A Pilot Study to Explore the Use of Percutaneous Spinal Stimulation in Participants With Multiple Sclerosis
Phase: NA
Conditions: Multiple Sclerosis, Demyelinating Disorder, Autoimmune Diseases
Sponsor: Kristin Zhao, PhD

Official Title:  A Pilot Study to Explore the Use of Percutaneous Spinal Stimulation in 
Participants with Multiple Sclerosis 
NCT Number: NCT06019611 
Document Date: 05 December 2023 

  ES in MS 
 
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Kristin D. Zhao, Ph.D.                                                                                                                                                      CONFIDENTIAL 
 
 
A Pilot Study to Explore the Use of Percutaneous Spinal Stimulation in Participants 
with Multiple Sclerosis 
 
 
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 
William Oliver Tobin, MBBCh, Ph.D. 
Department of Neurology 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
(507) 538-2679 
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 
Funding Sponsor: 
Mayo Clinic Center for Multiple Sclerosis and 
Autoimmune Neurology 
Study Product: 
Abbott percutaneous trial lead for epidural 
neurostimulation (Model 3086) 
Abbott Neuromodulation 
6901 Preston Road 
Plano, TX 75024 
Ripple Nomad Neurostimulator 
Ripple Neuro 
2056 South 1100 East 
Salt Lake City, UT 84106 

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Kristin D. Zhao, Ph.D.                                                                                                                                                      CONFIDENTIAL 
 
 
Abbott clinician programmer for epidural and dorsal 
root ganglion neurostimulation (Model 3874) 
Abbott Medical 
6901 Preston Road 
Plano, TX 75024 
 
Protocol Number: (IRBe) 
23-003967 
IDE Number: 
G210292 
 
 
Initial version: 
 
10/01/2021 (Version 1.0) 
Revision: 
 
 
02/08/2023 (Version 2.0) 
Revision: 
 
 
06/13/2023 (Version 2.1) 
Revision: 
 
 
06/23/2023 (Version 2.2) 
Revision: 
 
 
12/05/2023 (Version 2.3) 
 
Table of Contents 
A PILOT STUDY TO EXPLORE THE USE OF PERCUTANEOUS SPINAL STIMULATION IN PARTICIPANTS WITH MULTIPLE 
SCLEROSIS ......................................................................................................................................................................... 1 
REVISION: 
  02/08/2023 (VERSION 2.0) ......................................................................................................................... 2 
TABLE OF CONTENTS ......................................................................................................................................................... 2 
STUDY SUMMARY ........................................................................................................................................................... 5 
1 
INTRODUCTION ...................................................................................................................................................... 5 
1.1 
BACKGROUND ...................................................................................................................................................... 6 
1.2 
INVESTIGATIONAL DEVICE ................................................................................................................................... 8 
1.3 
PRECLINICAL DATA .............................................................................................................................................. 8 
1.4 
STUDY RATIONALE AND RISK ANALYSIS (RISKS TO BENEFITS RATIO) ................................................................ 9 
1.4.2 
ANTICIPATED RISKS ............................................................................................................................................. 9 
1.4.3 
POTENTIAL BENEFITS ......................................................................................................................................... 11 
1.5 
ANTICIPATED DURATION OF THE CLINICAL INVESTIGATION .............................................................................. 11 
2 
STUDY OBJECTIVES ............................................................................................................................................ 11 
2.1 
PRIMARY OBJECTIVE .......................................................................................................................................... 11 
2.2 
SECONDARY OBJECTIVE ..................................................................................................................................... 11 
3 
STUDY DESIGN ...................................................................................................................................................... 11 
3.1 
GENERAL DESIGN ............................................................................................................................................... 11 
3.2 
PRIMARY STUDY ENDPOINTS ............................................................................................................................. 12 
3.3 
PRIMARY SAFETY ENDPOINTS ............................................................................................................................ 12 
4 
SUBJECT SELECTION, ENROLLMENT AND WITHDRAWAL ................................................................... 13 
4.1 
INCLUSION CRITERIA .......................................................................................................................................... 13 
4.2 
EXCLUSION CRITERIA......................................................................................................................................... 13 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ................................................................................... 14 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ................................................................................................................... 14 
4.4.1 
WHEN AND HOW TO WITHDRAW SUBJECTS ....................................................................................................... 15 

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Kristin D. Zhao, Ph.D.                                                                                                                                                      CONFIDENTIAL 
 
4.4.2 
DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN SUBJECTS .................................................................... 15 
5 
STUDY DEVICE ...................................................................................................................................................... 15 
5.2 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ............................................................................ 15 
5.3 
PREPARATION AND ADMINISTRATION/IMPLANTATION OF INVESTIGATIONAL DEVICE ....................................... 15 
5.4 
SUBJECT COMPLIANCE MONITORING ................................................................................................................. 17 
5.5 
PRIOR AND CONCOMITANT THERAPY ................................................................................................................. 17 
5.6 
PACKAGING AND LABELING ............................................................................................................................... 17 
5.7 
MASKING/BLINDING OF STUDY .......................................................................................................................... 17 
5.8 
RECEIVING, STORAGE, DISTRIBUTION AND RETURN .......................................................................................... 17 
5.8.1 
RECEIPT OF INVESTIGATIONAL DEVICES ............................................................................................................ 17 
5.8.2 
STORAGE ............................................................................................................................................................ 18 
5.8.3 
DISTRIBUTION OF STUDY DEVICE ....................................................................................................................... 18 
5.8.4 
RETURN OR DESTRUCTION OF STUDY DEVICE .................................................................................................... 18 
6 
STUDY PROCEDURES .......................................................................................................................................... 18 
6.1 
SCREENING ......................................................................................................................................................... 18 
6.2 
EPIDURAL ELECTRICAL STIMULATION (ES) ....................................................................................................... 19 
6.3 
PERIOD OF FOLLOW-UP AFTER ES ...................................................................................................................... 20 
6.4 
OUTCOME MEASURES ........................................................................................................................................ 20 
7 
STATISTICAL PLAN ............................................................................................................................................. 22 
7.1 
SAMPLE SIZE DETERMINATION .......................................................................................................................... 22 
7.2 
STATISTICAL METHODS ...................................................................................................................................... 22 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ............................................................................................................ 22 
8 
SAFETY AND ADVERSE EVENTS ...................................................................................................................... 23 
8.1 
DEFINITIONS ....................................................................................................................................................... 23 
8.2 
RECORDING OF ADVERSE EVENTS ...................................................................................................................... 25 
8.3 
SPONSOR-INVESTIGATOR REPORTING OF UNANTICIPATED ADVERSE DEVICE EFFECTS AND UNANTICIPATED 
PROBLEMS ....................................................................................................................................................................... 25 
8.3.1 
SPONSOR-INVESTIGATOR REPORTING, NOTIFYING MAYO IRB .......................................................................... 26 
8.3.2 
SPONSOR-INVESTIGATOR REPORTING: NOTIFYING THE FDA ............................................................................. 26 
8.4 
STOPPING RULES ................................................................................................................................................ 27 
8.5 
MEDICAL MONITORING ...................................................................................................................................... 27 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................................... 27 
9.1 
CONFIDENTIALITY .............................................................................................................................................. 27 
9.2 
SOURCE DOCUMENTS ......................................................................................................................................... 28 
9.3 
CASE REPORT FORMS ......................................................................................................................................... 28 
9.4 
RECORDS RETENTION ......................................................................................................................................... 29 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................................ 29 
10.1 
STUDY MONITORING PLAN ................................................................................................................................ 29 
10.2 
AUDITING AND INSPECTING ................................................................................................................................ 30 
11 
ETHICAL CONSIDERATIONS ............................................................................................................................ 30 
12 
STUDY FINANCES ................................................................................................................................................. 30 
12.1 
FUNDING SOURCE .............................................................................................................................................. 30 
12.2 
CONFLICT OF INTEREST ...................................................................................................................................... 30 
12.3 
SUBJECT STIPENDS OR PAYMENTS ...................................................................................................................... 31 
13 
PUBLICATION PLAN ............................................................................................................................................ 31 
14 
REFERENCES ......................................................................................................................................................... 31 
 

