A Pilot Study to Compare Short-Term Transcutaneous or Epidural Spinal Stimulation for Enabling Motor Function in Humans With Spinal Cord Injury
Phase: NA
Conditions: Paraplegia, Tetraplegia, Paralysis, Quadraplegia
Sponsor: Kristin Zhao, PhD

Study Title: A Pilot Study to Compare Short-Term Transcutaneous or Epidural Spinal 
Stimulation for Enabling Motor Function in Humans with Spinal Cord Injury 
NCT#: NCT05095454 
Document Date: 07 November 2022 

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A Pilot Study to Compare Short-Term Transcutaneous or Epidural Spinal Stimulation 
for Enabling Motor Function in Humans with Spinal Cord Injury 
 
Principal Investigator 
 
 
 
 
 
 
[Co-Investigator(s)] 
Kristin Zhao, Ph.D. 
Department of Physical Medicine and Rehabilitation 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
(507) 284-8942 
 
Peter Grahn, Ph.D. 
Department of Physical Medicine and Rehabilitation 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
(507) 316-5556 
 
Megan Gill, P.T., D.P.T. 
Department of Physical Medicine and Rehabilitation 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
(507) 422-0139 
 
Markus Bendel, M.D. 
Department of Anesthesiology 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
 
Funding Sponsor: 
Mayo Clinic Center for Regenerative Medicine 
Multi Organ Functional Neuro-regeneration Practice 
Improvement Project 
 
 
Study Product: 
DS8R Isolated Biphasic Constant Current Electrical 
Stimulator  
Digitimer North America, LLC 
Suite 700, One East Broward Boulevard. 
Fort Lauderdale, 
FL 33301, USA 
 
Abbott percutaneous trial lead for epidural 
neurostimulation (Model 3086) 
Abbott Neuromodulation 
6901 Preston Road 

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Plano, TX 75024 
 
Ripple Nomad Neurostimulator 
Ripple Neuro 
2056 South 1100 East  
Salt Lake City, UT 84106 
 
Abbott clinician programmer for epidural and dorsal root 
ganglion neurostimulation (Model 3874) 
Abbott Medical 
6901 Preston Road 
Plano, TX 75024 
 
 
Protocol Number: (IRBe) 
21-006340 
IDE Number: 
G200133 
 
Initial version:  
07/30/2021 (Version 1.0)  
Revision: 
 
10/22/2021 (Version 1.1) 
Revision: 
 
01/10/2022 (Version 1.2) 
Revision: 
 
02/23/2022 (Version 1.3) 
Revision: 
 
05/24/2022 (Version 1.4) 
Revision: 
 
07/28/2022 (Version 1.5) 
Revision: 
 
08/25/2022 (Version 1.6) 
Revision: 
 
11/07/2022 (Version 1.7) 
 
 

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Table of Contents 
STUDY SUMMARY ................................................................................................................................7 
1 
INTRODUCTION ...........................................................................................................................8 
1.1 
BACKGROUND ...................................................................................................................................... 8 
1.2 
INVESTIGATIONAL DEVICE ................................................................................................................. 10 
1.3 
PRECLINICAL DATA ........................................................................................................................... 10 
1.4 
STUDY RATIONALE AND RISK ANALYSIS (RISKS TO BENEFITS RATIO) .............................................. 11 
1.4.1 
Study Rationale ................................................................................................................. 11 
1.4.2 
Anticipated Risks .............................................................................................................. 11 
1.4.3 
Potential Benefits .............................................................................................................. 13 
1.5 
ANTICIPATED DURATION OF THE CLINICAL INVESTIGATION .............................................................. 14 
2 
STUDY OBJECTIVES ................................................................................................................. 14 
3 
STUDY DESIGN .......................................................................................................................... 14 
3.1 
GENERAL DESIGN .............................................................................................................................. 14 
3.2 
PRIMARY STUDY ENDPOINTS ............................................................................................................. 15 
3.3 
SECONDARY STUDY ENDPOINTS ........................................................................................................ 15 
3.4 
PRIMARY SAFETY ENDPOINTS ............................................................................................................ 15 
4 
SUBJECT, SELECTION, ENROLLMENT, AND WITHDRAWAL ............................................ 16 
4.1 
INCLUSION CRITERIA ......................................................................................................................... 16 
4.2 
EXCLUSION CRITERIA ........................................................................................................................ 16 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING .................................................................. 17 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................... 18 
4.4.1 
When and How to Withdraw Subjects ................................................................................. 18 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ....................................................... 19 
5 
STUDY DEVICE ......................................................................................................................... 19 
5.1 
DESCRIPTION ..................................................................................................................................... 19 
5.2 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ........................................................... 19 
5.3 
PREPARATION AND ADMINISTRATION/IMPLANTATION OF INVESTIGATIONAL DEVICE ....................... 20 
5.4 
SUBJECT COMPLIANCE MONITORING ................................................................................................. 21 
5.5 
PRIOR AND CONCOMITANT THERAPY ................................................................................................ 22 
5.6 
PACKAGING AND LABELING ............................................................................................................... 22 
5.7 
MASKING/BLINDING OF STUDY ......................................................................................................... 22 
5.8 
RECEIVING, STORAGE, DISTRIBUTION AND RETURN .......................................................................... 22 
5.8.1 
Receipt of Investigational Devices ...................................................................................... 22 
5.8.2 
Storage ............................................................................................................................ 22 
5.8.3 
Distribution of Study Device .............................................................................................. 23 
5.8.4 
Return or Destruction of Study Device ................................................................................ 23 
6 
STUDY PROCEDURES............................................................................................................... 23 
6.1 
SCREENING: ....................................................................................................................................... 23 
6.2 
INTERVENTION 1: TRANSCUTANEOUS ELECTRICAL SPINAL STIMULATION (TS) AND TASK SPECIFIC 
TRAINING SESSIONS ......................................................................................................................................... 23 
6.3 
PERIOD OF FOLLOW-UP AFTER TS ...................................................................................................... 24 
6.4 
INTERVENTION 2: EPIDURAL ELECTRICAL STIMULATION (ES) .......................................................... 24 
6.5 
PERIOD OF FOLLOW-UP AFTER ES ..................................................................................................... 24 
6.6 
OUTCOME MEASURES ........................................................................................................................ 24 
6.6.1 
Primary: .......................................................................................................................... 25 
6.6.2 
Secondary: ....................................................................................................................... 29 
7 
FDA IDE-RELATED DEVICE PREPARATION AND ADMINISTRATION PROCEDURES .... 30 

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7.1 
RECEIPT OF FDA IDE-RELATED DEVICES .......................................................................................... 30 
7.2 
FDA IDE-RELATED DEVICE STORAGE ............................................................................................... 30 
7.3 
DISTRIBUTION OF FDA IDE-RELATED DEVICES ................................................................................ 31 
7.4 
RETURN OR DESTRUCTION OF FDA IDE-RELATED DEVICES ............................................................. 31 
8 
STATISTICAL DESIGN AND POWER ...................................................................................... 31 
8.1 
SAMPLE SIZE DETERMINATION .......................................................................................................... 31 
8.2 
STATISTICAL METHODS ..................................................................................................................... 31 
8.3 
SUBJECT POPULATION(S) FOR ANALYSIS ........................................................................................... 32 
9 
SAFETY AND ADVERSE EVENTS ............................................................................................ 32 
9.1 
UNANTICIPATED ADVERSE DEVICE EVENT (UADE) ......................................................................... 32 
9.2 
ADVERSE EVENT (AE) ....................................................................................................................... 32 
9.2.1 
Associated with the Investigational Device .......................................................................... 32 
9.2.2 
Life-threatening AE ........................................................................................................... 32 
9.2.3 
Serious AE ....................................................................................................................... 32 
9.2.4 
Unanticipated AE .............................................................................................................. 33 
9.3 
GENERAL PHYSICAL EXAMINATION FINDINGS ................................................................................... 33 
9.4 
HOSPITALIZATION, PROLONGED HOSPITALIZATION OR SURGERY...................................................... 33 
9.5 
POST-STUDY AE ................................................................................................................................ 33 
9.6 
PREEXISTING CONDITION ................................................................................................................... 33 
9.7 
UNANTICIPATED PROBLEMS INVOLVING RISK TO SUBJECTS OR OTHERS (UPIRTSO) ....................... 33 
9.7.1 
Serious ............................................................................................................................. 34 
9.7.2 
Unanticipated ................................................................................................................... 34 
9.7.3 
Related ............................................................................................................................. 34 
9.8 
AE RECORDING ................................................................................................................................. 34 
9.9 
ABNORMAL CLINICAL TESTING RESULTS .......................................................................................... 34 
9.10 
RELATIONSHIP AND SEVERITY ASSESSMENT ..................................................................................... 35 
9.11 
AE RELATIONSHIP INDEX .................................................................................................................. 35 
9.11.1 
Unrelated ..................................................................................................................... 35 
9.11.2 
Remotely Possible ......................................................................................................... 35 
9.11.3 
Possible ....................................................................................................................... 35 
9.11.4 
Probable ...................................................................................................................... 35 
9.11.5 
Definite ........................................................................................................................ 36 
9.12 
AE SEVERITY INDEX .......................................................................................................................... 36 
9.12.1 
Mild ............................................................................................................................ 36 
9.12.2 
Moderate ..................................................................................................................... 36 
9.12.3 
Severe .......................................................................................................................... 36 
9.13 
AE REPORTING ................................................................................................................................... 36 
9.14 
NOTIFYING THE FDA ......................................................................................................................... 36 
9.15 
DEVIATIONS FROM THE INVESTIGATIONAL PLAN ............................................................................... 37 
9.16 
STOPPING RULES ................................................................................................................................ 37 
9.17 
MEDICAL MONITORING ..................................................................................................................... 38 
9.17.1 
Safety Monitoring ......................................................................................................... 38 
9.17.2 
Risk Management and Emergency Response ................................................................... 38 
9.17.3 
Auditing and Inspecting ................................................................................................ 38 
9.17.4 
Monitoring AEs and Unanticipated Problems ................................................................. 38 
10 
DATA HANDLING AND RECORD KEEPING ........................................................................... 39 
10.1 
CONFIDENTIALITY.............................................................................................................................. 39 
10.2 
SOURCE DOCUMENTS......................................................................................................................... 39 
10.3 
CASE REPORT FORMS ........................................................................................................................ 40 
10.4 
DATA MANAGEMENT ......................................................................................................................... 40 
10.5 
DATA PROCESSING ............................................................................................................................. 40 
10.6 
DATA SECURITY AND CONFIDENTIALITY ........................................................................................... 40 
10.7 
DATA QUALITY ASSURANCE.............................................................................................................. 40 

