study, without reported 
morbidity secondary to the UDS.19 
 
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 used. 
 
 
 
3. 
STUDY POPULATION 
 
3.1. 
List the number of subjects to be enrolled. 
 
Consecutive patients meeting the inclusion/exclusion criteria admitted to inpatient rehabilitation 
for tSCI will be asked to enroll.  Children and pregnant women will be excluded. 
 
3.2. 
Criteria for Recruitment 
 
- 
Initial screening will be performed via documentation provided in the EMR. 
- 
Patients will be approached on the inpatient unit by the principle investigator or the research 
assistant to answer remaining questions and to consent the patient. 
- 
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 

IRB Page 13 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
to the consent. 
- 
Because of the time constraints of the study, they will have 1 day to decide upon whether 
they will participate or not. 
 
3.3. 
Inclusion Criteria 
 
The subject must meet all of the following inclusion criteria to participate in this study: 
 
- 
18-65 years old 
- 
Enrollment within 6 weeks of injury 
- 
Neurologic level rostral to T10 (T9 and above). This is a significant neurologic level 
because the bladder remains innervated at these levels, without damage to the 
nerve cell bodies of the bladder within the spinal cord. 
- 
Discharge setting and transportation available for follow-up appointments 
 
3.4. 
Exclusion Criteria 
 
Subjects meeting any of the exclusion criteria at baseline will be excluded from participation: 
- 
Subjects with pacemakers, defibrillators, insulin pumps, and similar devices will be 
excluded from the study 
- 
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.) 
- 
Known injury to the lumbosacral spinal cord or plexus, or pelvis with associated 
neuropathy 
- 
History of genitourinary diagnoses (i.e. prostate hypertrophy, overactive bladder, 
cancer, etc.) 
- 
Pregnancy 
- 
History of central nervous system disorder (i.e. prior SCI, stroke, brain injury, 
Parkinson’s disease, MS, etc.) 
- 
Ventilator dependent respiration 
- 
Significant autonomic dysreflexia during baseline urodynamic study. 
- 
Non-English speakers 
 
3.5. 
Withdrawal Criteria 
 
Possible reasons for discontinuation of study intervention: 
- 
Significant autonomic dysreflexia during baseline urodynamic study 
- 
Intolerant to electric stimulation 
- 
Unable to make follow-up appointment 
 
3.6. 
Subject Replacement 
 
Subjects who drop out will be replaced by screening the inpatient unit and asking for informed 
consent from those who meet the I/E criteria. 
 
 
4. 
TRIAL SCHEDULE 
 
Study Schedule with columns of 6-month intervals 
 
Study Startup 
xxxx 

IRB Page 14 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
 
Recruitment 
xxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxx 
Baseline UDS 
xxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
x 
Specific Aim 2 RCT 
xxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xx 
Post UDS 
xxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxx 
2-month UDS 
xxxxxxxxx xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxx 
 
 
 
 
 
5. 
STUDY DESIGN (Figure 1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Study Design 
 
 
 
Anticipated number of patients to screen: 80 
 
Anticipated number of patient to enrol: 70 
 
Anticipated drop out or loss to follow-up: 10 
 
Approximate time to complete study recruitment: 1 year 
Expected duration of subject participation: 4 months 
 
Specific Aim 1: To observe the safety of using TTNS during acute inpatient rehabilitation by 
prospectively tracking morbidity (infections, burns, and urgent transfers), pain during TTNS 
(visual analog scale), pain scores recorded per protocol by nursing, and changes in 
bowel/bladder programs. 
 
Specific Aim 2: To determine the effects of a 2-week TTNS RCT trial as seen in post-UDS and 
2-month follow-up UDS. 
 
 
Blinded randomized control trial of patients admitted to TIRR with acute SCI who meet I/E 
criteria and consent to participate in the study divided into three arms: 
o TTNS group: 10 sessions over a 2 week period of TTNS for 30 minutes, with 
electrode placement and settings as in SA 1. Current intensity may vary from patient 
to patient and will be documented and used in the analysis.  The current intensity 
per patient will remain the same and should it need to be lowered, it will be recorded 
and added to the analysis. 
o Control group: control ankle stimulation, 5 sessions per week for 2 weeks, for a total 
of 10 sessions. Control ankle stimulation will be performed identical to the TTNS 
group, but after the intensity is set, it will be decreased abruptly to off. 
 