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Kristin D. Zhao, Ph.D.                                                                                                                                                      CONFIDENTIAL 
 
 
 
 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event/Adverse Experience 
BWS 
Body weight support 
CFR 
Code of Federal Regulations 
CMSAN 
(Mayo Clinic) Center for Multiple Sclerosis 
and Autoimmune Neurology 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
EDSS 
Expanded Disability Severity Scale 
EMG 
Electromyography 
ES 
Epidural electrical spinal stimulation 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HRPO 
Human Research Protection Office 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
MAS 
Modified Ashworth Scale 
MS 
Multiple sclerosis 
MSQLI 
MS Quality of Life Inventory 
NSTEP-MS 
NeuroStimulation Therapy to Alleviate Symptoms of 
Progressive MS 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SCI 
Spinal Cord Injury 
SOP 
Standard Operating Procedure 
TUG 
Timed up and Go 
UADE 
Unanticipated Adverse Device Effect 

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Kristin D. Zhao, Ph.D.                                                                                                                                                      CONFIDENTIAL 
 
Study Summary 
Title 
A Pilot Study to Explore the Use of Percutaneous Spinal 
Stimulation in Participants with Multiple Sclerosis 
Running Title 
ES in MS 
IRB Protocol 
Number 
23-003967 
Phase 
Pilot Study 
Methodology 
Prospective study 
Overall Study 
Duration 
3-year duration 
Subject 
Participation 
Duration 
Less than 2 months per subject 
Objectives 
a) Evaluate the effectiveness of percutaneous ES and task-specific 
training in participants with Progressive MS to impact motor 
function and spasticity. 
b) Investigate the potential of ES and task-specific training to 
impact non-motor spinal related dysfunction in the same 
participants. 
Number of Subjects 
10 subjects 
Diagnosis and Main 
Inclusion Criteria 
Multiple Sclerosis with EDSS of 6.5 
Study Device 
Abbott percutaneous trial lead for epidural neurostimulation 
(Model 3086) 
Ripple Nomad Neurostimulator 
 
Abbott clinician programmer, (Model 3874) 
Duration of 
Exposure 
All subjects will complete 1 month of temporary epidural spinal 
stimulation (ES) with task-specific training. 
Reference therapy 
The reference therapy is clinical rehabilitation with MS. 
Statistical 
Methodology 
Descriptive statistics will be used to describe stimulation-related 
outcomes. Repeated measures analyses of variance will be used 
to detect changes in outcomes pre- to post-ES and training. 
1 Introduction 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the procedures described in this protocol, applicable United States 
government regulations and Mayo Clinic policies and procedures. 
 
Up to 75% of patients with MS develop progressive MS, and there is no current treatment to 
halt clinical progression or axonal loss in patients with progressive MS. Progressive MS is 

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Kristin D. Zhao, Ph.D.                                                                                                                                                      CONFIDENTIAL 
 
defined by a sustained clinical worsening, typically of walking difficulties, over more than 1 
year in the absence of clinically detectable MS relapses or attacks (Thompson et al., 2018). 
Pathologically, it is characterized by axonal loss in the absence of inflammatory disease. 
Patients typically have progressive difficulty walking with associated leg spasticity and 
urinary, bowel and sexual dysfunction. 
 
Like MS, there is no cure for traumatic injury of the spinal cord which results in lifelong 
impairment of autonomic, sensory, and motor functions in regions of the body that are distal 
to the damaged areas of the spinal cord. In response to the complete lack of available 
therapies to restore volitionally-controlled lower extremity motor function, we recently 
conducted a pilot-phase clinical trial of epidural spinal electrical stimulation (ES) in 
combination with task-specific training; ES consists of an implanted stimulator and electrode 
array placed over the dura mater on the dorsal aspect of the spinal cord. ES with task-specific 
training resulted in unprecedented outcomes, such as restoration of standing and walking in 
humans previously diagnosed with complete paralysis of their lower extremities due to a 
traumatic spinal cord injury (SCI) that occurred several years prior (M. Gill et al., 2020; M. 
L. Gill et al., 2018; Grahn et al., 2017). Likewise, other research teams have shown 
remarkable improvements in spinal stimulation-enabled motor functions that are retained 
after study participation in individuals with incomplete paralysis (Wagner et al., 2018). 
Herein, we propose leveraging the knowledge and expertise gained during our previous, and 
active, clinical trials of ES in participants with paralysis to determine the translational 
potential of epidural spinal electrical stimulation (ES) for improvement of motor function and 
spasticity in patients with myelopathy due to progressive multiple sclerosis (MS). The 
following are key aspects of the proposed work: 
 
• The proposed research is a pilot study which will explore epidural spinal stimulation 
(ES) in combination with task-specific training to improve lower limb function in 10 
participants with Progressive MS. 
• We will temporarily implant percutaneous ES leads through the skin overlying the 
lumbosacral enlargement and remove the leads following the 4-week study. 
• Participants will serve as their own control via a comparison of pre- and post- 
stimulation outcomes and outcome metrics captured during ES and when ES is off. 
• Safety will be continuously evaluated during the 4-week stimulation and task specific 
training period, and during a post lead removal neurologist visit. 
• The percutaneous leads are currently used clinically and are approved for patients 
with low back pain; use in participants with MS will be possible under an FDA IDE. 
 