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10.8 
DATA CLARIFICATION PROCESS ......................................................................................................... 40 
10.9 
RECORDS RETENTION ........................................................................................................................ 41 
11 
STUDY MONITORING, AUDITING, AND INSPECTING ......................................................... 41 
11.1 
PROTOCOL COMPLIANCE MONITORING.............................................................................................. 41 
11.2 
STUDY MONITORING PLAN ................................................................................................................ 41 
11.3 
AUDITING AND INSPECTING ............................................................................................................... 41 
12 
PRIOR AND CONCOMINANT THERAPY ................................................................................ 42 
13 
STUDY FINANCES ..................................................................................................................... 42 
13.1 
FUNDING SOURCE .............................................................................................................................. 42 
13.2 
CONFLICT OF INTEREST ...................................................................................................................... 42 
13.3 
STIPENDS OR PAYMENTS .................................................................................................................... 42 
14 
PUBLICATION OF RESULTS .................................................................................................... 42 
15 
ETHICAL CONSIDERATIONS .................................................................................................. 42 
16 
REFERENCES ............................................................................................................................ 43 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
AIS 
ASIA 
BWS 
BWST 
Adverse Event/Adverse Experience 
American spinal injury association Impairment Scale 
American Spinal Injury Association 
Body Weight Support 
Body Weight Support Treadmill 
CFR 
Code of Federal Regulations 
CRF 
CSF 
CT 
Case Report Form 
Cerebrospinal Fluid 
Computed Tomography 
DSMB 
DEXA 
ES 
Data and Safety Monitoring Board 
Dual Energy X-Ray Absorptiometry 
Epidural Electrical Stimulation 
EMG 
FDA 
Electromyography 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
HDL 
Health Insurance Portability and Accountability Act 
High-Density Lipoprotein 
IDE 
IPG 
Investigational Device Exemption 
Implantable Pulse Generator 
IRB 
LDL 
MAS 
MEP 
mFRT 
MRI 
MRSA 
Institutional Review Board 
Low-Density Lipoprotein 
Modified Ashworth Scale 
Motor Evoked Potentials 
Modified Functional Reach 
Magnetic Resonance Imaging 
Methicillin-resistant Staphylococcus aureus 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
SCI 
SCI-SET 
SCS 
6-MWT 
Serious Adverse Event/Serious Adverse Experience 
Spinal Cord Injury 
Spinal Cord Injury Spasticity Evaluation Tool 
Spinal Cord Stimulator 
Six Minute Walk Test 
SOP 
SSEP 
TS 
TMS 
Standard Operating Procedure 
Somatosensory Evoked Potentials 
Transcutaneous Electrical Spinal Stimulation 
Transcranial Magnetic Stimulation 
UADE 
UPIRTSO 
WISCI-II 
X-Ray 
Unanticipated Adverse Device Effect 
Unanticipated Problems Involving Risk to Subjects or Others  
Walking Index for Spinal Cord Injury 
X-Radiation 
 
 
 
 
 

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STUDY SUMMARY 
Title 
A Pilot Study to Compare Short-Term Transcutaneous or Epidural 
Spinal Stimulation for Enabling Motor Function in Humans with 
Spinal Cord Injury 
Running Title 
Service Line Comparison of Transcutaneous or Epidural 
Stimulation 
IRB Protocol 
Number 
21-006340 
Phase 
Pilot study 
Methodology 
Prospective study  
Overall Study 
Duration 
1-year duration 
Subject 
Participation 
Duration 
Less than 6 months duration per subject 
Objectives 
a. Identify relationships between stimulation inputs delivered to 
lumbosacral spinal circuitry and the corresponding 
electrophysiological outputs, during 4 weeks of motor training with 
stimulation, and over 16 weeks post-stimulation to determine 
residual effects, in individuals with SCI. 
 
b. Assess motor, sensory, and functional outcomes during 4 weeks 
of motor training with stimulation, and the retained effects over 16 
weeks post-stimulation, in individuals with SCI. 
Number of Subjects 
8 subjects 
Diagnosis and Main 
Inclusion Criteria 
American Spinal Injury Association Impairment Scale A-D 
Study Device 
DS8R Isolated Biphasic Constant Current Electrical Stimulator 
(Digitimer Ltd) 
Abbott percutaneous trial lead for epidural neurostimulation (Model 
3086) 
Ripple Nomad Neurostimulator 
 
Duration of 
Exposure 
All subjects will complete either 1 month of transcutaneous spinal 
stimulation (TS) or temporary epidural spinal stimulation (ES) 
enabled  rehabilitation sessions. Subjects will then be followed for 
an additional 4 months to complete follow-up assessments.   
Reference therapy 
The reference therapy is clinical rehabilitation after SCI. 
Statistical 
Methodology 
Descriptive statistics will be used to describe stimulation-related 
outcomes for each intervention. Repeated measures analyses of 
variance will be used to detect changes in outcomes over the course 
of rehabilitation. 

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1 
INTRODUCTION 
This document describes the protocol of a pilot stage clinical trial intended to study 8 humans 
diagnosed with chronic, incomplete, or complete loss of motor function below the level of 
traumatic spinal cord injury (SCI). The purpose of this trial is to improve the scientific 
understanding of how two electrical stimulation techniques, one which delivers electricity to 
the skin surface over the spine (transcutaneous spinal stimulation (TS)) and another which 
implants temporary percutaneous electrodes into the epidural space of the spinal cord 
(epidural spinal stimulation (ES)), facilitate spinal circuitry to enable function for individuals 
with SCI representing all levels of severity. Furthermore, we hope to determine responders 
versus non responders to spinal stimulation task-specific motor training following a 
condensed rehabilitation program as well as identify retained effects following 4 months of 
no intervention. Over the past decade, clinical investigations using either TS or ES have 
reported positive outcomes, such as regained control of leg movement (Gerasimenko, Lu, et 
al. 2015; P. S. H. PhD et al. 2011; Angeli et al. 2014; P. J. G. PhD et al. 2017; Gad et al. 
2017) and cardiovascular improvements (Phillips et al. 2018; Harkema, Ditterline, et al. 
2018; West et al. 2018). Independent investigations of either TS or ES have yielded some 
knowledge of the interactions between the electric field and spinal cord networks (Minassian, 
Persy, Rattay, Pinter, et al. 2007; Minassian, Persy, Rattay, Dimitrijevic, et al. 2007; Danner 
et al. 2016; Hofstoetter et al. 2018; Sayenko, Atkinson, Floyd, et al. 2015; Sayenko et al. 
2014; Sayenko, Atkinson, Dy, et al. 2015; Rattay et al. 2000; Danner et al. 2013; Capogrosso 
et al. 2013). 
 
To summarize, the paradigms used to characterize basic electrophysiological responses 
to stimulation in prior studies differed significantly from those used to facilitate 
functional movements in participants with lower extremity paralysis, specifically 
stimulation intensity and frequency. Therefore, there is a gap in knowledge of the 
electrophysiological and biomechanical outcomes produced by function-enabling TS 
and/or ES waveforms. Further, there is a lack of knowledge of the functional impact of 
brief rehabilitation with spinal stimulation in humans with SCI impairments. Finally, 
the extent to which stimulation-related changes are retained following the intervention 
is unknown. This protocol describes the experiments we will carry out to address this gap in 
knowledge of the interactions of either TS or ES over the course of brief rehabilitation 
periods. This clinical trial will be carried out in accordance with the procedures described in 
this protocol, applicable United States government regulations, and Mayo Clinic policies and 
procedures. All study procedures will be performed at Mayo Clinic’s campus in Rochester, 
Minnesota. 
1.1 
Background 
Spinal cord injury 
Severe SCI results in permanent loss of motor, sensory, and autonomic functions below the 
level of injury, leading to in catastrophic, lifelong changes in quality of life for SCI survivors. 
In the United States of America, nearly 300,000 people are living with neurological deficits 
due to SCI (National Spinal Cord Injury Statistical Center 2017). The effects of SCI are 
defined relative to physical and functional characteristics. It is well accepted that trauma to 
the spinal cord leads to functional disconnection of ascending and descending neural 
pathways between brain circuitry, spinal cord networks, and peripheral end organs, impairing 

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bodily functions innervated by spinal cord networks located below the lesion (Kandel 2013). 
A systematic review of studies that directly surveyed people with SCI found that the major 
priorities of functional recovery were: motor function (arm/hand for tetraplegia and mobility 
for paraplegia), bowel, bladder and sexual function, as well as a desire to improve 
psychosocial health (Simpson et al. 2012). 
 
Spinal electrical stimulation to enable functions after SCI 
Significant progress has been made in the field of spinal electrical stimulation to enable 
motor functions previously thought to be permanently lost after SCI. Specifically, Harkema 
and colleagues reported that, after months of rehabilitation with ES, volitional control of 
joint-specific muscles and independent standing were achieved by four humans with motor 
complete paraplegia (Harkema et al. 2011; Angeli et al. 2014).Recently, we reported that ES 
enabled control of stepping leg movements, which over the course of rehabilitation, 
translated to independent standing and stepping (Grahn et al. 2017; Gill et al. 2018). In 
addition to reports of ES enabling lower extremity motor functions, improvements in upper 
extremity (Lu et al. 2016), cardiovascular (Harkema et al. 2018; West et al. 2018; Harkema, 
Wang, et al. 2018; Aslan et al. 2018), and urologic functions (Herrity et al. 2018) have been 
reported. 
 
In parallel investigations, electrical stimulation applied to the skin surface over the spine (i.e., 
TS) has emerged from prior use as a neurophysiological tool to interrogate spinal circuitry, 
(Danner, 2016; Sayenko, 2015; Sayenko, 2015; Krenn, 2017; Andrews, 2015; Roy, 2014) to 
a non-invasive approach to facilitate spinal circuitry and generate coordinated motor activity 
below the level of SCI (Inanici et al. 2018; Gad et al. 2018; Gerasimenko, Lu, et al. 2015; 
Gad et al. 2017). Similar to ES, TS has recently been shown to improve cardiovascular 
(Phillips et al. 2018) and urologic functions (Gad et al. 2018). 
 
Pathophysiology relevant to potential study treatment action 
Evidence from human cadavers suggests that even in cases diagnosed as complete loss of 
function below the level of SCI, as defined by the American Spinal Injury Association 
Impairment Scale-A (AIS-A), a portion of neural tissue commonly remains intact across the 
injury site (Kakulas 1984). These intact tissues may transmit non-specific supraspinal signals 
to sublesional spinal circuitry (Dimitrijevic et al. 1983). The unique electrophysiological 
characteristics associated with this injury profile have led to an injury description known as 
“discomplete SCI” (Dimitrijevic et al. 1983; McKay et al. 2004; Sherwood et al. 1992). The 
mechanisms by which TS and ES enable volitional control are thought to involve facilitation 
of sublesional spinal networks to that a “functional” state of excitability in order to properly 
receive signals transmitted across the discomplete SCI and to produce functional outputs 
(Grahn et al. 2017; Gill et al. 2018; Taccola et al. 2018).   
 
TS and ES interactions with spinal circuitry have been preliminarily investigated using 
computational models (Capogrosso et al. 2013; Danner et al. 2015; Rattay et al. 2000; 
Danner et al. 2011) and basic properties of the evoked spinal motor potentials have been 
described (Sayenko et al. 2015; Sayenko et al. 2014; Sayenko et al. 2015; Danner et al. 2016; 
Hofstoetter et al. 2018). However, the stimulation paradigms used in prior studies were 
focused on eliciting motor potentials via single stimulus pulses in order to establish a basic 

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understanding of the evoked response properties during electrical facilitation of spinal 
circuitry (i.e., the intent was not focused on enabling functional activities that had been lost 
in subjects with SCI).  
 
Description of the population to be studied 
This study will include adult humans that sustained a traumatic SCI at least one year before 
trial enrollment. To qualify for this study, SCI severity must be previously diagnosed with an 
AIS classified injury. One participant will be enrolled from each AIS classification (A, B, C, 
and D) for each intervention. All injuries must be located at or above the tenth thoracic 
vertebrae. Detailed inclusion and exclusion criteria are provided within the appropriate 
section of this protocol. 
1.2 
Investigational Device 
DS8R Isolated Biphasic Constant Current Electrical Stimulator (Digitimer Ltd) 
 
Abbott percutaneous trial lead for epidural neurostimulation (Model 3086) 
 
Abbott clinician programmer for epidural neurostimulation (Model 3874) 
 
Ripple Nomad Neurostimulator 
 
The temporary percutaneous implantation of epidural stimulation electrode leads will be 
surgically implanted to activate lumbosacral spinal networks in four humans diagnosed with 
chronic, complete, or incomplete loss of motor function below the level of SCI. By 
delivering electrical stimulation over the spinal cord during rehabilitation we aim to compare 
electrophysiological activity produced by spinal sensorimotor networks in response to 
transcutaneous or percutaneous epidural stimulation and quantify changes in motor 
performance metrics over the course of 12 motor rehabilitation sessions with either 
transcutaneous or percutaneous epidural stimulation. 
1.3 
Preclinical Data 
Several decades of human investigation have focused on using ES to activate what was 
thought to be isolated spinal circuitry below the level of functionally complete SCI in order 
to study central pattern generator activity (Dimitrijevic et al. 1998; Jilge et al. 2004; 
Minassian et al. 2004; Roy et al. 2012) In 2011, Harkema and colleagues published a 
landmark report that after months of training, ES facilitated intentional control of joint-
specific muscles and independent standing by a human with motor complete paraplegia 
(Harkema et al. 2011). The same research group successfully replicated their results in three 
additional subjects (Rejc et al. 2015; Rejc et al. 2017; Angeli et al. 2014). Based on these 
results, we initiated a clinical trial (NCT02592668) and in 2017, we reported successful 
replication of Harkema et al., along with additional outcomes (Grahn et al. 2017). Based on 
observations made during NCT02592668, we have designed this protocol to gain additional 
scientific knowledge with respect to mechanisms by which TS and ES enables functions in 
humans. 
  