Pain scores on the visual analog scale will be recorded before stimulation is started, during, 
and after. This will be recorded for analysis. 
Urine sample collected at baseline, discharge and at the follow-up appointments for all groups. 

IRB Page 15 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
Samples will either be frozen or refrigerated and stored on site until shipped to the lab. 

 
UDS protocol: 
The UDS is performed in the procedure suite at TIRR Memorial Hermann, where nursing staff 
and technicians routinely perform this study on spinal cord injury patients.  Briefly: 
o Sterile technique is used to empty the bladder with a lubricated catheter that inserts 
into the urethra and enters the bladder. 
o When the bladder is empty, sterile technique is used to insert lubricated catheters 
with pressure sensors through the urethra into the bladder and into the rectum while 
the patient is supine on the procedure table. 
o Surface EMG electrodes are placed on the perineal are to record the muscle activity 
of the pelvic muscles and viscera, including the internal urethral sphincter. 
o Infusion of warm saline into the bladder at a rate of 40ml/min begins the UDS, while 
the computer records the activity of the bladder. Measurements include the 
pressure of the bladder and the abdominal pressure, as well the capacity and 
compliance of the bladder. 
o The conclusion of the study occurs when bladder capacity is reached and the 
bladder will be emptied. 
o Overall, the UDS will be performed following the guidelines of good urodynamic 
practices from the International Continence Society.22 
o During the UDS, we will concurrently test novel high density (hd) surface electrodes 
to see if there is correlation between the electrical activity seen by the hd surface 
electrodes and the pressure recordings of the bladder. 
 
The surface electrodes will be placed externally above the bladder, below the 
navel. 
 
TTNS protocol: electrodes 2 inch by 4 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 
Recording of the bladder activity with high density EMG surface electrodes will occur during 
session 1, session 5, and session 10. These are the same types of electrodes used in the 
UDS.  Surface electrodes will adhere to the skin and placed above and below the pubic 
bone, placed by the research assistant.  Recordings will last the entire stimulation session. 
 
 
Information gathered: 
o Clinical demographics and Neurologic Exam findings from interview with patients 
and EMR review. 
o Morbidity information from clinical findings and EMR review. 
o Urodynamic findings will be retrieved from the report generated from the 
urodynamics machine. 
o TTNS intensity will be recorded for each patient.  Pain scores will be collected during 
the randomized control trial. 
o Skin examination where the electrodes were placed will be performed before and 
after each trial. 
o Information will be tabulated on an Excel spreadsheet on my personal work desktop, 
password protected. No paper data will be retained. 

IRB Page 16 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
5.1. 
Summary of Study Design 
 
In Specific Aim 1, we will monitor for safety and feasibility of TTNS during acute inpatient 
rehabilitation of SCI. In Specific Aim 2, the efficacy of TTNS will be studied by randomizing into 
2 groups in a 2:1 ratio of TTNS:control.  Control will be receiving brief ankle stimulation that will 
be turned off after the maximal intensity is found. After 2 weeks of stimulation, the RCT will 
have completed.  Half of those in the TTNS group will be randomized to receive one 
maintenance dose of TTNS in the clinic.  All those that participate will have UDS to measure 
outcomes at 2 months in clinic. 
 
 
6. 
METHODS AND ASSESSMENTS 
 
a. 
Urodynamic Studies will be performed per protocol described above.  Data from the 
study is generated on a graph and printed. The pertinent values will be added to the 
data spreadsheet and the paper will be discarded. 
b. 
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. 
c. 
Transcutaneous Tibial Nerve Stimulation (TTNS) will be placed daily by trained research 
assistants.  Electrodes will be removed after the 30 minute session is completed.  Pain 
scores will be collected before, during, and after the TTNS session.  Skin inspection will 
be performed before and after each stimulation session at the electrode sites. 
d. 
Bladder activity will be recorded at session 1, 5 and 10 lasting the whole stimulation 
session of all groups using the same type of electrodes used in the UDS placed below 
and above the pubic bone. 
e. 
Urinary levels of NGF, cytokines and chemokines will be measured at baseline, 
discharge and follow-up appointment. Urine will be collected by sterile catheter or clean 
catch midstream (CCMS) voided specimen. Specimens will be processed at the time of 
collection, de-identified with an untraceable number. 
 