1.1 
Background 
Clinical Presentation of Progressive Multiple Sclerosis 
Multiple sclerosis (MS) is characterized by inflammatory central nervous system 
demyelination which can be subclinical or clinical. Clinical attacks typically manifest as 
optic neuropathy, sensory or motor myelopathy, which worsen over days to weeks and 
resolve over weeks to months. Most patients recover a significant degree of function 
following a clinical attack. Although clinical recovery occurs, persistent demyelination or 
partial remyelination of the lesion is present. The partially denuded axons redistribute 
sodium-potassium ATPase channels along the axon to compensate for the myelin loss. This 
results in increased energy expenditure, and loss of signal coherence in the remaining axons. 

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Kristin D. Zhao, Ph.D.                                                                                                                                                      CONFIDENTIAL 
 
Mitochondrial expansion is necessary within the affected axons to compensate for the 
increased energy demand. Rapid mitochondrial expansion is associated with defects in 
mitochondrial replication, which ultimately leads to energy failure in the affected axons, and 
axonal loss. The stressed neurons subsequently retract synaptic connections and disengage 
from neural networks, triggering additional metabolic stress and engagement of 
transcriptional programs that push the neurons, axons, and circuits away from homeostasis. 
Clinically, this manifests as slow worsening of walking ability in the absence of clinical 
relapses. The presence of progressive disease does not exclude the presence of inflammatory 
disease. Medications which have been approved for the treatment of progressive MS, 
exclusively treat the inflammatory component of the disease. No pharmacologic agent has 
yet been shown to prevent or reverse neuronal death and axonal loss in MS. This process 
occurs typically over decades, and appears to be an age dependent phenomenon, with the 
onset of motor progression becoming apparent in the late fifth decade. 
 
Patients typically have gradual worsening of walking with associated leg spasticity and 
urinary, bowel and sexual dysfunction. Recent work from our group has shown that 
progressive motor dysfunction in MS is most common in patients who have spinal cord 
lesions or lesions in the brainstem involving the motor tracts (Kassa et al., 2021; Keegan et 
al., 2018; Sechi et al., 2019). This can occur even in the presence of a single cord lesion, and 
in the absence of brain disease. This provides a good rationale for targeting spinal cord 
disease as a therapeutic target in patients with progressive MS. Crucially, although 
progressive MS is characterized by axonal loss, complete loss of axons in any particular tract 
is unusual, meaning that if conduction block and slowing can be overcome, there is potential 
to facilitate volitional motor function. 
 
Stimulation in MS and SCI 
Other research groups have shown benefit of transcutaneous (through the skin) lumbar 
stimulation in improving spasticity (Keegan et al., 2018), gait dysfunction (Keegan et al., 
2018), postural instability (Roberts et al., 2021), and bladder dysfunction (Kreydin et al., 
2020) in participants with MS. However continuous use of transcutaneous stimulation is 
impractical due to the delivery through the skin using an external device, and the results are 
likely to be short lived in the absence of continued stimulation. By contrast, permanently 
implanted epidural stimulation leads are widely used in clinical practice for the management 
of chronic pain. These allow for continuous stimulation which can easily be manipulated to 
optimize response through means of a remote-control device. Significant progress has been 
made in the research use of these permanent leads for spinal stimulation in participants with 
SCI, to enable motor functions previously thought to be permanently lost after SCI. 
Specifically, Harkema and colleagues reported that, after months of rehabilitation with 
permanently implanted spinal stimulators for ES, volitional control of joint-specific muscles 
and independent standing were achieved by four humans with motor complete paraplegia 
(Angeli et al., 2014; S. Harkema et al., 2011). Recently, our team reported that the same 
intervention enabled control of stepping leg movements, which over the course of 
rehabilitation, translated to independent standing and stepping (M. L. Gill et al., 2018; Grahn 
et al., 2017). 
 
Our initial case report described that our study goals were achieved within the first few 
sessions of permanent ES. To summarize, in the first study participant we enrolled, ES 

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Kristin D. Zhao, Ph.D.                                                                                                                                                      CONFIDENTIAL 
 
enabled: 1) intentional control of motor activity and leg movement; 2) standing; 3) 
intentional control of step-like movements while side lying with legs suspended in a gravity 
neutral position, and 4) intentional control of bilateral leg flexion and extension while upright 
with body weight supported by a harness. More recently, we reported that the same 
participant achieved independent standing, stepping on a treadmill while using arm support 
bars to maintain balance, and posture and over ground walking with minimal assistance (M. 
L. Gill et al., 2018). To date, the second participant demonstrated similar ES-enabled motor 
achievements. In addition to reports of ES enabling lower extremity motor functions, 
improvements in upper extremity(Lu et al., 2016), cardiovascular (Aslan et al., 2018; S. J. 
Harkema, Legg Ditterline, et al., 2018; S. J. Harkema, Wang, et al., 2018; Herrity et al., 
2018; West et al., 2018), and urologic functions (Herrity et al., 2018) have been reported in 
participants with SCI. 
 
Prior to proposing a trial to assess the use of permanently implanted epidural spinal 
stimulation in participants with progressive MS, it is pertinent to assess whether these 
individuals are responsive to stimulation using a temporary percutaneous lead used 
commonly in clinical practice for low back pain and in research for participants with 
spinal cord injury. 
 