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In addition to studying ES as described in this protocol, we intend to gather comparative data 
from the non-invasive spinal neuromodulation approach known as transcutaneous electrical 
spinal stimulation (TS). Prior evidence has shown that TS generates patterned motor activity 
and limb movements in healthy humans (Gerasimenko et al. 2016; Gerasimenko et al. 2015; 
Minassian et al. 2007; Minassian et al. 2007). More recently, TS has been reported to enable 
motor function in humans with SCI (Inanici et al. 2018; Gerasimenko, Lu, et al. 2015). 
  
Our Mayo team recorded preliminary TS data in two subjects during supine activities prior to 
ES implantation. TS-evoked responses were recorded during low-frequency TS to investigate 
spinal sensorimotor activity generated to produce leg muscle activity. We compared 
responses across TS and ES. Preliminary data indicate smaller latency from stimulation to 
response in ES when compared to TS, indicating different mechanisms of action may 
underlie each approach. However, more subjects need to be investigated with a more 
structured study design to determine key differences between TS and ES. Completion of the 
proposed experiments in this protocol will provide data that can be used to improve the 
scientific understanding of how each technique enables function after SCI. This knowledge 
will be used to design future investigations that focus on safety and therapeutic efficacy of 
TS and ES. 
1.4 
Study Rationale and Risk Analysis (Risks to Benefits Ratio) 
1.4.1 Study Rationale 
There is no cure for SCI, which results in permanent loss of movement and sensation in body 
regions below the level of injury and a significant reduction in quality of life for SCI 
survivors. To address the lack of curative options following SCI, research efforts over the 
past decade have led to the development of neuromodulation approaches, such as TS and ES 
to activate spinal cord circuitry below the injury and enable lost functions. Scientific 
investigations of small numbers of humans with SCI have demonstrated positive functional 
outcomes such as standing, stepping, enhanced bladder function, and improved 
cardiovascular function, can be achieved using spinal stimulation. However, from a scientific 
perspective, the spinal sensorimotor circuitry activated using TS or ES has yet to be directly 
compared. Additionally, subjects need to be investigated within a structured study design to 
better understand the effect of rehabilitation on TS and ES enabled functions. Completion of 
the proposed experiments in this protocol will provide data that can be used to improve the 
scientific understanding of how each technique enables function after SCI. This knowledge 
will be used to help determine if TS is a viable and useful tool in determining which subjects 
may be best suited for ES through a clinical service line. 
1.4.2 Anticipated Risks 
Risks associated with rehabilitation: 
In combination with TS and ES, the rehabilitation techniques used during this study will 
focus on maximizing independence, load bearing, body position, and kinematics during 
motor tasks while providing the minimum amount of trainer assistance and body weight 
support necessary to safely perform tasks. Risks associated with daily training include skin 
irritation and minor bruising from pressure applied during trainer assistance and body weight 
support, musculoskeletal discomfort, fatigue, and bladder or bowel incontinence due to 

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exertion and abdominal pressure from support harness. There is a slight risk of fracture in the 
lower extremities. Orthostatic hypotension is a risk associated with abrupt position changes 
against gravity, specifically transitioning from sit to stand quickly.   
 
Risks associated with weight-bearing tasks: 
Risks include muscle soreness, fatigue, skin irritation, fracture, changes in blood pressure, 
and potential for a fall.  
 
Risks associated with TS: 
Skin irritation due to electrical current passing through human tissue, skin irritation due to 
adhesives used to apply skin surface electrodes, discomfort or abdominal tightness during 
TS, increased or decreased spasticity, bowel or bladder incontinence, shortness of breath, 
muscle soreness, or fatigue may occur. Autonomic dysreflexia is a risk for those with mid-
thoracic or higher-level injuries. Skin irritation or burns may occur during high-amplitude 
stimulation and/or prolonged stimulation sessions; skin breakdown may also occur as a result 
of this stimulation, with ensuing infection being a potential risk.  
Risks associated with temporary percutaneous implantation of ES electrode leads: 
ES electrodes will be implanted via commonly used percutaneous implantation techniques 
for FDA-approved treatment of medically refractory pain conditions. Therefore, the risks 
associated with percutaneous implantation of the ES system for this study match the risks 
associated with ES system implantation for treatment of FDA-approved conditions.  
 
• Undesirable changes in stimulation may occur over time. These changes in 
stimulation are possibly related to cellular changes in tissue around the electrodes, 
changes in the electrode position, loose electrical connections and/or lead failure. 
• Placement of a lead in the epidural space is a surgical procedure that may expose the 
patient to risks of epidural hemorrhage, hematoma, infection, spinal cord 
compression, and/or paralysis. 
• Radicular chest wall stimulation. 
• Cerebrospinal fluid (CSF) leakage. 
• Persistent pain at the electrode site or receiver site. 
• Seroma at the incision site, as well as serosanguinous drainage. 
• Implant migration. 
• Allergic or rejection response to implant materials. 
• Lead migration and/or local skin erosion. 
• Paralysis, weakness, clumsiness, numbness, or pain below the level of implantation. 
 
Risks associated with ES following implantation: 
Hardware malfunction, discomfort, or abdominal tightness during ES, increased or decreased 
spasticity, bowel or bladder incontinence, shortness of breath, muscle soreness, or fatigue 
may occur during ES. Autonomic dysreflexia is a risk for those with mid-thoracic or higher-
level injuries. 
 

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Risks associated with MRI 
Dislodgement of some metal implants and claustrophobia may occur during MRI. Subjects 
will be rigorously screened in the same fashion as clinical patient by MRI technicians prior to 
each scan. Earplugs will also be provided to keep MRI noise within a safe audible range. Due 
to the potential for tissue heating, image artifacts, induced voltages in the neurostimulator or 
leads, and lead dislodgement, MRIs will not be obtained after epidural stimulator 
implantation. 
 
Risks associated with Transcranial magnetic stimulation 
Transcranial magnetic stimulation is electrical pulses from the magnet to the brain. Risks are 
possible hearing changes, headache, and a chance of heating on the skull where the magnet is 
placed. 
Risks associated with electromyography and electroneurography 
Risks involved with EMG include skin irritation or allergic reaction from the adhesive used to 
apply sensors. Additionally, electroneurography carries the risk of pain and discomfort from 
needle placement, and infection at the needle stick site. 
Risks associated with urodynamic studies 
Urodynamic studies may carry the risk of autonomic dysreflexia, mild irritation of the urethra, 
and infection. 
 
Steps taken to minimize the occurrence and severity of associated risks: 
Trained study staff and medical technicians will directly oversee all tasks. Body weight 
support, a safety gait belt, and other safety measures as necessary will be utilized to lessen 
the risks involved with rehabilitation and weight-bearing tasks. Transcutaneous electrode 
sites will be checked routinely throughout rehabilitation sessions, and if skin irritation or 
damage is observed, no further stimulation will occur until the site has healed. To mitigate 
risks in general, the protocol will be conducted as stated, medical professionals will be 
consulted, and care will be provided to address any study-related concerns that arise. All 
members of the research team will be trained to identify the occurrence of risks related to this 
study. If risk occurrence is observed, study-related activities will be halted until appropriate 
medical care is given and it is deemed safe for the subject to continue study-related activities. 
Because the interventions have been used for individuals with spinal cord injury and subjects 
will have been carefully screened, we do not anticipate any serious adverse events in this 
study. However, if they do occur, serious adverse events will be reported to the PI, medical 
monitor, IRB, and FDA within the appropriate reporting timeframes. Adverse events will be 
reported to the PI, the site medical monitors IRB, and FDA within the appropriate reporting 
timeframes. 
1.4.3 Potential Benefits 
The benefits which may result from this research study may include recovery of sensorimotor 
function below the level of SCI, recovery of bladder, bowel, or sexual function, improved 
thermoregulation, improved body mass composition, and improved sense of wellbeing. The 
certainty and degree to which these benefits may or may not occur is unknown. 

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1.5 
Anticipated Duration of the Clinical Investigation 
The anticipated duration of study participation for each human subject is approximately 6 
months. During the 6 months, subjects will complete either TS rehabilitation sessions for the 
1 month, or ES rehabilitation sessions for 1 month. After 1 month of either TS or ES, 
subjects will be followed for an additional 4 months for follow-up assessments. ES electrodes 
will be removed following 1 month of rehabilitation sessions.   
2 
STUDY OBJECTIVES 
We propose to compare motor activity and clinical outcomes over the course of 1 month of 
TS or ES in combination with physical rehabilitation. 
 
2.1 
Primary Objective  
The primary outcome data collected will be used to compare spinal sensorimotor activity in 
muscles below the level of injury during TS or ES-enabled motor tasks in persons with 
chronic motor complete paralysis of the lower extremities due to traumatic SCI.  
 
2.2 
Secondary Objective 
Quantify changes in motor performance metrics over the course of 12 motor rehabilitation 
sessions with transcutaneous or percutaneous epidural stimulation 
3 
STUDY DESIGN 
3.1 
General Design 
This is a pilot study that will include a total of 8 subjects with chronic, motor complete or 
incomplete paralysis below the level of SCI. All subjects will complete either 1 month of TS 
or ES driven physical rehabilitation sessions (Table 1). All subjects will then be followed for 
an additional 4 months for follow-up assessments. Expected duration of subject participation 
is less than 6 months.  
 
Table 1: Study Design 
 
Week 8
Week 20 
Clinical, Electrophysiology, Kinematic  Assessments 
& Surveys
Follow-Up
Clinical, Electrophysiology, Kinematic  Assessments 
& Surveys
STUDY END
Stimulation + Motor 
Training
Clinical, 
Electrophysiology, 
Kinematic Assessments  
& Surveys
Stimulation + Motor 
Training
Transcutaneous Stimulation 
Clinical, 
Electrophysiology, 
Kinematic Assessments 
& Surveys
Baseline Assessments
INTERVENTION
POST-INTERVENTION
Minimum 12 Sessions
End Assessments
50% of Subjects
Week 0-1
Weeks 1-4
Week 4
Percutaneous Epidural Stimulation 
50% of Subjects
PRE-INTERVENTION
INTERVENTION
POST-INTERVENTION
Baseline Assessments
Minimum 12 Sessions
End Assessments
PRE-INTERVENTION
Clinical, 
Electrophysiology, 
Kinematic Assessments 
& Surveys
Clinical, 
Electrophysiology, 
Kinematic Assessments 
& Surveys

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3.2 
Primary Study Endpoints 
Due to the pilot phase design of this clinical trial, it is not feasible to designate primary study 
endpoints. With this in mind, we do consider the biomechanical assessments and 
electrophysiology tests to be the primary sets of endpoints used to quantify TS and ES-
related datasets associated with addressing the specific aims of this proposal.  
3.3 
Secondary Study Endpoints 
Similarly, it is not feasible to designate secondary study endpoints. We do consider clinical 
assessments of spasticity and subjective surveys to be secondary study endpoints. 
3.4 
Primary Safety Endpoints 
Primary safety endpoints of the study will be oriented to adverse events that could originate 
from the implantation of the ES electrodes, or the operation of either neurostimulator device 
as well as to those that could arise from performing the locomotor rehabilitation sessions. 
Patients will be asked to report any discomfort that they encounter throughout the study. A 
detailed selection of the candidates by the Principal Investigators and the study team will be 
crucial to select individuals who fit the inclusion criteria of the study, minimizing risk for 
potential adverse events throughout the study. Subjects will undergo a screening phase 
oriented to identify conditions that could potentially represent a higher than the expected risk 
for conducting this study.  
 