6.2. 
Randomization and Blinding 
 
a. 
Blinding: The P.I. will be blinded to the study allocation groups. Trained research 
assistants will apply the electrodes and collect the data during the 30 minute sessions. 
b. 
Randomization:  After consent and the baseline UDS, subjects will be assigned a 
number which will have already been designated as control or experimental group. 
Stratification will occur based on the UDS findings of areflexia versus no areflexia. The 
PI will be blinded to this randomization.  The research assistant will have access to this 
file. Unplanned breaking of randomization will occur should rates of morbidity 
significantly increase.  If breaking of randomization is required, the research assistant 
will provide the randomization file to the PI. 
 
6.3. 
Contraception and Pregnancy Testing 
 
For females of childbearing age included in the trial, pregnancy testing is typically performed 
prior to their admission to TIRR, available in the EMR or in the provided charting.  Patient 
contraception is not applicable in acute spinal cord injury as the normal menstrual cycle is 
impaired in the acute setting and the study will be performed while the patient is admitted to 
inpatient rehabilitation. 

IRB Page 17 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
6.4. 
Study Visits and Procedures 
 
- 
Screening Visits and Procedures 
 
Screening will be performed upon admission to inpatient rehabilitation via EMR. If there is 
missing information to complete the screen, it will be requested from the attending physician. 
 
Those that meet the I/E criteria will be approached by the PI or research assistant and asked 
for informed consent. They will have 1 day, if needed, to decide.  If the subject decides to 
participate, they will be scheduled for the baseline UDS in the following days and a urine 
sample will be collected. . 
 
- 
Study Visits and Procedures 
 
The baseline UDS will be scheduled by our therapy scheduling team and the UDS procedure 
suite will be prepared to accept the patient.  Patients and the PI will be blinded to the 
randomization. Both groups will have the electric stimulation electrodes placed on their legs and 
the experimental group will have 30 minutes of the stimulation, with the parameters entered by 
the research assistant. This will occur for 10 sessions within a 2 week period. 
 
Bladder activity will be recorded at session 1, 5 and 10 lasting the whole stimulation session of 
all groups using the same type of electrodes used in the UDS by placing them below and above 
the pubic bone. 
 
Upon completion of the RCT, patients will be scheduled for a post-UDS. This will be similar to 
the baseline study. A second urine sample will be collected upon discharge. 
 
Patients will then be scheduled for a discharge follow-up appointment that is estimated to be at 
2 months. They will be given the Voiding Journal to fill in daily on discharge until their follow-up 
appointment.  Some will be randomized to the maintenance group, 1 month after completion of 
the RCT. They will come to clinic and have the TTNS applied by the research assistant. The PI 
will continue to remain blinded. A third and final urine sample will be collected during the 
followup appointment for all groups. 
 
- 
Final Study Visit: 
 
The final study visit is the 2-month follow-up, in which the patients typically see their attending 
physician.  The 2-month UDS will be scheduled for the same date.  Subjects will perform UDS 
as in the post-UDS. The Voiding Journal will be reviewed with the patient and collected. 
Missing information will be asked of the patient. 
 
As this UDS is part of the standard care at TIRR Memorial Hermann, recommendations on the 
management of neurogenic bladder will be given by the PI based on this study and recorded in 
the EMR.  This includes prescriptions for bladder medications, as needed. 
 
- 
Post Study Follow up and Procedures 
 
The data will be statistically analysed in the post-study follow up. Subject participation is not 
required. 

IRB Page 18 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
- 
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. 
 