1.2 
Investigational Device 
Abbott percutaneous trial lead for epidural 
neurostimulation (Model 3086) 
 
Ripple Nomad Neurostimulator 
 
Abbott clinician programmer (Model 3874) 
 
The temporary percutaneous implantation 
of epidural stimulation (ES) electrode leads 
along the dorsal epidural surface of the 
lumbosacral enlargement (Figure 1) will be 
performed to activate spinal networks in 
ten humans diagnosed with Progressive 
MS. The externalized ends of the ES 
electrode leads will be connected to the 
Nomad neurostimulation system. By 
delivering ES over the spinal cord during 
task-specific training for one month, we 
aim to quantify motor and non-motor improvements. 
 
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- 
Figure 1. Epidural stimulation (ES) will be 
delivered via percutaneous electrodes implanted 
over the dura mater of the lumbosacral 
enlargement. 

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Kristin D. Zhao, Ph.D.                                                                                                                                                      CONFIDENTIAL 
 
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 how ES may enable functions in humans with multiple 
sclerosis. 
 
1.4 
Study Rationale and Risk Analysis (Risks to Benefits Ratio) 
 
1.4.1 Study Rationale 
There is no cure for MS, which results in gradual loss of many functions and a significant 
reduction in quality of life. In parallel, there is no cure for traumatic injury of the spinal cord 
which results in lifelong impairment of autonomic, sensory, and motor functions in regions 
of the body that are distal to the damaged areas of the spinal cord. In response to the 
complete lack of available therapies to restore volitionally-controlled lower extremity motor 
function, we recently conducted a pilot-phase clinical trial of epidural spinal electrical 
stimulation (ES) in combination with task-specific training for individuals with complete 
SCI. Likewise, other research teams have shown remarkable improvements in spinal 
stimulation-enabled motor functions that are retained after study participation in individuals 
with incomplete paralysis (Wagner et al., 2018). Herein, we propose leveraging the 
knowledge and expertise gained during our previous, and active, clinical trials of ES in 
participants with paralysis to determine the translational potential of ES for improvement of 
motor function and spasticity in patients with myelopathy due to progressive MS. 
Completion of the proposed experiments in this protocol will provide data that can be used to 
improve the scientific understanding of how ES may enable functional improvement after 
MS onset. This knowledge will be used to help determine if ES is a viable and useful tool in 
determining which subjects may be best suited for permanently implanted ES in the future. 
 
1.4.2 Anticipated Risks 
Risks associated with task-specific training: 
In combination with 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 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. 
 
 

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Kristin D. Zhao, Ph.D.                                                                                                                                                      CONFIDENTIAL 
 
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. 
• 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 possible risk factor for subjects as well. 
 
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 electromyography 
Risks involved with EMG include skin irritation or allergic reaction from the adhesive used to 
apply sensors. 
 
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. 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 

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Kristin D. Zhao, Ph.D.                                                                                                                                                      CONFIDENTIAL 
 
is given and it is deemed safe for the subject to continue study-related activities. Because the 
interventions have been used for individuals with subjects 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, 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. 
 
1.5 
Anticipated Duration of the Clinical Investigation 
The anticipated duration of study participation for each human subject is approximately 2 
months. Subjects will receive ES and task-specific training sessions for 1 month. Electrodes 
will be removed following 1 month of sessions. 
 
2 Study Objectives 
We propose to compare motor and non-motor outcomes over the course of 1 month of ES in 
combination with task-specific training in participants with Progressive MS. 
 
2.1 Primary Objective 
The primary objective is to evaluate the effectiveness of percutaneous ES and task-specific 
training over 1 month in participants with Progressive MS to impact motor function and 
spasticity. 
 
2.2 Secondary Objective 
The secondary objective is to investigate the potential of ES and task-specific training to 
impact non-motor spinal related dysfunction in the same participants with Progressive MS. 
3 Study Design 
3.1 
General Design 
This is a pilot study that will include a total of 10 subjects with Progressive MS (EDSS 6.5). 
All subjects will complete 1 month of ES and task-specific training. Expected duration of 
subject participation is less than 2 months. Baseline assessments will be obtained prior to 
implantation and post-stimulation assessments will be obtained prior to explantation, with 
stimulation on and off. 
 
 
 
 

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Kristin D. Zhao, Ph.D.                                                                                                                                                      CONFIDENTIAL 
 
SCREENING 
BASELINE 
STIMULATION 
POST- 
STIMULATION 
STUDY END 
Assessment of 
Inclusion/Exclusi on 
criteria by study 
team 
Baseline 
Assessments 
Minimum 12 Sessions 
End Assessments 
Clinical, 
Electromyography, 
Movement 
Assessments & 
Surveys 
Stimulation + Task- 
Specific Training 
Clinical, 
Electromyography, 
Movement Assessments 
& Surveys 
No Stim 
Percutaneous 
Stimulation 
Stim on/Stim off 
1-month pre- 
enrollment 
Week 0-1 
Weeks 1-4 
Week 4-5 
 
 
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 voluntary movement assessments, gait 
analysis, and functional mobility tests to be the primary sets of endpoints used to quantify 
ES-related datasets associated with addressing the specific aims of this proposal. 
 
Secondary Study Endpoints 
Secondary endpoints include spasticity and MS Quality of Life Inventory. 
 
 
 
3.3 
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 the neurostimulator device as 
well as to those that could arise from performing the task-specific training sessions. 
Participants 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 
Pre/ 
No 
Stim
Post/ 
Stim 
ON 
and 
OFF
Outcomes
Specific Measure
wk 0
wk 1
wk 2
wk 3
wk 4
wk 4/5
Gait Analysis
EMG, Kinematics, Kinetics
X
X
Voluntary Movement
EMG, Kinematics
X
X
X
X
Spasticity
MAS, Pendulum Test
X
X
Functinal Mobility
TUG
X
X
MS Quality of Life Inventory
MSQLI
X
X
Stimulation + Task-specific 
Training
Primary
Secondary