To visualize electrode positioning of the ES neurostimulator system, fluoroscopy and spine 
computed tomography will be performed. To limit adverse events that could result from 
operating the neurostimulator device, stimulation parameters will be selected within safe 
ranges as provided by the manufacturer’s specifications of ES pulse generators. Specifically, 
we will deliver stimulation within the following ranges:  
 
ES parameters: pulse width 50-1000 microseconds; frequency 0.5-200 Hz; amplitude 0-25.5 
mA 
 
The procedure to connect the externalized ends of the percutaneous electrodes (model 3086) 
to the Ripple NOMAD will consist of minimizing strain on the connections by creating loops 
in the externalized lead wires and lead extensions (model 3386). The loops will be positioned 
in proximity to the implant site using adhesive tape. Additionally, each connection will be 
secured using adhesive tape. Finally, each connection and implantation site, as well as the 
strain relief loops, will be protected using an adhesive bandage. 
 
During sessions of rehabilitation with stimulation, the looped lead wires and lead extensions 
will be connected to Abbott’s battery-powered pulse generator (model 3599) via “multilead 
trial cables” (model 3013). Stimulation waveforms and electrode configurations will be 
transmitted wirelessly from the “clinician programmer” (model 3874) to the battery powered 
pulse generator. The battery-powered pulse generator, multilead trial cables, and clinician 
programmer are manufactured by Abbott for use with their ES system. 
 
 
 

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4 
SUBJECT, SELECTION, ENROLLMENT, AND WITHDRAWAL 
 
A total of eight humans with a history of a traumatic SCI will be enrolled in this pilot phase 
clinical trial (Table 2). Four subjects will be assigned to “intervention 1” cohort and four 
will be assigned to the “intervention 2” cohort. Subjects will be selected based on the criteria 
described within sections 4.1 and 4.2: 
 
Year 1 
  
  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
1 
2 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
= 
Intervention 1 
  
  
= 
Intervention 2 
  
  
  
  
  
= Washout/Follow-Up 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
1 
  
  
  
  
  
  
  
  
2 
  
  
  
  
  
  
  
  
  
  
3 
  
  
  
  
  
  
  
  
4 
  
  
  
  
  
  
  
  
  
  
  
5 
  
  
  
  
  
  
  
6 
  
  
  
  
  
  
  
  
  
7 
  
  
  
  
  
  
  
  
8 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Table 2: Study Timeline 
4.1 
Inclusion Criteria 
 
 
          
• Spinal cord injury due to trauma located at or above the tenth thoracic vertebrae (T10) 
• American Spinal Injury Association grading scale of A-D (2 from each) below the 
level of SCI  
• Intact spinal reflexes below the level of SCI 
• At least 1-year post-SCI 
• At least 22 years of age 
• Willing to use medically acceptable methods of contraception, if female and of child-
bearing potential 
4.2 
Exclusion Criteria 
• Currently a prison inmate, or awaiting trial, related to criminal activity 
• Pregnancy at the time of enrollment 
• History of chronic and/or treatment resistant urinary tract infection 
• Unhealed decubitus ulcer 
• Unhealed skeletal fracture 

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• 
Untreated clinical diagnosis of depression 
• Undergoing, or planning to undergo, diathermy treatment 
• Active participation in another interventional clinical trial 
• Presence of conditions or disorders which require MRI monitoring 
• Other implanted stimulation devices (e.g. deep brain stimulator, cardiac pacemaker, 
diaphragmatic pacer, etc.) 
• A history of coagulopathy or other significant cardiac or medical risk factors for  
surgery  
• Current use of a ventilator 
• Clinically diagnosed cardiopulmonary complications such as chronic obstructive 
pulmonary disease, cardiac failure, or heart arrhythmia that contraindicate changes in 
body position such as supine-to-sit-to-stand activities, prolonged standing, or stepping 
• History of frequent hypotension characterized by light headedness, or loss of 
consciousness 
• History of frequent hypertension characterized by headache, or bradycardia 
• History of frequent, severe, autonomic dysreflexia 
• Any illness or condition which, based on the research team’s assessment, will 
compromise with the patient’s ability to comply with the protocol, patient safety, or 
the validity of the data collected during this study.  
4.3 
Subject Recruitment, Enrollment and Screening 
A total of 8 subjects will undergo the experiments described within this protocol. Subjects 
will be recruited from the following:  
 
• Mayo Clinic’s volunteer research subject database 
• Mayo Clinic’s clinical trials website 
• Mayo Clinic’s electronic medical record database search tools 
• ClinicalTrials.gov  
 
Prior to participating in the screening phase, a member of the research team will provide a 
detailed explanation of the study and answer questions asked by the potential study subject. 
If the potential subject is willing to participate in the study, they will be given sufficient time 
to make an informed decision, review relevant informed consent documents, and ask 
questions. Once questions and concerns have been addressed to the potential subject’s 
satisfaction, the informed consent form will be signed and dated by the subject and an 
Investigator. A copy of the signed consent documents will be provided to the subject. The 
original signed consent documents will be retained within study records. 
 
Following informed consent, screening tests will be performed including a thorough history 
and physical examination by a physician and physical therapist. Pre-existing clinical results 
to screening assessments may be accepted at the investigators’ discretion if the testing was 
done within the timeframe specified for each test in the Study Procedures section. The ASIA 
Impairment Scale (AIS) examination will also be completed during screening to determine 
severity and classification of SCI. Urine tests will be completed to rule out an active urinary 
tract infection; if the testing is positive for a urinary tract infection, the subject will be 

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retested after two weeks’ time for resolution. The subject will also be screened during a 
mock-up therapy session utilizing body weight supported harness system over the treadmill 
and trainer assistance to facilitate stand and step activities while monitoring blood pressure, 
tolerance, and range of motion. Due to an absence of standardized clinical practice guidelines 
that inform rehabilitation task safety decisions, if any concerns related to upright and load 
bearing activities exists, i.e. limited range of motion of load bearing joints, high spasticity, 
low blood pressure, osteoporosis (defined as a DEXA t-score of -3.5 or lower at the spine and 
hip), or high body weight, participants will receive motor training while seated and/or supine 
on a mat table, to avoid injury related to load-bearing activities. Based on screening results, a 
final decision on study participation will be made by the PI and study team. If any 
exclusionary screening results are transitory in nature, the subject may be re-screened at the 
discretion of the investigators. Screening tests will be repeated as indicated in the Study 
Procedures section. 
4.4 
Early Withdrawal of Subjects 
Subjects will be informed that they have the right to withdraw from the study at any time. 
Similarly, the PI has the authority to withdraw the subject from the study at any time. 
4.4.1 When and How to Withdraw Subjects 
Factors that may lead to withdrawal: 
• Study subject health concerns 
• Protocol violation (e.g., non-compliance) 
• Study-related serious adverse events 
• Study subject’s decision to pursue activities outside of the study protocol, that in the 
opinion of the PI, may compromise data collected within the study protocol 
• The emergence of other problems, events, or information, that may adversely affect 
the rights, safety, or welfare of the study subject, or may substantially compromise 
data collected within the study protocol 
If a serious adverse event occurs during an activity described in this protocol, a consensual 
decision will be made between the study subject and the PI regarding withdrawal from the 
study.  
In the event of study withdrawal, the ES electrodes will be surgically explanted. If 
explanation surgery is urgent due to concern for the subject’s health, the cost of the 
explanation surgery will be covered by the research study. Aside from standard surgical 
recovery, no adverse effects are anticipated from the removal of an epidural electrical 
stimulator.  
If a subject is withdrawn from the study for any reason other than treatment-related adverse 
events, an additional subject may be recruited as a replacement within the same study cohort. 
If a subject fails to attend protocol activities and fails to respond for follow-up, a 
communication attempt will be made to determine if non-compliance is related to an adverse 
event. 

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4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
If a subject withdraws or is withdrawn from the study for any reason before study 
completion, an attempt will be made to carry out an exit interview. The reason for 
withdrawal will be documented by the research team. 
 
5 
STUDY DEVICE 
5.1 
Description 
Epidural spinal cord stimulator 
(Model 3086, Model 3874, Abbott Neuromodulation; Nomad, Ripple Neuro) 
 
The ES electrode lead is an implantable neurostimulation device that is FDA-approved for 
treatment of neuropathic pain disorders. ES leads will be implanted temporarily along the 
dorsal epidural surface of the lumbosacral enlargement (i.e., L2-S1 spinal segments). The 
externalized ends of the ES electrode leads will be connected to the Nomad neurostimulation 
system in order to deliver testing-specific electrical pulse waveforms to the epidural surface 
(Figure 4). ES pulses will be synchronized to electrophysiological and biomechanical 
recordings of spinal motor output, and in turn, motor functions that are enabled by ES. 
Electrophysiological data will be collected from skin surface electrodes. Additionally, during 
ES using the Ripple Nomad, signals will also be captured from passive electrodes (i.e., not 
configured as an anode or cathode during stimulation) on the ES lead (Abbott, Model 3086). 
During ES-enabled rehabilitation sessions, when non-testing-specific electrical pulse 
waveforms are applied, the Abbott clinician programmer device designated for the ES leads 
will be used. 
 
 
Transcutaneous spinal cord stimulator  
(DS8R, Digitimer LLC) 
 
The DS8R is designed for human research rather than diagnosis or therapy; it does not have a 
medical device certification. The DS8R is an isolated, constant current stimulator for human 
research studies involving nerve and muscle stimulation via surface electrodes. It features a 
high compliance voltage and can be triggered and controlled by multiple external sources. 
For the purpose of delivering TS to the surface of the skin over the spine, customized 
electrical waveforms built within Labchart electrophysiological data acquisition software 
(ADInstruments Inc., Colorado). The DS8R will be triggered to deliver TS waveforms via 
PowerLab digital outputs (ADIstruments Inc., Colorado). The DS8R is capable of delivering 
monophasic or biphasic current pulses of up to 2ms duration, with an output range of 2mA to 
1000mA* (from 400V). The actual current achieved will be restricted by a pulse energy limit 
of 300mJ per pulse and the skin/electrode resistance. 
5.2 
Method for Assigning Subjects to Treatment Groups 
Four subjects will be assigned to each treatment arm based on availability at the time the 
subject volunteers to participate (Total subjects studied: 8). If both arms are enrolling in 

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parallel at the time a subject volunteers to participate, he/she will be allowed to choose the 
treatment arm in which to enroll.  
5.3 
Preparation and Administration/Implantation of Investigational Device 
Description of TS administration 
A constant-current stimulator DS8R (Digitimer LLC) will be used to deliver TS to the skin 
surface over the spine. At locations where self-adhesive bipolar recording electrodes will be 
placed onto the skin, the area will be cleaned with alcohol to ensure secure attachment and 
enhance signal recordings. The stimulation will be administered using self-adhesive 
electrodes placed as cathodes on the skin between the T7 and L3 vertebrae, with the option of 
ultrasound (US) guided imaging to locate the spinous processes at each segment. In addition, 
self-adhesive electrodes will be placed symmetrically on the skin serving as anodes. A foam 
pad may be placed over the cathode and secured using adhesive tape and/or an elastic belt to 
tightly wrap around the subject’s trunk to ensure cathode electrodes do not shift or peel away 
during rehabilitation activities. The stimulation waveform will consist or bi-phasic pulses 
(duration between 0.1 – 1.0 ms), at frequencies between 0.2 –100Hz. We will also test the 
efficacy of a recently developed carrier frequency of 4 – 10 kHz, using stimulation intensities 
of up to 100 mA. Skin under the electrodes will be inspected frequently during sessions to 
ensure no irritation occurs from stimulation. 
 