 
 
7. 
TRIAL MATERIALS 
 
The electric stimulation device used for TTNS is the Empi Continuum. The control is the Empi 
Continuum with the stimulation intensity set to zero. Low-binding plastic containers will be used 
for handling and storing urine.  Urine will be processed via protocol for frozen and preserved 
specimen. The use of ethanol, betamercaptoethanol, and centrifugation will be used to process 
the urine for storage. 
 
 
 
7.1. 
Trial Product (s) 
 
The Empi Continuum 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 

IRB Page 19 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
The high density surface EMG device has been evaluated by the FDA and has been found to 
be substantially equivalent to other medical devices used in people. FDA letter has been 
attached. 
 
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. Urine samples will either be frozen or refrigerated and stored on 
site until shipped to the lab. 
 
 
 
8. 
TREATMENT 
 
8.1. 
Rationale for Selection of Dose 
 
Bladder neuromodulation in acute rehabilitation is not common.  Neuromodulation of the 
detrusor has been successfully performed as early as 2 months after injury with transcutaneous 
surface electrodes applied directly over the bladder.7  Thirty session of electric stimulation over 
a 5 week period sustained significant improvements in UDS measures at 2 years.7   Invasive 
sacral neuromodulation has also been successfully performed early in spinal cord injury, while 
the bladder is atonic, with beneficial UDS outcomes.11   Neuromodulation outcomes are typically 
measured after weeks of stimulation, however improvements in bladder parameters seen on 
UDS can be seen on initial electric stimulation of the tibial nerve.13  Stimulation frequency of 10 
Hz and pulse width of 200ms in continuous mode will be used.13,14 
 
The 2 week period for the randomized control trial was chosen because it is feasible to perform 
during inpatient rehabilitation.  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.14 
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 
 
Participants in the randomized control trial will be restricted from using any other form of electric 
stimulation in the lower extremities until the post-UDS is completed. 
 
8.5. 
Blinding 
 
Study participants will be blinded to the stimulation parameters of the TTNS.  The research 
assistant will apply the electrodes and the PI will be blinded the stimulation setting as well. 
Unblinding is expected to occur after the 2 month follow up, at which point both subject and PI 
will be made aware of their group assignment. 
 
Early unblinding will occur in the case of adverse events, including adverse events unrelated to 
the research. The attending physician will be made aware of the group in which the patient was 

IRB Page 20 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
included. 
 
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. 
 
 
 
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 Instiute. 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 

IRB Page 21 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
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 
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 control group. Based on literature, the rate of UTIs ranges 
from 20% to 50% in acute SCI patients, plus the addition of the incidence of UTI post UDS in 
acute SCI may be nearly 16%.  As a result, we will stop the study if there is evidence to support 
UTI rate more than 40% in the TTNS group. The stopping rules are based on exact lower 95% 
Blyth-Still-Casella confidence bounds.  If the number of cases of UTI exceed the specified 
stopping rules: ≥ 8 UTIs in 10 patients, ≥ 13 UTIs in 20 patients, ≥ 18 UTIs in 30 patients, ≥ 23 
UTIs in 40 patients, then patient accrual will be paused pending a review by the Safety 
Monitoring Committee. 
 
 
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. 
 
 
 
11. 
SAMPLE SIZE AND STATISTICAL METHODS 
 
11.1. Determination of Sample Size 
 
Our working hypothesis is that responders to TTNS would increase bladder capacity 100ml or 
50%, which requires n=60.  Sample size consideration was based on the working hypothesis 
with at least 80% power to detect an effect size of 1.0, regarding increased bladder capacity 

IRB Page 22 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
and volume of first involuntary detrusor contraction with TTNS. These values were estimated 
based on the findings of Amarenco et al. and Chartier-Kastler et al.13, 18   With an effect size of 
1.0, this sample would result in a power of 88.3%.  Power analysis was performed using the 
Proc Power in SAS with the paired sample t-test under assumed pairwise correlation of 0.5. 
 