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Kristin D. Zhao, Ph.D.                                                                                                                                                      CONFIDENTIAL
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 device, X-ray imaging will be performed. To
limit adverse events that could result from operating the device, stimulation parameters will
be selected within safe ranges as provided by the manufacturer.
4
Subject Selection, Enrollment and Withdrawal
Ten subjects with a diagnosis of Progressive MS (EDSS 6.5) will be enrolled. Subjects will
be selected based on the following criteria:
4.1
Inclusion Criteria
• Myelopathy secondary to Progressive MS
• No clinical or radiologic MS relapses for > 5 years
• EDSS score of 6.5 (constant bilateral assistance required to walk about 20 meters
without resting) as assessed by a Neurologist with a specialty in MS
• Able to ambulate 10 feet independently with or without gait aid use
• At least 21 years of age
• No changes to spasticity medications or dalfampridine over the last 3 months
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
• Spasticity (grade of 4) measured bilaterally in two muscle groups using Modified
Ashworth Scale (MAS). Muscle groups tested will include bilateral knee flexors, 
extensors; ankle plantarflexors, dorsiflexors
• Unhealed decubitus ulcer
• Unhealed skeletal fracture
• Receiving diathermy treatment
• Active participation in an interventional clinical trial
Subject 1
Screening and baseline visit
Stim + task-specific training,
post-visit
Subject 6
Subject 7
Subject 8
Subject 9
Data Analysis, Interpretation, Documentation
Subject 10
Subject 5
Subject 4
Subject 2
Subject 3
34-36
31-33
28-30
25-27
22-24
19-21
16-18
13-15
10-12
7-9
4-6
1-3
Month
Year 3
Year 2
Year 1
Study Start-up,
RegulatoryApprovals, 
Recruitment, Staff

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• Any illness or condition which, based on the research team’s assessment, will 
compromise the patient’s ability to comply with the protocol, patient safety, or the 
validity of the data collected during this study. 
• History of coagulopathy or other significant cardiac or medical risk factors for 
surgery 
• Ventilator-dependent respiration 
• Diagnosed with cardiopulmonary dysfunction (e.g., chronic obstructive pulmonary 
disease, cardiac failure, or heart arrhythmia) 
• Untreated clinical diagnosis of depression 
• History of frequent hypotension characterized by light headedness, or loss of 
consciousness 
• History of frequent hypertension characterized by headache, or bradycardia 
• Any active, implanted medical device 
• Treatment of chemodenervation and/or neurolysis during the trial, or within 6 
months of initiating the trial 
 
4.3 
Subject Recruitment, Enrollment and Screening 
We will initially recruit participants from existing resources including individuals who have 
expressed interest in clinical research through the Mayo Clinic Multiple Sclerosis Clinic, 
Mayo Clinic volunteer research participant database, Mayo Clinic clinical trials website, 
Mayo Clinic electronic medical record, and ClinicalTrials.gov. The Mayo Clinic Center for 
Multiple Sclerosis and Autoimmune Neurology (CMSAN) has prospectively enrolled over 
1000 patients with MS in an observational biorepository study. These patients are consented 
for further contact to discuss enrolment in clinical trials, such as the proposed study. In 
addition, a subspeciality MS clinic is run daily, 52 weeks per year. Patients are seen by 
neurology, physiatry, urology, ophthalmology, and neuropsychology. Mayo Clinic’s prior 
research in progressive MS, particularly in remyelinating therapies has resulted in a 
continuous stream of solicitations from candidates interested in therapy for progressive MS. 
The rate of up to four subjects enrolled annually will be easily achievable. We have 
successfully recruited individuals with similar inclusion/exclusion criteria as the proposed 
work, and we have had very successful recruitment, retention, and compliance. 
 
Prior to participating in the screening phase, a member of the research team will provide an 
explanation of the study and answer questions asked by the potential study participant. 
Participants 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 participant and the PI. A copy of the signed consent documents will be provided 
to the subject. Following informed consent, screening tests will be performed. A final 
decision on study participation will be made by the PI and study team. 
 
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. 
 

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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 explanted. If explanation surgery 
is urgent due to concern for the subject’s health, the cost of the explanation procedure will be 
covered by the research study. Aside from standard recovery, no adverse effects are 
anticipated from the removal of percutaneous electrical stimulator. 
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. 
 
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, Abbott Neuromodulation; Nomad, Ripple Neuro) 
The ES electrode lead is an implantable neurostimulation device that is FDA-approved for 
treatment of neuropathic pain disorders. Up to two ES electrode 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 to deliver electrical pulse waveforms to the epidural surface. 
 
5.2 
Method for Assigning Subjects to Treatment Groups 
Subjects will be all receive ES combined with task-specific training. 
 
5.3 
Preparation and Administration/Implantation of Investigational Device 
Description of ES system implantation/administration 
We recently published a detailed explanation of the procedure to implant a permanent 

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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. 
 
To implant the temporary spinal electrodes, under fluoroscopy an electrode insertion 
needle will be placed into the epidural space using a paramedian approach and loss of 
resistance technique to advance through 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. 
 
 
Then, the leads are advanced in an anterograde fashion to the level of the lumbosacral 
enlargement utilizing 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. One day 
post implantation, the first follow up will take place to evaluate for adverse events. Trained 

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Kristin D. Zhao, Ph.D.                                                                                                                                                      CONFIDENTIAL 
 
team members will monitor the percutaneous site on an ongoing basis during training 
session to ensure the site remains intact and sterile. Study team members have received 
training from a registered nurse within the pain specialty program at Mayo Clinic. 
 
Procedure to explant ES electrode leads 
After completing task-specific training 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 task-specific training. Participants 
will be followed up within 5 days of explantation for adverse events. They will be 
provided information for monitoring the site remotely as well. 
 
 
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. 
 
5.5 
Prior and Concomitant Therapy 
A subject’s prior therapy regimen will not impact the PI’s decision regarding enrollment into 
the study. If the subject fits the inclusion criteria and does not demonstrate any exclusion 
criteria characteristics, 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 concurrent activities. For example, if the study subject 
performed locomotor training at a local gym prior to the study, they would be asked to 
continue 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 not be blinded, and 
all participants will receive the same treatment. 
 
5.8 
Receiving, Storage, Distribution and Return 
 
5.8.1 Receipt of Investigational Devices 
The percutaneously-delivered ES electrode leads will be acquired either through purchase or 
donation from Abbott. A representative from Abbott will ship the devices to Mayo Clinic and 
will be properly inventoried prior to the scheduled date of surgical implantation. 