Description of ES system implantation/administration 
We recently published a detailed explanation of the procedure to implant a permanent 
electrode array connected to an implanted pulse generator, along with a detailed description 
of the electrophysiological approach used to guide electrode positioning over the lumbosacral 
enlargement in humans with SCI (Calvert, 2018). The same approach will be used during this 
study to guide electrode placement via electrophysiological monitoring of spinal motor 
evoked potentials.  
 
The procedures for percutaneously implanting Abbott ES electrodes are performed daily at 
Mayo Clinic to treat patients suffering from neuropathic pain. Prior to implantation, subjects 
will undergo a pre-operative evaluation to minimize the risk of unexpected complications. 
Pre-operative assessments may be performed to check for any signs of infection.  
 
In order to implant the temporary spinal electrodes, an incision will be made at the entry site 
to the depth of the subcutaneous fascia. Under fluoroscopy, an electrode insertion needle will 
be place into the epidural space using a paramedial approach until resistance is felt from the 
ligamentum flavum, followed by fluoroscopic visualization of the needle’s position. Once 
positioning is confirmed, the needle stylet will be removed and the needle will be advanced 
into the epidural space.  

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Then, the leads are advanced in an anterograde fashion to deliver them into the intervertebral 
foramen under fluoroscopic guidance. Following electrophysiologic confirmation of 
electrode positioning, the needle and stylet will be removed, the implantation site will be 
dressed, and the leads will be secured to the skin via an adhesive bandage. The implantation 
site will be monitored for signs of infection, tissue erosion, or dislodged lead wires. 
 
Procedure to explant ES electrode leads 
 
After completing 12 sessions of rehabilitation with ES, the adhesive bandage covering the 
implantation site will be removed, the incision site will be opened, and the leads will be 
carefully retracted. Finally, the incision site will be cleaned and dressed. 
 
If complications associated with temporary lead implantation (e.g., infection, severe lead 
migration, device malfunction, etc.) are observed, the PI will make an informed decision 
whether to perform explantation prior to completion of 12 rehabilitation sessions. 
5.4 
Subject Compliance Monitoring 
Throughout the study, research staff will monitor study protocol compliance. This will 
include review and verification of all protocol-related procedures and records. The PI will 
oversee compliance and determine the appropriate response to non-compliance events. 

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5.5 
Prior and Concomitant Therapy 
A subject’s prior therapy regimen will not impact the PI’s decision regarding enrollment into 
the study. As long as the subject fits the inclusion criteria and does not demonstrate any 
exclusion criteria characteristics (i.e., bone fractures, joint contractures, or skin lesions), prior 
exercise or therapy programs will not exclude their participation in the study. While enrolled 
in the study, subjects will be asked to follow the instructions from the study staff regarding 
the home exercise program prescribed from the research team. For example, if the study 
subject performed locomotor training at a local gym prior to the study, they would be asked 
to discontinue that activity while participating in the trial.    
5.6 
Packaging and Labeling 
The packaging of the devices will be from the manufacturer’s clinical supply. The following 
will be added to the devices used within this investigation: 
“CAUTION – Investigational Device. Limited by Federal (or United States) law to 
investigational use”  
5.7 
Masking/Blinding of Study 
This is an unblinded study. The PIs, co-investigators, and subjects will know what treatment 
they received. 
5.8 
Receiving, Storage, Distribution and Return 
5.8.1 Receipt of Investigational Devices 
The ART laboratory owns two transcutaneous electrical spinal stimulators (DS8R Isolated 
Biphasic Constant Current Electrical Stimulator, Digitimer Ltd), which serve as a primary 
unit and a reserve unit. If either device becomes damaged or unusable, use of the device will 
be discontinued until the supplier repairs the unit. All communication between study staff 
and the supplier will be documented in the study files.    
 
A representative from Abbott will ship the devices to Mayo Clinic and they will be properly 
inventoried prior to the scheduled date of surgical implantation.  The representative will also 
train study personnel on how to use the clinician programmer during non-testing 
rehabilitation sessions. 
 
The Nomad neurostimulation system will be purchased from Ripple Neuro, shipped to Mayo 
Clinic, and inventoried within the ART Lab. 
 
Any product discrepancies or damage will be documented in the study files and the supplier 
will be notified. Then, appropriate action will be taken by the PI to fully address the issue. 
5.8.2 Storage 
The TS device (Digitimer) is stored in the ART laboratory, a secured area requiring badge 
access.  
 

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ES electrode leads will be stored within a secured surgical materials area of Mayo Clinic’s 
Pain Clinic. Access to this area is granted solely to Mayo Clinic staff involved in surgical 
implantation procedures. 
 
The Ripple Nomad system will be stored in the ART Lab, which is a secured area that can 
only be accessed by ART Lab staff. 
5.8.3 Distribution of Study Device 
The TS devices (Digitimer) will not be assigned to individual subjects, but the devices on 
hand will be tracked in the Device Accountability form, and the serial number of the device 
used in a given session will be tracked in the subject’s case file. 
 
In accordance with Mayo Clinic policy, the brand, model, date of implantation, and date of 
explantation of all ES electrode leads will be recorded in the Surgical Inventory Management 
System. This information will be made available within the electronic medical record of each 
subject. Additionally, a copy of this information will be stored within each subject’s case file. 
5.8.4 Return or Destruction of Study Device 
At routine intervals and at the completion of the study, there will be a reconciliation of 
devices shipped, devices utilized, and devices remaining. This reconciliation will be logged 
on the Device Accountability form, signed and dated. Any discrepancies noted will be 
documented, the PI will be notified, and an investigation will be conducted to determine the 
cause of the discrepancy.  
 
6 
STUDY PROCEDURES 
 
6.1 
Screening: 
Subjects will complete a variety of assessments and procedures to determine their enrollment 
eligibility. When possible, eligible subjects will have their screening data used as baseline data 
collection. Primary outcomes include biomechanical assessments related to motor tasks, 
electrophysiology tests, and an ASIA examination. Secondary outcomes include spasticity 
assessments, subjective surveys, and various spine imaging. 
 
6.2 
Intervention 1: Transcutaneous Electrical Spinal Stimulation (TS) and Task 
Specific Training Sessions 
Subjects will report to the ART lab at St. Mary’s Hospital for daily sessions of TS and task-
specific training interventions. TS stimulation will be applied to the skin surface over the 
spine as described previously. 
 
Training sessions will begin upon completion of baseline testing. Subjects will participate in 
a 3 days per week training regimen over 1 month with a goal of achieving 12 sessions. 
Activities include tasks specific to supine intentional leg movement training, balance 
training, stand and step (reciprocal flexion/extension) training. Heart rate will be recorded 
prior to, and after, each session, and at any time the intervention is paused due to a concern. 
Environments include the body weight support treadmill (BWST) system to allow trainer-
assisted stand and step activities as needed, custom standing frame, and a hi/lo mat for supine 

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and seated activities. As the subjects progress their intentional motor ability with standing 
and stepping, BWS will be removed, and assist will continue to be provided on an as needed 
basis. Any visit to the laboratory when TS is enabled will be considered a training session. 
Activities chosen for each session will be based on the subject’s progression.  
6.3 
Period of Follow-up after TS 
After 1 month of TS and motor training, each subject will be asked to complete two follow-
up assessments at time points 1 month and 4 months after completing the intervention to 
monitor changes in primary and secondary outcome measures. Subjects will be asked to 
refrain from partaking in additional therapies or interventions with the goal of improving 
functional measures related to their SCI during this 4-month follow-up period. 
6.4 
Intervention 2: Epidural Electrical Stimulation (ES) 
ES rehabilitation daily sessions will consist of lower extremity stretching, supine and side 
lying activities, seated trunk strengthening and balance activities, and locomotor training 
including task-specific stand and step training on a treadmill and over ground. Standing and 
stepping training activities may be performed with body weight support and trainer assistance 
as needed to ensure the safety of subjects. 
 
Training sessions will begin upon completion of baseline testing. Subjects will participate in 
3 days a week training regimen over 1 month with a goal of achieving 12 sessions. Activities 
include tasks specific to supine intentional leg movement training, balance training, stand and 
step (reciprocal flexion/extension) training. Heart rate will be recorded prior to, and after, 
each session, and at any time the intervention is paused due to a concern. Environments 
include the body weight support treadmill (BWST) system to allow trainer-assisted stand and 
step activities as needed, custom standing frame, and a hi/lo mat for supine and seated 
activities. As the subjects progress their intentional motor ability with standing and stepping, 
BWS will be removed, and assist will continue to be provided on an as needed basis. Any 
visit to the laboratory when ES is enabled will be considered a training session. Activities 
chosen for each session will be based on the subject’s progression.  
6.5 
Period of Follow-Up after ES 
After 1 month of ES and motor training, each subject will be asked to complete two follow-
up assessments at time points 1 month and 4 months after completing the intervention to 
monitor changes in primary and secondary outcome measures. Subjects will be asked to 
refrain from partaking in additional therapies or interventions with the goal of improving 
functional measures related to their SCI during this 4-month follow-up period. 
6.6 
Outcome Measures 
The following outcome measures will be collected as scheduled in Table 3 with tests 
occurring over an approximately one-week period of time for each time point. Photographic 
and video images will be recorded throughout the study, but will not be shown to anyone 
outside the study team without the subject’s written consent.  

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6.6.1 
Primary: 
Biomechanical assessments 
During a variety of tasks including supine, side-lying, reaching, standing, and stepping 
activities, kinematics, EMG, and foot pressure measurements may be obtained, with or without 
spinal stimulation, using the following metrics: 
 
Kinematics: We will use commercially available markers placed on the skin surface via a 
non-irritant adhesive to record limb movement and joint angles. Available systems we 
may use include video-based, inertial measurement units, electromagnetic.  
 
Electromyography: We will collect muscle activity using skin surface electrodes placed 
at anatomical locations of muscle groups below the level of injury. Activity will be 
recorded using a 16-channel signal amplifier and data acquisition system (PowerLab, 
ADInstruments, Colorado). At locations where self-adhesive bipolar recording electrodes 
will be placed onto the skin, the area will be cleaned with alcohol to ensure secure 
attachment and enhance signal recordings. A subset of the following muscles or muscle 
groups will be tested: soleus, gastrocnemius, tibialis anterior, hamstrings, quadriceps, hip 
adductors, gluteus maximus, gluteus medius, abdominals, triceps, trapezius, and spinal 
extensors.  
 
Foot pressure: Foot pressure will be measured with shoe-insole pressure sensors (F-
SCAN, Tekscan Inc., Boston, MA). 
 
Seated pressure: Seated pressure will be assessed via a force sensing array placed beneath 
the buttocks (Vista Medical BodiTrak force sensing array, Winnipeg, MB, Canada). 
 
Over the course of rehabilitation, if the research team observes stimulation-enabled functions 
that could be enhanced by further optimization of stimulation parameters, biomechanical  
assessment equipment may be used during select rehabilitation sessions in addition to the 
main assessment timepoints described in Table 3. 
 