11.2. Statistical and Analytical Plans 
 
The primary outcome measures for SA 1 are markers of morbidity between the control and 
experimental groups. This includes differences in rates of infections, skin irritation, urgent 
transfers, and pain scores. For these comparisons, the analysis will use a proportion test or 
generalized linear models. 
 
The non-parametric Mann-Whitney U-test or paired t-test (for continuous measures) and 
McNemar test (for discrete measures) will be used to compare data as two samples come from 
the same subject.  Multivariate analysis will be considered when patients’ clinical variables are 
included as a confounding factor.  If significant differences are found, then we will use post-hoc 
analyses using ANOVA to compare each of the primary end points. We will also conduct 
pairwise comparisons to identify which pairs of the study arms have different mean outcomes. 
 
The primary outcome measures for SA 2 are the changes in the UDS parameters after 2 weeks 
of TTNS versus sham stimulation, with UDS performed at the end of the 2-week trial and again 
on follow-up in 2 months, which will use a similar statistical approach as in SA 1. When the 
study concerns multiple comparisons among four groups, the Bonferroni method will be used to 
ensure that the overall type I error remains below 0.05.  A p-value of <0.05 is considered 
statistically significant.  All statistical analysis will be conducted using SAS version 9.3 (SAS 
Institute, Inc. Cary, NC). 
 
The secondary outcome measures include analyses of the differences amongst the 2 groups of 
neurogenic bladder in SCI according to baseline UDS. This will be analyzed with generalized 
mixed models (GMMs) which can also afford a multivariate analysis to account for potential 
confounders.26   To correct potential selection bias by response, the analysis will be 
supplemented by weighted estimating approach.27 
 
12. 
ETHICAL CONSIDERATIONS 
 
12.1. Informed Consent 
 
The PI will obtain informed consent from subjects meeting I/E criteria, within 1 week of their 
admission to TIRR Memorial Hermann.  Subjects will have 1 day to decide whether they want to 
participate. 
IRB-approved study participation material will be provided to the subjects. 
Non-English speakers will be excluded. 
 
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. 

IRB Page 23 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
Reports generated from the UDS will be de-identified and placed in a binder, stored in a locked 
drawer in the office of the PI. 
 
 
 
 
 
13. 
PUBLICATIONS 
 
We anticipate publication in a peer-reviewed journal within 2 years of beginning this study 
describing the effects of TTNS in acute SCI upon the bladder. Upon completion of the study in 
year 3, we anticipate publication of another manuscript within the year to describe the outcomes 
at 2 months. 
 
 
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 Page 24 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
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.  Bacsu CD, Chan L, Tse V. Diagnosing detrusor sphincter dyssynergia in the 
neurological patient. BJU Int. 2012 Apr;109 Suppl 3:31-4. 
3.  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. 
4.  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. 
5.  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. doi: 
10.1007/s11255-015-0911-6. Epub 2015 Jan 22. 
6.  Gupta P, Ehlert MJ, Sirls LT, Peters KM. Percutaneous tibial nerve stimulation and 
sacral neuromodulation: an update. Curr Urol Rep. 2015 Feb;16(2):4. doi: 
10.1007/s11934-014-0479-1. 
7.  Radziszewski K. Outcomes of electrical stimulation of the neurogenic bladder: results 
of a two-year follow-up study. NeuroRehabilitation. 2013;32(4):867-73. doi: 
10.3233/NRE-130911. 
8.  Patel DP, Elliott SP, Stoffel JT, Brant WO, Hotaling JM, Myers JB. Patient reported 
outcomes measures in neurogenic bladder and bowel: A systematic review of the 
current literature. Neurourol Urodyn. 2014 Oct 18. 
9.  McDonald III JW, Sadowsky CL, Stampas A. The changing field of rehabilitation: 
optimizing spontaneous regeneration and functional recovery. In: Verhaagen J, 
McDonald III JW, eds. Handbook of Clinical Neurology, Spinal Cord Injury. Vol 109. 
3rd edition. Amsterdam, TheNetherlands: Elsevier; 2012. 
10. Stampas A, Tansey KE. Spinal cord injury medicine and rehabilitation.  Semin 
Neurol. 2014 Nov;34(5):524-33. 
11. Sievert KD, Amend B, Gakis G, Toomey P, Badke A, Kaps HP, Stenzl A. Early sacral 
neuromodulation prevents urinary incontinence after complete spinal cord injury. Ann 
Neurol. 2010 Jan;67(1):74-84. 
12. de Groat WC, Yoshimura N. Mechanisms underlying the recovery of lower urinary 
tract function following spinal cord injury. Prog Brain Res. 2006;152:59-84. Review. 
13. Amarenco G, Ismael SS, Even-Schneider A, Raibaut P, Demaille-Wlodyka S, 
Parratte B, Kerdraon J. Urodynamic effect of acute transcutaneous posterior tibial 
nerve stimulation in overactive bladder. J Urol. 2003 Jun;169(6):2210-5. 
14. Finazzi Agrò E, Campagna A, Sciobica F, Petta F, Germani S, Zuccalà A, Miano R. 
Posterior tibial nerve stimulation: is the once-a-week protocol the best option? 
Minerva Urol Nefrol. 2005 Jun;57(2):119-23. 
15. Dubeau CE. The aging lower urinary tract. J Urol. 2006 Mar;175(3 Pt 2):S11-5. 
Review. 
16. https://www.nscisc.uab.edu/Public/Facts%202015.pdf. 
17. http://www.emsci.org/index.php/project/the-project/time-schedule 
18. Chartier-Kastler EJ, Denys P, Chancellor MB, Haertig A, Bussel B, Richard F. 
Urodynamic monitoring during percutaneous sacral nerve neurostimulation in 