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Kristin D. Zhao, Ph.D.                                                                                                                                                      CONFIDENTIAL 
 
 
The Nomad neurostimulation system has been 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 
ES electrode leads will be stored within a secured surgical materials area at Mayo 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 
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. The following tests/activities will be performed to determine eligibility based 
on the inclusion/exclusion criteria listed in this document. 
• Review of available medical records 
• Neurology and Physical Medicine and Rehabilitation clinical exams 
• EDSS score evaluation 
• Pregnancy test 
• Spasticity examination 
• Evaluation of rehabilitation task ability and range of motion of impaired joints 
• Spine MRI 
• Body weight 
 
 

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6.2 
Epidural Electrical Stimulation (ES) 
Study engineers, physical therapists, and research technicians perform the device 
programming and determine maximum stimulation parameters in real time. Device operators 
have been trained by industry partners (i.e., Abbott) on device manipulation during previous 
studies utilizing the same technology in SCI patients. 
 
The surface area of each OCTRODE electrode is 0.1319 cm^2 based on manufacturer’s 
specifications. 
Based on literature, we conclude that stimulation that results in a charge density per pulse of 
no more than 30 µC/cm^2, poses no safety concerns. 
The charge density per pulse is defined by multiplying the stimulation current amplitude 
originating from an electrode by the pulse width of the stimulation pulse and dividing by the 
total electrode surface area. 
The lower limit for current amplitude per electrode that will be applied in this study is 0.1 
mA; The lower limit for the pulse width that will be applied in this study is 250 µs. 
Therefore, if we applied the lower limit stimulation amplitude of 0.1 mA, the upper limit of 
pulse width that could be selected to stay below the current density per pulse threshold per 
pulse is 39570 µs; since the manufacturing limit of the device is 1000 µs, 1000 µs will be 
selected as the pulse width upper limit for this study.  Similarly, if a stimulation pulse width 
of the stated minimum of 250 µs was selected, up to 15.8 mA could be applied to stay below 
the charge density per pulse threshold; therefore, 15.8 mA will be selected as the upper limit 
for current density in this study. No combination of parameters will be selected to drive the 
charge density per pulse over 30 µC/cm^2 (S.F Cogan et al., 2016; Mccreery et al., 1990). 
 
ES task-specific daily training 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 at least 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. At or 
near the conclusion of the training regimen, a Neurologist with a specialty in MS will 
conduct a clinical examination with stimulation turned on. 
 
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Kristin D. Zhao, Ph.D.                                                                                                                                                      CONFIDENTIAL 
 
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 either ES lead. 
 
6.3 
Period of Follow-Up after ES 
After 1 month of ES and task-specific training, each subject will be asked to complete 
follow-up assessments. 
 
6.4 
Outcome Measures 
The following outcome measures will be collected 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. 
 
 
 
Aim 1 will quantify the effect of ES and task-specific training on lower extremity motor 
function in individuals with severe lower extremity motor disability due to progressive MS 
using the primary outcomes of kinematics (movement), kinetics (forces), and 
electromyography (muscle activity, EMG) collected during gait, standing, and side lying 
motor tasks. Data will be reduced and summarized using standard biomechanical approaches, 
to quantify gait rhythm, lower extremity joint and body center of mass ranges of motion 
(during gait, standing, and side lying), and timing of muscle activations and ground reaction 
force peaks. Secondary outcomes include functional mobility assessments utilizing motion 
capture data, as well as the Timed Up and Go (TUG) test. Safety and tolerability will be 
assessed while monitoring vital signs and stimulation responsiveness during daily sessions 
and testing dates. 
 
Aim 2 will determine the impact of ES and task-specific training on non-motor spinal 
related dysfunction in individuals with severe lower extremity motor disability due to 
progressive MS using the primary outcomes of the qualitative pendulum test (Smith et al., 
2000) and the Modified Ashworth Scale to describe spasticity levels. Secondary outcomes 
will include the MS Quality of Life inventory that includes questions about bowel, bladder 
and sexual function, quality of life and pain, among others. 
 
Aim 3 will be an exploratory aim to collect electrophysiological and biomarker data that 
may help us gain a mechanistic understanding of findings in Aims 1 and 2. To assess the 
Pre/ 
No 
Stim
Post/ 
Stim 
ON 
and 
OFF
Outcomes
Specific Measure
wk 0
wk 1
wk 2
wk 3
wk 4
wk 4/5
Gait Analysis
EMG, Kinematics, Kinetics
X
X
Voluntary Movement
EMG, Kinematics
X
X
X
X
Spasticity
MAS, Pendulum Test
X
X
Functinal Mobility
TUG
X
X
MS Quality of Life Inventory
MSQLI
X
X
Stimulation + Task-specific 
Training
Primary
Secondary

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functional states of spinal connectivity, we will deliver transcutaneous electrical stimulation 
via pulses of 1 ms duration at intensities of up to 100 mA using biphasic, charge balanced 
stimulation (DS8R, Digitimer Ltd., UK). Stimulation will be delivered to the skin over the 
intra-spinous space between the spinous processes of the T10, T11, T12, L1, L2vertebrae, 
with subjects in a supine position. Evoked 
potentials will be recorded via surface EMG electrodes placed bilaterally over the rectus 
femoris, vastus lateralis, medial hamstring, tibialis anterior, medial gastrocnemius, and soleus 
muscles. We will record evoked potentials while relaxed using stimulus intensities from 1- 
100 mA at increments of 10 mA for each stimulus locationT10-L2. Stimulus intensities that 
are at the threshold for evoking motor potentials will be delivered during the following 
actions: while attempting prolonged maximal contractions of all muscles; during attempts to 
contract the left leg; and during attempts to contract the right leg. 
 
Gait analysis: Full body kinematic parameters will be acquired with a computerized video 
motion analysis system. A surface electromyography (EMG) system will be used for data 
collection. Muscle activity will be collected from all or a subset of the following lower 
extremity and trunk muscles: soleus, gastrocnemius, tibialis anterior, hamstrings, 
quadriceps, hip adductors, gluteus maximus, gluteus medius, abdominals and spinal 
extensors. Ground reaction force data will be acquired from force plates or pressure mat 
technology located in the floor or as in-shoe sensors. EMG and ground reaction force data 
will be time-synchronized with the motion cameras. 
 
Voluntary movement in side-lying and supine postures: Voluntary movement data will be 
acquired during a variety of volitional tasks including standing, and supine and side-lying 
stepping movements. Kinematics and EMG measurements will be obtained from a motion 
analysis system and surface EMG system. All or 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 and spinal 
extensors. 
 