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Table 3: Outcome Measures
 
Screening
Pre
Implant
Explant
Post
Follow-Up
Weeks
0
Baseline
5
8, 20
Motor Training
Urinalysis
X
DEXA1
X
Kinematics2
X
EMG2
X
X
X
SSEPs
X
X
X
TMS MEPs
X
X
X
TMS + ES or 
TS2
X
X
X
TS MEPs
X
X
X
ES MEPs
BBS, TUG, 
6MWT
X
X
X
FRT/mFRT
X
ISNCSCI
X
X
X
Spine CT or 
MRI
X
Urodynamic Studies
X
X
Surveys
X
X
X
1. DEXA scan measured at either left or right femur, and AP spine; not to include total body scan.   
DEXA=Dual Emission X-ray Absorptiometry, EMG=Electromyography, SSEPs=Somatosensory Evoked Potentials, TMS=Transcranial Magnetic 
Stimulation, MEPs=Motor Evoked Potentials, ES=Epidural Stimulation, TS=Transcutaneous Stimulation, BBS=Berg Balance Score, TUG=Timed Up and 
Go, 6MWT=6 Minute Walk Test, mFRT=Modified Functional Reach Test, ISNCSCI=International Standards of Neurological Classification of Spinal Cord 
Injury
Primary Outcomes
Secondary Outcomes
X
X
X
X
X
X
X
X
2. Further optimization may occur during training weeks 1-4.      
Study Timeline
Spinal Stimulation + 
Motor training
1
2
3
4
X
X
X
X
X
X

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Electrophysiology tests 
Somatosensory evoked potentials (SSEPs): SSEPs will be recorded through surface 
electrodes to measure conduction in the peripheral nerves, cervical and lumbosacral 
spinal cord, deep brain structures, and sensory cortex. Skin will be cleaned with alcohol 
and prepared using mild abrasive tape for placement of surface electrodes. For tibial 
recordings the tibial nerve will be stimulated behind the medial malleolus with recordings 
on the scalp utilizing a Fz,-CZ montage (International 10-20 System for EEG electrode 
placement), the cervical spine (C5 reference to Fz), the L1 spine (referenced to iliac 
crest), and the popliteal region. For median SSEPs, the median nerve will be stimulated at 
the wrist with recording electrodes at the scalp (C3-C4), the cervical spine (C5-Fz), Erb’s 
point (referenced to contralateral Erb’s) and the elbow. Repeated single-pulse electrical 
stimulation will be delivered at intensities of 1-1.5 times motor threshold for visual twitch 
for each of the four nerves evaluated. Averaged responses for up to 256 stimuli will be 
recorded for each of these two intensities for the right and left median and tibial nerves. 
Simultaneous bilateral stimulation will be applied if no recognizable responses are 
recorded from the scalp leads. Stimulation delivery rates will not exceed 2 per second. 
Recorded data will include amplitudes, peak latencies and interpeak latencies. Existing 
SSEPs within 6 months of screening may be acceptable for Baseline results at the 
investigators’ discretion. 
 
Transcranial magnetic stimulation (TMS) Motor evoked potentials (MEP): TMS MEPs 
will be evoked by placing a magnetic coil over the vertex of the head to elicit MEP. 
Upper limb MEPs will be recorded from the deltoid, triceps brachii, flexor carpi radialis 
and abductor pollicis brevis using the EMG system described in the biomechanics testing. 
The “threshold” TMS intensity will be defined as the minimum stimulus intensity 
required to elicit a response, recorded from muscles above the injury, that appears in 
response to >50% of the stimuli pulses delivered. If no MEPs are observed in EMG 
recordings from muscles that are innervated by the spinal cord below the level of injury, 
but are present in muscles innervated by spinal segments above the injury, then the injury 
severity will be deemed functionally motor complete. Data will be digitized, and MEPs 
responses averaged for each muscle. Latencies (interval from stimulus artifact to onset of 
response) and peak-to-peak amplitudes of MEPs responses will be assessed from all 
muscles. Existing TMS-MEPs within 6 months of screening may be acceptable for 
Baseline results at the investigators’ discretion. 
 
TMS Pulses Paired to TS or ES Pulses 
In order to interrogate the corticospinal connectivity which may be responsible for 
transmitting volitional motor commands during TS and/or ES through the injury site in 
participants with SCI, we will apply pulses of TMS at time intervals ranging from 5-
100ms prior to activation of lumbosacral spinal circuitry via pulses of either TS or ES. 
Evidence suggests both TS and ES, applied over the thoracolumbar spine, activate dorsal 
roots to elicit a motor reflex root-evoked potential. At each assessment time point, we 
will incrementally increase TS or ES pulse amplitudes to identify the stimulus intensity 
that consistently generates spinal reflex activity recorded via lower extremity EMG. 
Then, two TS or ES pulses will be delivered 50 ms apart to characterize the trans-
synaptic nature of the reflex which will be determined by observing suppression of a 

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response to the second stimulus pulse (i.e., post activation depression). Next, we will 
examine the conditioning effect (e.g., no change, increased amplitude of reflex, or 
decreased amplitude of reflex) of delivering TMS pulses at time intervals ranging from 5-
100ms prior to pulses of TS or ES while recording spinal circuitry outputs via lower 
extremity EMG. 
 
TS MEPs 
To assess the functional states of the spinal circuitry, we will deliver transcutaneous 
spinal stimulation via pulses of 1 ms duration at intensities of up to 100 mA. Stimulation 
will be delivered to multiple locations of the lumbosacral region with participants in a 
supine position. Evoked potentials will be recorded via surface EMG electrodes placed 
bilaterally over the soleus, gastrocnemius, tibialis anterior, hamstrings, quadriceps, hip 
adductors, gluteus maximus, gluteus medius, abdominals and spinal extensors. We will 
record evoked potentials while relaxed using stimulus intensities from 1-100 mA at 
increments of 10 mA for each stimulus location. Evoked potentials for each stimulus 
location and intensity will be averaged and visualized in real-time to determine the 
optimal location for evoking threshold potentials across all recorded muscles. Stimulus 
intensities that are at the threshold for evoking motor potentials will be delivered: while 
attempting prolonged maximal contractions of all muscles; during attempts to contract 
the left leg; and during attempts to contract the right leg. Evoked potentials will be 
analyzed according to task, stimulus intensity, and stimulus location.  
 
ES MEPs 
To assess the effects of delivering ES pulses to various regions of the lumbosacral spinal 
cord, we will record skin surface EMG from lower extremity muscles while ES is 
delivered to the temporarily implanted electrodes using a subset of anode/cathode 
configurations. Electrode configurations will be selected in order to selectively stimulate 
the rostral or caudal regions of the spinal cord within the T11-L1 vertebral bodies. This 
region of the spinal cord innervates the left and right proximal or distal muscles of the 
left/right lower extremities. ES pulses will be delivered as biphasic charge-balanced 
rectangular pulses ranging in pulse width (0.05-1ms), amplitude (0-25.5mA), and 
frequency (0.5-200  Hz). Within the implanted lead, each electrode could be configured 
as a cathode, anode, or off, and individual electrode configurations in order to target 
specific rostral-caudal and medial-lateral regions of the spinal cord to generate specific 
motor outputs. 
 
 
Overground mobility 
For subjects with motor incomplete injuries, attempts to stand and generate steps with 
varying degrees of body-weight support will be assessed using the Timed Up and Go (TUG), 
Berg Balance Score (BBS) while using the 6 Minute Walk Test (6MWT) to assess endurance 
changes. Measurements made as part of intake for the SCI Service Line may be used, if 
available. 
 

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Balance Assessment 
A motion capture camera system will be used to assess trunk stability according to the 
protocol from the modified functional reach test (mFRT) for subjects unable to stand. The 
subject will be outfitted with reflector markers on specific upper limb, trunk, pelvic, and 
lower limb landmarks. This procedure will consist of the subject sitting with hips, knees, and 
ankles position at 90 degrees of flexion with feet positioned flat on the floor. The subject is 
then asked to reach forward and laterally with their upper extremities while maintaining 
trunk stability. The extent to which the subject can reach before trunk balance becomes 
unstable (requiring assistance to regain balance from the physical therapist) is measured for 
multiple reaching trials. 
 
During the trunk stability assessment, skin surface EMG will be collected bilaterally from 
lower extremity and trunk muscles, as well as the trapezius. Pressure recordings will also be 
collected from under both feet and under the buttocks.  
 
Subjects capable of standing will undergo assessment via Berg Balance Assessment, the 
standing version of the Functional Reach Test (FRT), and the modified functional reach test 
(mFRT). 
 
International Standards of Neurological Classification of SCI (ISNCSCI) 
We will conduct ASIA Impairment Scale (AIS) to assess severity of the injury. This test 
focuses mainly on sensory and motor functions. Measurements made as part of intake for the 
SCI Service Line may be used, if available. 
6.6.2 
Secondary: 
Spine Imaging 
Baseline CT of the spine will be used to evaluate the structural integrity of the spine prior to 
study onset, and to visualize spine fusion hardware with respect to TS location and preparation 
of ES implantation location. Baseline spine MRI will be used to evaluate injury severity and 
assess potential of spared tissue (discomplete SCI) despite complete loss of motor function. 
Spine CT will be repeated for subjects following ES implantation to visualize array location, 
and at the end of the study to evaluate changes in array location. Existing spine CTs and MRI 
within 6 months of screening may be acceptable for Baseline results at the investigators’ 
discretion. 
Over the course of rehabilitation sessions with ES, one additional x-ray may be performed to 
visualize the location of implanted leads. This x-ray will be performed if stimulation-enabled 
motor activity is remarkably inconsistent from session to session, which might indicate 
migration of the ES lead(s). 
 
Bladder function 
A urodynamic test consisting of a filling phase and a voiding phase cystometrogram along with 
perineal patch muscle electromyography (EMG) will be performed with the stimulator both on 
and off. Specifically, a 9F double-lumen catheter will be introduced transurethrally into the 
bladder. One lumen of this catheter will be used for bladder filling at an average flow rate of 
20-25 ml/min (according to ICS guidelines), and another will record intravesical pressure. 
Intra-abdominal pressure will be recorded by a 12F rectal catheter. Through multichannel 
pressure transduction, intravesical and intra-abdominal pressures will be simultaneously 

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transduced on a strip chart recorder. Detrusor pressures will be simultaneously calculated by 
subtracting vesical from abdominal pressures. Sphincter EMG activity is observed by using 
patch electrodes.  Existing urodynamic studies within 6 months of screening may be acceptable 
for Baseline results at the investigators’ discretion. 
 
Surveys 
A battery of clinical surveys will be captured to assess subjects’ assessment of quality of life, 
and health habits such as bowel and bladder function, and sexual function. Any of these surveys 
done as part of intake for the SCI Service Line may be used, if available. 
 
 
7 
FDA IDE-RELATED DEVICE PREPARATION AND ADMINISTRATION 
PROCEDURES 
 
Study-related device packaging will not be altered with respect to the device manufacturer’s 
clinical supply packaging. However, the following label will be added to the devices 
described within the FDA IDE protocol associated with this clinical trial: 
 
*** CAUTION *** 
***Limited to Investigational Use by Federal Laws and Regulations*** 
 
7.1 
Receipt of FDA IDE-related Devices 
A representative from Abbott will ship the devices to Mayo Clinic and they will be properly 
inventoried prior to the scheduled date of surgical implantation.  The representative will also 
train study personnel on how to use the clinician programmer during non-testing 
rehabilitation sessions. 
 
The Nomad neurostimulation system will be purchased from Ripple Neuro, shipped to Mayo 
Clinic, and inventoried within the ART Lab. 
 
Any product discrepancies or damage will be documented in the study files and the supplier 
will be notified. Then, appropriate action will be taken by the PI to fully address the issue. 
 
 
7.2 
FDA IDE-related Device Storage 
ES electrode leads and the clinician programmer will be supplied directly by the Abbott 
distribution representative and/or stored in the ART Lab, which is a secured area that can 
only be accessed by ART Lab staff. 
 
The Nomad system will be stored in the ART Lab. 
 

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7.3 
Distribution of FDA IDE-related Devices 
In accordance with Mayo Clinic policy, the brand, model, date of implantation, and date of 
explantation of all ES electrode leads will be recorded in the Surgical Inventory Management 
System. This information will be made available within the electronic medical record of each 
participant. Additionally, a copy of this information will be stored within each participant’s 
case file. 
 