IRB Page 25 of 24 
NUMBER: HSC-MS-15-0806 
Protocol Number, Version No. 5 and 8/29/2016. 
IRB APPROVAL DATE: 10/04/2016 
 
patients with neurogenic detrusor hyperreflexia. Neurourol Urodyn. 2001;20(1):61- 
71. 
19. Bellucci CH, Wöllner J, Gregorini F, Birnböck D, Kozomara M, Mehnert U, Schubert 
M, Kessler TM. Acute spinal cord injury--do ambulatory patients need urodynamic 
investigations? J Urol. 2013 Apr;189(4):1369-73. 
20. Ho CH, Linsenmeyer TA, Millis SR. The reproducibility of urodynamic studies of 
neurogenic bladders in spinal cord injury. J Spinal Cord Med. 2000 Winter;23(4):276- 
83. 
21. Chou FH, Ho CH, Chir MB, Linsenmeyer TA. Normal ranges of variability for 
urodynamic studies of neurogenic bladders in spinal cord injury. J Spinal Cord Med. 
2006;29(1):26-31. 
22. Schäfer W, Abrams P, Liao L, Mattiasson A, Pesce F, Spangberg A, Sterling AM, 
Zinner NR, van Kerrebroeck P; International Continence Society.  Good urodynamic 
practices: uroflowmetry, filling cystometry, and pressure-flow studies. Neurourol 
Urodyn. 2002;21(3):261-74. 
23. Klingler HC, Pycha A, Schmidbauer J, Marberger M. Use of peripheral 
neuromodulation of the S3 region for treatment of detrusor overactivity: a 
urodynamic-based study. Urology. 2000 Nov 1;56(5):766-71. 
24. Vandoninck V, Van Balken MR, Finazzi Agró E, Petta F, Caltagirone C, Heesakkers 
JP, Kiemeney LA, Debruyne FM, Bemelmans BL. Posterior tibial nerve stimulation in 
the treatment of urge incontinence. Neurourol Urodyn. 2003;22(1):17-23. 
25. Büchele G, Och B, Bolte G, Weiland SK. Single vs. double data entry. Epidemiology. 
2005 Jan;16(1):130-1. 
26. Stroup WW. Generalized Linear Mixed Models: Modern Concepts, Methods and 
Applications. Boca Raton, FL: CRC Press. 2012. 
27. Hernán MA, Robins JM. Estimating causal effects from epidemiological data. J 
Epidemiol Community Health. 2006 Jul;60(7):578-86.