Spasticity: One or both of the following will be used to measure lower extremity spasticity: 
the Modified Ashworth Scale (MAS) (Bohannon et al., 1987) where the subject will be 
placed in a supine position and flexor and extensor muscles are assessed according to the 
MAS protocol; and the pendulum test  which is a biomechanical method of evaluating 
muscle tone using surface-based kinematic assessments that uses gravity to provoke muscle 
stretch reflexes during passive swinging of the lower limb. 
 
Functional mobility test: The following test will be performed: Timed Up and Go (TUG) 
(Podsiadlo et al., 1991). The TUG test is used to assess a person's mobility and requires 
both static and dynamic balance. 
 
MS QOL Inventory (MSQLI): Multiple Sclerosis Quality of Life Inventory (Fischer et al., 
1999), a comprehensive outcomes assessment battery will be administered to assess many 
facets of the participants’ quality of life. Several scores, are captured, including Overall 
Health Status, Modified Fatigue Scale, Sexual Satisfaction Scale, Bladder Control Scale, 
Bowel Control Scale, Perceived Deficits Questionnaire and Mental Health Inventory. 
 

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7 Statistical Plan 
7.1 
Sample Size Determination 
Due to the pilot phase of this study, no formal power calculations were performed for this 
proposal. The number of subjects was selected based on budgetary, space, and personnel time 
constraints. Ten participants (five males; five female) will be enrolled to complete this study, 
depending on need for contingency subjects. Participants will receive 4 weeks of ES and 
serve as their own control. 
 
7.2 
Statistical Methods 
Statistical Methods: Continuous data will be summarized as median (inner quartile range). 
Categorical data will be presented as frequency (percentage). Graphical presentations of 
subject-level data will be used for all endpoints. Individual data points will be plotted over 
time, from pre to post stimulation and training. 
 
Modeling: Statistical models will be used both to estimate the ES effect on endpoints, as well 
as to provide estimates of variability to enable sample size estimation for future studies. 
Models for post-ES treatment will be fit using linear regression using the baseline measure as 
a covariate. Both the ES treatment effect and the residual variance estimate will be reported. 
Standard deviations of the differences in pre- and post-ES measurements will also be 
reported. Furthermore, correlations between pre- and post-ES assessments, as well as post 
task specific training stim-off and stim-on assessments will be calculated to aid future study 
design. Transformations of endpoints to achieve symmetry in the distribution (normality will 
be difficult to assess with this sample size) will be used as necessary. 
 
Handling of Missing Data: Due to the small sample size, sophisticated missing data 
techniques like imputation are likely to be unreliable. For all analyses, only subjects with 
complete data for the necessary analysis will be included. We will attempt to limit missing 
data by only enrolling participants who have the physical capacity to complete the training 
sessions. Only prospective enrollees who have been fully optimized from a rehabilitation 
point of view will be offered enrollment in the study. To minimize the financial burden on 
study participants and their families, they will be offered money to offset the cost of travel 
and accommodation during the study. If a study participant ends the study early, a similar 
replacement participant will be sought. Missing data in survey instruments will be minimized 
by allocating time during the study for survey completion, and inspection for completion by 
study coordinators before moving to the next component of the study. 
 
7.3 
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 most of the study visits and procedures. 
 
 
 

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8 Safety and Adverse Events 
All adverse events 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 submitted to the FDA 
and IRB according to the regulatory requirements. Expected clinical adverse events and 
nonsignificant (not serious) clinical adverse events will not be reported. 
 
8.1 
Definitions 
Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device if that effect, problem or death was not previously 
identified in nature, severity, or degree of incidence in the investigational plan or 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 subjects. 
 
Adverse Effect (Event) 
Any untoward medical occurrence in a subject involved in clinical study of an investigational 
device; regardless of the causal relationship of the problem with the device or, if applicable, 
other study related treatment(s). 
 
Associated with the investigational device: There is a reasonable possibility that the adverse 
effect may have been caused by the investigational device. 
 
Life-threatening adverse effect: Any adverse effect that places the subject, in the view of either 
the investigator or the sponsor, at immediate risk of death from the effect as it occurred. It does 
not include a reaction that, had it occurred in a more severe form, might have caused death. 
 
Serious adverse effect: An adverse effect is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
death 
• a life-threatening AE 
• inpatient hospitalization or prolongation of existing hospitalization 
• a persistent or significant disability/incapacity 
• a congenital anomaly/birth defect. 
 
Unanticipated adverse effect: Any adverse effect, the nature, specificity, severity, or frequency 
of which is not consistent with the risk information in the clinical study protocol or elsewhere in 
the current IDE application. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition. At the end of the study, any new clinically significant findings/abnormalities that meet 
the definition of an adverse event must also be recorded and documented as an adverse event. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 

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documented and reported as an unanticipated adverse device effect unless specifically instructed 
otherwise in this protocol. Any condition responsible for surgery should be documented as an 
adverse event if the condition meets the criteria for an adverse event. 
 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as 
an adverse event 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 
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained. At the last 
scheduled visit, the local investigator should instruct each subject to report, to the local 
investigator, any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study. The local investigator should 
notify the study regulatory sponsor of any death or adverse event occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this 
study. The sponsor should also be notified if the local investigator should become aware of the 
development of problems, cancer or of a congenital anomaly in a subsequently conceived 
offspring of a subject that has participated in this study. 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets all of the following three criteria: 
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 adverse experience; (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, AND 
Unanticipated: (i.e. unexpected) problems or events are those that are not already described as 
potential risks in the protocol, consent document, not listed in the Investigator’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 

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increased frequency or at an increased severity than expected, AND 
Related: A problem or event is "related" if it is possibly related to the research procedures. 
8.2 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination. Study subjects will be routinely 
questioned about adverse effects at study visits. Information on all adverse events should be 
recorded immediately in the source document, and also in the appropriate adverse event 
section of the case report form (CRF) or in a separate AE worksheet. All clearly related 
signs, symptoms, and abnormal diagnostic, laboratory or procedure results should be 
recorded in the source document. 
 
All adverse events occurring during the study period must be recorded. All observed or 
volunteered adverse effects (serious or non-serious) and abnormal test findings, regardless of 
the treatment group if applicable or suspected causal relationship to the investigational device 
or if applicable other study treatment or diagnostic product(s) will be recorded in the 
subjects’ case history. For all adverse effects 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 adverse effect and the investigational device or, if applicable other 
study treatment or diagnostic product. The clinical course of each event should be followed 
until resolution, stabilization, or until it has been ultimately determined that the study 
treatment or participation is not the probable cause. Serious adverse events that are still 
ongoing at the end of the study period must be followed up, to determine the final outcome. 
Any serious adverse event that occurs after the study period and is considered to be at least 
possibly related to the study treatment or study participation should be recorded and reported 
immediately. 
 