7.4 
Return or Destruction of FDA IDE-related Devices 
Each month, as well as upon receipt of new or repaired devices, and at the completion of the 
study, there will be a reconciliation of devices shipped, devices utilized, and devices 
remaining. This reconciliation will be logged, signed, and dated within the Device 
Accountability Form. Any discrepancies noted will be documented and an investigation will 
be conducted to determine the cause of the discrepancy.   
8 
STATISTICAL DESIGN AND POWER 
8.1 
Sample Size Determination 
Due to the pilot phase of this clinical trial, no formal power calculations were performed for 
this study. The number of subjects was selected based on budgetary, space, and personnel 
time constraints. Eight subjects will be enrolled to complete the activities of this clinical trial, 
depending on need for contingency subjects. All subjects will receive either 1 month of TS 
and rehabilitation or 1 month of ES and rehabilitation. Following either intervention, all 
subjects will be followed for follow-up assessments at 2 time points during 4 additional 
months. 
8.2 
Statistical Methods 
Descriptive Statistics and Graphics 
Continuous data will be summarized as median (inner quartile range). Categorical data will 
be presented as frequency (percentage). Graphical presentations of data will be used for all 
endpoints. Individual data points will be plotted over time, with distinctions made between 
data from TS and ES groups. Additionally, associations between measurements prior to and 
following ES intervention will be assessed using bivariate scatterplots. These associations 
will be summarized numerically with Spearman’s correlation coefficient. 
 
Modeling 
The overall ES effect will be assessed by comparing models with and without the treatment 
indicators. Additionally, measurements taken under various conditions can be modeled 
simultaneously with appropriate effects for the different conditions. For example, SSEPs will 
be measured at the tibial and median nerves, each at 2 intensities. Effects for the different 
locations and intensities will be added to the model, along with effects for the 2 nerves as 
random effect nested within subject. Models will also be used to quantify associations 
between assessments at baseline and during the first month, with assessments at the end of 
the study. This may be used to determine whether there may be markers available to predict 
which subjects may respond to treatment.    
 

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Handling of Missing Data 
Mixed modeling will not require complete data collection to conduct the analysis. Other 
analysis, such as bivariate analyses, which require complete data will be, conducted primarily 
using complete cases analysis. Sensitivity analyses will be conducted by imputing missing 
data with predictions from regression models based on baseline data.  
 
8.3 
Subject Population(s) for Analysis  
All-completed population: Only subjects who completed all study related procedures and 
follow-up will be included; however, the PI may adjust this to include a subject who 
completed the majority of the study visits and procedures. 
 
9 
SAFETY AND ADVERSE EVENTS 
 
All AEs occurring during the study, including those not meeting the criteria of an 
Unanticipated Adverse Device Effect (UADE) will be recorded on the appropriate case 
report form. Records of these events will be maintained, and reports will be submitted to the 
FDA and IRB according to the regulatory requirements. Expected clinical AEs and 
nonsignificant (not serious) clinical AEs will not be reported. 
 
9.1 
Unanticipated Adverse Device Event (UADE) 
A UADE is any SAE that impacts the health or safety, or any life-threatening problem or 
death caused by, or associated with, a device if that event, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan or 
IDE 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 
participants. 
 
9.2 
Adverse Event (AE) 
Any untoward medical occurrence of an investigational device; regardless of the causal 
relationship of the problem with the device or, if applicable, other study related treatment(s). 
The following categorization of AEs will be used: 
 
9.2.1 Associated with the Investigational Device  
There is a reasonable possibility that the AE may have been caused by the investigational 
device. 
 
9.2.2 Life-threatening AE 
Any AE that places the participant at immediate risk of death from the event as it occurred, 
excluding events where a reaction that, had it occurred in a more severe form, might have 
caused death. 
 
9.2.3 Serious AE 
An AE will be considered “serious” if it results in any of the following outcomes:  
 
• death  

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• a life-threatening AE 
• inpatient hospitalization or prolongation of existing hospitalization 
• a persistent or significant disability/incapacity 
• a congenital anomaly/birth defect. 
 
9.2.4 Unanticipated AE 
Any AE, the nature, specificity, severity, or frequency of which is not consistent with the 
anticipated risks described within the clinical study protocol. 
 
9.3 
General Physical Examination Findings 
At screening, any clinically significant abnormality will be recorded as a preexisting 
condition. At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an AE will also be recorded and documented as an AE. 
 
9.4 
Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization will be documented and 
reported as an unanticipated adverse device effect unless specifically instructed otherwise in 
this protocol. Any condition responsible for surgery will be documented as an AE if the 
condition meets the criteria for an AE. 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as 
an AE in the following circumstances:  
 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition. Surgery will not be reported as an outcome of 
an AE if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful 
• 
Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as 
judged by the clinical investigator 
 
9.5 
Post-study AE 
All unresolved AE will be followed by the PI until the AE is resolved, the participant is lost 
to follow-up, or the AE is otherwise explained. At the last scheduled visit, the PI will instruct 
each participant to report any subsequent event(s) that might reasonably be related to 
participation in this study. The PI will notify the institutional regulatory office of any death 
or AE that occurs at any time after participants have discontinued or terminated study 
participation and may reasonably be related to this study.  
 
9.6 
Preexisting Condition 
Any preexisting conditions that do not result in exclusion during screening will be recorded 
as an AE if the frequency, intensity, or the character of the condition worsens. 
 
9.7 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problems or AEs that meet all of the following three criteria: 
 

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9.7.1 Serious 
Serious problems or events that results in significant harm, (which may be physical, 
psychological, financial, social, economic, or legal) or increased risk for the subject or others 
(including individuals who are not research subjects). These include: (1) death; (2) life 
threatening AE; (3) hospitalization - inpatient, new, or prolonged; (4) disability/incapacity - 
persistent or significant; (5) birth defect/anomaly; (6) breach of confidentiality and (7) other 
problems, events, or new information (i.e. publications, DSMB reports, interim findings, 
product labeling change) that in the opinion of the local investigator may adversely affect the 
rights, safety, or welfare of the subjects or others, or substantially compromise the research 
data. 
 
9.7.2 Unanticipated  
Events that are not already described as potential risks in the protocol, consent document, not 
listed in the PI’s brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or event 
is "unanticipated" when it occurs at an increased frequency or at an increased severity than 
expected, AND 
 
9.7.3 Related 
A problem or event is "related" if it is possibly related to the research procedures. 
 
9.8 
AE Recording 
At each contact with the participant, the PI will seek information on AEs. Study participants 
will be routinely questioned about AE at study visits. Information on all AE will be recorded 
immediately in the source document, and also in the appropriate AE section of the case report 
form (CRF). All clearly related signs, symptoms, and abnormal diagnostic, laboratory or 
procedure results will be recorded in the source document. 
 
All observed or volunteered AEs (serious and non-serious) and abnormal test findings, 
regardless of treatment group or suspected causal relationship to the investigational device, 
will be recorded in the participant’s case history. For all AEs, sufficient information will be 
pursued and or obtained as to permit; an adequate determination of the outcome, an 
assessment of the casual relationship between the AE and the investigational device or, if 
applicable other study treatment or diagnostic product. The clinical course of each event will 
be followed until resolution, stabilization, or until it has been ultimately determined that the 
study treatment or participation is not the probable cause. Serious AEs that are unresolved at 
the end of the study period will be followed up to determine the final outcome. Any serious 
AE that occurs after the study period and is considered to be at least possibly related to the 
study treatment or study participation will be recorded and reported immediately. 
 
9.9 
Abnormal Clinical Testing Results 
If an unexpected abnormal clinical testing result is observed, and is believed to be unrelated 
to participation in study-related activities, the abnormal result it will be documented as an AE 
and the study participant will be instructed to consult with their clinical provider to determine 
if additional testing is needed. 
 

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9.10  Relationship and Severity Assessment 
The PI, or their delegate, will promptly review documented AEs and abnormal test findings 
to determine if:  
 
• The abnormal test finding will be classified as an AE 
• There is a reasonable possibility that the AE was caused by the investigational device 
or other study treatments 
• The AE meets the criteria of serious AE 
 
If the PI’s final determination of causality is “unknown and of questionable relationship to 
the investigational device or other study treatments,” the AE will be classified as associated 
with the use of the investigational device or other study treatments for reporting purposes. If 
the PI’s final determination of causality is “unknown but not related to the investigational 
device or other study treatments,” this determination and the rationale for the determination 
will be documented in the respective participant’s case history. 
 
9.11 AE Relationship Index  
The relationship of an AE to the investigational device will be decided by the PI based on all 
available information at the time of the completion of the CRF and will be graded as follows: 
 
9.11.1  Unrelated 
Sufficient information exists to indicate that the etiology is unrelated to the study device; the 
temporal sequence of the AE onset relative to administration of the study device is not 
reasonable or the event is clearly related to other factors such as the participant’s clinical 
state, therapeutic intervention, or concomitant therapy. 
 
9.11.2  Remotely Possible  
Temporal relationship to device administration which makes a causal relationship 
improbable, and in which other drugs, chemicals, procedures, surgeries, or underlying 
disease provide plausible explanations. 
 
9.11.3  Possible 
A reasonable relationship to administration of the device could be established but the AE 
could also be explained by concurrent disease or other drugs, chemicals, procedures, or 
surgeries. 
 
9.11.4  Probable  
A clinical event including laboratory test abnormality, with a reasonable time sequence to 
administration of the device, unlikely to be attributed to concurrent disease or other drugs, 
chemicals, procedures, or surgeries. 
 
 

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9.11.5  Definite 
A reaction that follows a reasonable temporal sequence from administration of the device, or 
which is confirmed by imaging or clinical laboratory values, that follows a known or 
expected response pattern to the study device and/or procedure. 
 
9.12  AE Severity Index 
The maximum intensity of an AE during a day will be graded according to the definitions 
below and recorded in detail as indicated on the CRF. If the intensity of an AE changes over 
a number of days, then separate entries will be made having distinct onset dates. The PI will 
systematically determine the severity of each AE: 
 
9.12.1  Mild 
Transient, requiring no special treatment, and tolerable. Does not interfere with daily 
activities. 
 
9.12.2  Moderate  
Sufficient reaction interfering with daily activities and/or reduced level of activity. AE is 
ameliorated by simple therapeutic measures. 
 
9.12.3  Severe  
Significant impairment resulting in an inability to carry out usual activities and/or the 
participant’s life is at risk due to the event. Management may include systemic drug therapy 
or other treatment. 
 
9.13 AE reporting 
When an AE has been identified, the PI will take appropriate action to protect the participant 
and then complete the Study Adverse Event Worksheet and log. The PI will evaluate the AE 
and determine the necessary follow-up and reporting required. Then, the PI will promptly 
review documented UADE and report the results to the FDA within 10 working days and the 
Mayo Clinic’s IRB within 5 working days Thereafter, the PI will submit additional reports as 
requested. 
 
Additionally, information related to the AE will be recorded on CRFs and within the research 
database. The PI will review all AE reports to determine if specific reports need to be made 
to the IRB and FDA. The PI will sign and date the AE report when it is reviewed. For this 
protocol, only directly related SAEs/UPIRTSOs will be reported to the IRB. 
 
9.14  Notifying the FDA 
The PI will report all unanticipated AEs to the FDA according to the required reporting 
timelines, formats, and regulations. 
 
The PI will submit a completed FDA Form 3500A to the FDA’s Center for Devices and 
Radiological Health for any observed or reported AE that is determined to be an 
unanticipated AE. A copy of this completed form will be provided to the DSMB and all co-
investigators. 
 

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The completed FDA Form 3500A will be submitted to the FDA as soon as possible, but no 
later than 10 working days after receiving notice of the AE. 
 
If the results of the PI’s follow-up evaluation indicate that an AE that was initially 
determined to not constitute an unanticipated adverse device effect meets the requirements 
for reporting, the PI will submit a completed FDA Form 3500A as soon as possible, but no 
later than 10 working days after the determination was made. 
 
For each submitted FDA Form 3500A, the PI will identify all previously submitted reports 
that that addressed a similar AE experience and will provide an analysis of the significance 
of newly reported AE in light of any previous, similar report(s). 
 
Subsequent to the initial submission of a completed FDA Form 3500A, the PI will submit 
additional information concerning the reported AE as requested by the FDA. 
 
Unanticipated Adverse Device Effect reports will be submitted on FDA Form 3500A. 
 
Contact information for submitting reports: 
 
Food and Drug Administration 
Center for Devices and Radiological Health 
Document Mail Center - WO66-G609 
10903 New Hampshire Avenue 
Silver Spring, Maryland 20993-0002 
 
9.15  Deviations from the investigational plan 
The PI will notify Mayo IRB (see 21 CFR 56.108(a) (3) and (4)) of any deviation from the 
investigational plan to protect the life or physical well-being of a participant in an 
emergency. Such notice shall be given as soon as possible, but in no event later than 5 
working days after the emergency occurred. Except in such an emergency, prior approval by 
the PI is required for changes in or deviations from a plan, and if these changes or deviations 
may affect the scientific soundness of the plan or the rights, safety, or welfare of human 
subjects, FDA, and IRB notification in accordance with 21 CFR 812.35(a) will occur. 
 
9.16  Stopping Rules 
Study enrollment and treatment procedures will be suspended in the event: 
 
• A participant experiences an SAE probably or definitely related to the study device or 
due participation in the study. 
• The PI determines that the study should be discontinued for any reason. 
 
In the event that the study enrollment is suspended for any reason, enrollment and treatment 
would only be resumed after a thorough review of the incidents and any corrective and 
preventative actions have been put in place along with consultation between the study team 
and the IRB. 
 

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9.17  Medical Monitoring 
Safety monitoring will include careful assessment and appropriate reporting of AEs as noted 
above, as well as the construction and implementation of a site data and safety-monitoring 
plan. Medical monitoring will include a regular assessment of the number and type of serious 
AEs. 
 
9.17.1  Safety Monitoring  
Safety monitoring and oversight will be performed the PI. The PI will have the authority 
temporarily or permanently to discontinue a particular protocol and/or the involvement of a 
given subject, if deemed necessary or appropriate for the safety of the subject. We will 
establish an internal Data and Safety Review Group (DSRG) comprised of the co-
Investigators. The internal DSRG will meet quarterly. In addition to our internal DSRG, we 
are prepared to appoint a medical health care professional or appropriate expert with relevant 
expertise to serve as Independent Safety Monitor. His/her duties will be to review study 
protocols, procedures, AEs, outcomes, and milestones. If any concern or unexpected issue is 
identified by the Independent Safety Monitor appointed with any subject that could be of 
potential risk or concern to other subjects, action will be taken to address, mitigate, and/or 
eliminate such risk from the study. AEs will be reported immediately, i.e., within 24 hours, to 
the study coordinator and PI. The PI and independent safety monitor will determine if any 
action is required to resolve the AE. The PI will also report the AE to the IRB, and to the 
study coordinator and PI.  
 
 
9.17.2  Risk Management and Emergency Response 
Risks will be managed by study staff who will accompany the subjects, and who will be 
reachable by cell phone or pager when the subject is not on-site. Study staff will 
communicate with the PI if any concerns arise.  
 
 
9.17.3  Auditing and Inspecting 
The PI will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, 
and government regulatory agencies, of all study related documents (e.g., source documents, 
regulatory documents, data collection instruments, study data etc.). The PI will ensure the 
availability for inspections of applicable study-related facilities (e.g., laboratories, etc.). 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
 
9.17.4  Monitoring AEs and Unanticipated Problems 
Assessment of AEs (including Unanticipated Problems) will be performed continuously 
during the study period. Possible AEs will be detected through spontaneous reports by the 
subject, direct questioning of the subject, and direct examination during study visits. When 
an AE has been identified, the study team will take appropriate action necessary to protect 
the study participant and then complete the Study Adverse Event Worksheet and/or log. 
Recording for each AE will include a description of the event, whether or not it is considered 
serious (SAE), duration (onset and resolution dates), severity (mild, moderate, severe), 
potential contributory factors, treatment rendered, and outcome. The PI will have the 

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authority temporarily or permanently to discontinue a particular protocol and/or the 
involvement of a given subject, if deemed necessary or appropriate for the safety of the 
subject. If any AE or unanticipated problem is identified with one subject that could be of 
potential risk or concern to other subjects, action will be taken by the PI to address, mitigate, 
and/or eliminate such risk from the study, with the direction of the Independent Safety 
Monitor. Any such AE will be reported immediately, i.e., within 24 hours, to the PI. The PI 
will consult with the Independent Safety Monitor as appropriate, and will determine if any 
action is required to resolve the AE. The PI will also report any such AE to the IRB. The 
clinical course of each AE will be followed until resolution, stabilization, or until it has been 
ultimately determined that the study treatment or participation is not the probable cause. The 
PI will evaluate all apparent AEs and determine the necessary follow-up and reporting 
required. 
 
 
10 DATA HANDLING AND RECORD KEEPING 
 
10.1 Confidentiality 
Participant information will be kept confidential and managed according to the requirements 
of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following: 
 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI 
 
In the event that a participant revokes authorization to collect or use PHI, the PI, by 
regulation, retains the ability to use all information collected prior to the revocation of 
authorization. For participants that have revoked authorization to collect or use PHI, attempts 
will be made to obtain permission to collect at least vital status at the end of their scheduled 
study period. 
 
10.2 Source Documents 
Source data comprise all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Source data are contained in source documents. Examples of these original documents, and 
data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, diaries or evaluation checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies or transcriptions certified after verification as being 
accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-
rays, files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. When applicable, information recorded on the CRF 
will match Source Data recorded on the Source Documents. 
 

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10.3 Case Report Forms 
The study case report form (CRF) will be the primary data collection instrument for the 
study. All data requested on the CRF will be recorded, and all missing data explained as 
follows: 
 
• If a space on the CRF is left blank because the procedure was not done or the 
question was not asked, write “N/D”. 
• If the item is not applicable to the individual case, write “N/A”. 
• All entries should be printed legibly in black ink. 
• If a data entry error is identified, it will be corrected by drawing a single straight line 
through the incorrect entry and the correct data will be entered above it. All such 
changes will be initialed and dated.  
• Clarification of illegible or uncertain entries will be printed above the item, then 
initialed and dated. 
 
10.4 Data Management 
Study Source Data will be kept in hard copy (where applicable) within participant case files, 
which will be kept in limited-access space reserved for study staff only. Electronic data will 
be managed within a password-protected study-specific internal database. 
 
10.5 Data Processing 
Data will be processed within a study-specific Mayo Clinic internal database. Quality control 
will be applied to each stage of data handling to ensure that all data are reliable and have 
been processed correctly. Original data will be preserved in such a way that any data 
transformed during processing can be compared to the original data. 
 
10.6 Data Security and Confidentiality 
The Mayo Clinic internal database system has built in systems for control of access, data 
integrity and audit trails. Access and confidentiality are controlled in a manner similar to 
other institutional systems. 
 
10.7 Data Quality Assurance 
A Quality Assurance audit may be conducted by the PI, or designee, at any time during or 
after this study. The audit may include, but not be limited to: 
 
• A review of all ICFs 
• A review of CRFs and source documents 
• A review of regulatory documents 
• An assessment of trial conduct and compliance 
• And a review of investigational device storage and accountability records 
 
10.8 Data Clarification Process 
In response to a query on the part of the FDA, or in the event that the Mayo Clinic internal 
database program identifies a discrepancy, missing value, or other discrepancy in the CRF 
database, the error will be addressed, and a Data Clarification Form will be completed. 
 

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10.9 Records Retention 
The PI will maintain records and essential documents related to the conduct of the study. 
These will include subject case histories and regulatory documents. 
 
The PI will retain the specified records and reports during the study and for the longer of the 
following; 
 
1. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” http://mayocontent.mayo.edu/research-policy/MSS_669717,  
 
OR 
 
2. A period of 2 years after the latter of the following two dates: The date on which the 
investigation is terminated or completed, or the date that the records are no longer 
required for purposes of supporting a premarket approval application or a notice of 
completion of a product development protocol. 
 
11 STUDY MONITORING, AUDITING, AND INSPECTING 
 
11.1 Protocol Compliance Monitoring 
Throughout the study, research staff will monitor study protocol compliance by reviewing all 
protocol-related procedures and records. The PI will oversee compliance and determine the 
appropriate response to instances that are deemed non-compliant. 
 
11.2 Study Monitoring Plan 
The PI will allocate adequate time for study monitoring activities. The PI will also ensure 
that the monitor, compliance, and/or quality assurance reviewer is provided access to all 
study-related documents and study-related facilities (e.g., pharmacy, diagnostic laboratory, 
etc.). Study monitors will be provided adequate space and resources to successfully conduct 
monitoring activities. 
 
This study will be monitored on a routine basis during the conduct of the trial. The Mayo 
Clinic Office of Research Regulatory Support will assist the PI with monitoring of the trial. 
Clinical trial monitoring requires review of the study data generated from protocol activities 
to ensure the validity and integrity of the data while also protecting the rights and safety of 
study participants. They will also assist the PI with maintaining compliance to appropriate 
Food and Drug Administration regulations. 
 
Medical safety monitoring will be conducted on an ongoing basis by medical doctor sub-
investigators and clinician study staff with the appropriate credentials to treat this patient 
population in a clinical setting.  
 
11.3 Auditing and Inspecting 
The PI will permit study-related monitoring, audits, and inspections by the IRB, the monitor, 
and government regulatory agencies, of all study related documents (e.g., source documents, 
regulatory documents, data collection instruments, study data etc.). The PI will ensure the 

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capability for inspections of applicable study-related facilities (e.g., pharmacy, diagnostic 
laboratory, etc.). 
 
The PI will also permit inspection by government regulatory authorities and applicable 
compliance offices. 
 
12 PRIOR AND CONCOMINANT THERAPY 
 
Participation in therapy regimens prior to study enrollment will not influence the PI’s 
decision regarding enrollment into the study. While enrolled in the study, participants will be 
asked to follow the instructions from the study staff regarding participation in exercise 
programming that is outside the scope of this clinical trial.  
 
13 STUDY FINANCES 
 
13.1 Funding Source 
This study will be funded by the Mayo Clinic Center for Regenerative Medicine.  
 
13.2 Conflict of Interest 
If a conflict of interest is identified by study personnel, (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) it will be 
reviewed by a Conflict of Interest Committee with a Committee-sanctioned conflict 
management plan that has been reviewed and approved by the PI prior to participation in this 
study. 
 
13.3 Stipends or Payments 
Participants will not be remunerated $500 for time spent performing the activities of this 
protocol.  
 
14 PUBLICATION OF RESULTS 
 
The PI holds the primary responsibility for publication of the results of this study, deciding 
authorship, and finalizing the order of authorship. Approval will be obtained from the PI 
before any information related to this study can be used or passed on to a third party. Once 
this study is approved, it will be registered to ClinicalTrials.gov. 
 
15 ETHICAL CONSIDERATIONS 
 
This study is to be conducted according to United States government regulations and Mayo 
Clinic’s institutional research policies and procedures. 
 
This protocol, and any future amendments, will be submitted to Mayo Clinic’s Institutional 
Review Board (IRB) for formal approval. The decision of the IRB will be made in writing to 
the PI before commencement of this study. 
 
All subjects for this study will be provided a consent form that was previously reviewed and 
approved by the IRB. The consent form will provide an overall description of this study 

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along with sufficient information of activities the subject is expected to participate in as 
described within this protocol. The formal consent of a subject will be documented using the 
IRB-approved consent form. Consent will be obtained before participation in any study-
related activities. The consent form must be signed and dated by the subject, or the subject’s 
legally authorized representative. The consent form will also be signed and dated by a 
research team member that is approved to obtain informed consent. 
 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study. The decision of the IRB concerning the conduct of the study will be 
made in writing to the sponsor-investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study. This consent form will be submitted with the protocol for review 
and approval by the IRB for the study. The formal consent of a subject, using the Approved 
IRB consent form, must be obtained before that subject undergoes any study procedure. The 
consent form must be signed and dated by the subject or the subject’s legally authorized 
representative, and the individual obtaining the informed consent. 
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