Causality and severity assessment 
The sponsor-investigator will promptly review documented adverse effects and abnormal test 
findings to determine 1) if the abnormal test finding should be classified as an adverse effect; 
2) if there is a reasonable possibility that the adverse effect was caused by the investigational 
device or other study treatments; and 3) if the adverse effect meets the criteria for a serious 
adverse effect. 
 
If the sponsor-investigator’s final determination of causality is “unknown and of questionable 
relationship to the investigational device or other study treatments,” the adverse effect will be 
classified as associated with the use of the investigational device or other study treatments for 
reporting purposes. If the sponsor-investigator’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 
subject’s case history. 
 
8.3 
Sponsor-Investigator Reporting of Unanticipated Adverse Device Effects and 
Unanticipated Problems 
When an adverse event has been identified, the study team will take appropriate action 
necessary to protect the study participant and then complete the Study Adverse Event 

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Worksheet and log. The sponsor-investigator will evaluate the event and determine the 
necessary follow-up and reporting required. 
 
The sponsor-investigator will promptly review documented Unanticipated Adverse Device 
Effects and as necessary shall report the results of such evaluation to FDA within 10 working 
days and Mayo IRB within 5 working days of initial notice of the effect. Thereafter the 
sponsor-investigator will submit such additional reports concerning the effect as requested. 
 
8.3.1 Sponsor-Investigator Reporting, Notifying Mayo IRB 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs 
according to the Mayo IRB Policy and Procedures. 
 
8.3.2 Sponsor-Investigator Reporting: Notifying the FDA 
The sponsor-investigator will report to the FDA all unanticipated adverse device effects 
according to the required reporting timelines, formats and regulations. 
 
The sponsor-investigator will submit a completed FDA Form 3500A to the FDA’s Center for 
Devices and Radiological Health for any observed or reported adverse effect that is 
determined to be an unanticipated adverse device effect. A copy of this completed form will 
be provided to the DSMB and all participating sub-investigators. 
 
The completed FDA Form 3500A will be submitted to the FDA as soon as possible and, in 
no event, later than 10 working days after the sponsor-investigator first receives notice of the 
adverse effect. 
 
If the results of the sponsor-investigator’s follow-up evaluation shows that an adverse effect 
that was initially determined to not constitute an unanticipated adverse device effect does, in 
fact, meet the requirements for reporting; the sponsor-investigator will submit a completed 
FDA Form 3500A as soon as possible, but in no event later than 10 working days, after the 
determination was made. 
 
For each submitted FDA Form 3500A, the sponsor-investigator will identify all previously 
submitted reports that that addressed a similar adverse effect experience and will provide an 
analysis of the significance of newly reported adverse effect in light of any previous, similar 
report(s). 
 
Subsequent to the initial submission of a completed FDA Form 3500A, the sponsor- 
investigator will submit additional information concerning the reported adverse effect as 
requested by the FDA. 
 
Reporting Process 
Unanticipated Adverse Device Effect reports will be submitted on FDA Form 3500A. 
The contact information for submitting reports is: 
 
Food and Drug Administration 
Center for Devices and Radiological Health 

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Document Mail Center - WO66-G609 
10903 New Hampshire Avenue 
Silver Spring, Maryland 20993-0002 
 
Deviations from the investigational plan. 
The sponsor-investigator shall 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 subject 
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 sponsor-investigator 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) 
also is required. 
 
8.4 
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. 
 
8.5 
Medical Monitoring 
It is the responsibility of the sponsor-investigator to oversee the safety of the study. This 
safety monitoring will include careful assessment and appropriate reporting of adverse events 
as noted above, as well as the construction and implementation of a site data and safety- 
monitoring plan (see Section 10 Auditing, Monitoring and Inspecting). Medical monitoring 
will include a regular assessment of the number and type of serious adverse events. 
 
9 Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects 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 subject revokes authorization to collect or use PHI, the investigator, by 

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regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization. For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (long term 
survival status that the subject is alive) at the end of their scheduled study period. 
 
9.2 
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, subjects’ 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, subject 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 shall match the Source Data recorded on the Source Documents. 
 
9.3 
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. 
 
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. 
 
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. 
 
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 

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other institutional systems. 
 
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 
 
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. 
 
9.4 
Records Retention 
The sponsor-investigator will maintain records and essential documents related to the 
conduct of the study. These will include subject case histories and regulatory documents. 
 
The sponsor-investigator 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. 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
The investigator will allocate adequate time for such monitoring activities. The Investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is given 
access to all the study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 
 
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 

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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 an independent 
medical monitor, a physiatrist co-director of the Mayo Clinic Rehabilitation Medicine 
Research Center. 
 
10.2 Auditing and Inspecting 
The sponsor-investigator 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 
sponsor-investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g., pharmacy, diagnostic laboratory, etc.). 
 
Participation as a sponsor-investigator in this study implies acceptance of potential inspection 
by government regulatory authorities and applicable compliance offices. 
 
11 Ethical Considerations 
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. 
 
12 Study Finances 
12.1 Funding Source 
This study will be funded by the Mayo Clinic Center for Multiple Sclerosis and 
Autoimmune Neurology. 
 
12.2 Conflict of Interest 
Any study team member who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) must 
have the conflict reviewed by a properly constituted Conflict of Interest Committee with a 
Committee-sanctioned conflict management plan that has been reviewed and approved by the 

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study sponsor-investigator prior to participation in this study. 
 
12.3 Subject Stipends or Payments 
Participants will be offered a $1,000 remuneration to be submitted at the end of the study. If they 
do not complete the study, they will be paid $55.55 per visit attended. They will also be offered 
parking passes for the Mayo Clinic lots on an ongoing basis. 
 
13 Publication Plan 
The PI holds the primary responsibility for publication of the results of this study, deciding 
authorship, and finalizing the order of authorship. If multiple manuscripts result from the 
research, authorship will be aligned with individuals’ expertise and career objectives. 
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. 
 
14 References 
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