Transcutaneous Electrical Spinal Stimulation (tSCS) for Improving Upper Limb Function in People With MS
Phase: NA
Conditions: Multiple Sclerosis
Sponsor: Parc de Salut Mar

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Transcutaneous Electrical Spinal Stimulation (tSCS) for Improving Upper Limb Function in 
People with MS 
 
Protocol Number: tSCS-MS-01 
ClinicalTrails.gov number: pending 
Investigational Product: SCONETM from SpineX 
Phase: Pilot study 
 
Short title: tSCS for MS 
Sponsor: Hospital del Mar Research Institute  
Doctor Aiguader 88 
Barcelona 08003 
SPAIN 
 
 
Protocol Version: 1.1 
Protocol Date: May 11th, 2025 
 
 
 

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Table of Contents 
1.0 TRIAL OUTLINE ........................................................................................................... 6 
2.0 TRIAL DESIGN ............................................................................................................. 9 
2.1 Trial Design ........................................................................................................................ 9 
2.2 
Trial Diagram ............................................................................................................... 9 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) ................................................................................. 9 
3.1  
Co- Primary Objective(s) & Hypothesis(es) .................................................................... 9 
3.2  
Key Secondary Objective(s) & Hypothesis(es) ............................................................. 10 
3.3.  
Exploratory endpoints ................................................................................................ 10 
3.4. Safety endpoints ............................................................................................................. 10 
4. BACKGROUND & RATIONALE ...................................................................................... 11 
4.1 
Background ............................................................................................................... 11 
4.1.1  
Therapeutic Background ............................................................................................................... 11 
 ..................................................................................................................................................................... 13 
4.2 
Rationale ................................................................................................................... 21 
4.2.1 
Rationale for the Trial and Selected Subject Population .............................................................. 21 
Current disease-modifying therapies aim to prevent the development of new lesions; unfortunately, 
there are no current FDA-approved therapies to promote Central Nervous System (CNS) repair 
mechanisms. Thus, strategies to promote functional recovery from lesion-related deficits in adults with 
multiple sclerosis remain an unmet need. This proposal seeks to remedy this significant gap in MS care.
 ..................................................................................................................................................................... 21 
4.2.2 
 Rationale for Stimulation Protocols Selection/Regimen ............................................................. 21 
4.2.3 
Rationale for Endpoints ................................................................................................................ 21 
4.3 
Benefit/Risk ............................................................................................................... 22 
5.0 METHODOLOGY........................................................................................................ 22 
5.1 
Entry Criteria ............................................................................................................. 22 
5.1.1 
Diagnosis/Condition for Entry into the Trial ................................................................................. 22 
Patients with MS (McDonald criteria 2017) with moderate to severe upper-limb disability defined as 
9HPT in the dominant hand/functional hand > 33.3 sec (range: 33.3-240 sec) ......................................... 22 
5.1.2 
Subject Inclusion Criteria .............................................................................................................. 22 
5.1.3 
Subject Exclusion Criteria .............................................................................................................. 23 
5.2 
Trial Treatment(s) ...................................................................................................... 23 
5.2.1 
 Therapeutic regimen Selection: TPS stimulation protocols......................................................... 23 
5.2.2 
 Timing of Therapeutic Regimen Administration .......................................................................... 23 
5.2.3 
Trial Blinding/Masking .................................................................................................................. 24 
5.3 
Randomization .......................................................................................................... 25 
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS). There are 2 treatment arms: stim and 
sham. Subjects will be assigned randomly in a 1:1 ratio to either tSCS or sham. ....................... 25 
5.4 
Stratification .............................................................................................................. 25 

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Randomization will be stratified by center. ............................................................................. 25 
5.5 Concomitant Treatments (Allowed) .................................................................................. 25 
5.6 
Rescue Treatments & Supportive Care ........................................................................ 25 
5.7 
Diet/Activity/Other Considerations ............................................................................ 25 
5.7.1 Diet ..................................................................................................................................................... 25 
5.7.2 
Use of Alcohol, Caffeine, and Tobacco ......................................................................................... 25 
5.7.3 
Activity .......................................................................................................................................... 25 
5.8 
Subject Withdrawal/Discontinuation Criteria .............................................................. 25 
5.9 
Subject Replacement Strategy .................................................................................... 26 
5.10 Beginning and End of the Trial......................................................................................... 26 
5.11 Clinical Criteria for Early Trial Termination ...................................................................... 26 
6.0 TRIAL FLOW CHART .................................................................................................. 26 
7.0 TRIAL PROCEDURES .................................................................................................. 27 
7.1 
Trial Procedures ......................................................................................................... 27 
7.1.1 
Administrative Procedures ........................................................................................................... 27 
7.1.2 
Clinical Procedures/Assessments ................................................................................................. 29 
7.1.3 
Laboratory Procedures/Assessments ........................................................................................... 30 
7.1.4 
Other Procedures .......................................................................................................................... 30 
7.1.5 
Visit Requirements ........................................................................................................................ 31 
7.2 
Assessing and Recording Adverse Events .................................................................... 31 
7.2.1 
Definition of an Over-treatment for this Protocol and Reporting of Over-treatment ................. 32 
7.2.2 Reporting of Pregnancy and Lactation ............................................................................................... 32 
7.2.3 
Immediate Reporting of Adverse Events ...................................................................................... 33 
7.2.4 
Evaluating Adverse Events ............................................................................................................ 34 
7.2.5 
Investigator Responsibility for Reporting Adverse Events ........................................................... 39 
8.0 STATISTICAL ANALYSIS PLAN ..................................................................................... 39 
8.1 
Statistical Analysis Plan Summary............................................................................... 39 
8.2 Responsibility for Analyses ............................................................................................... 40 
The statistical analysis of the data obtained from this study will be the responsibility of the 
Principal Investigator (Pablo Villoslada, HMar) and the biostatistician of the study (Andrew 
Humbert, UW). ...................................................................................................................... 40 
8.3 
Hypotheses ................................................................................................................ 40 
8.4 
Analysis Endpoints ..................................................................................................... 41 
8.4.1. Efficacy Endpoints ............................................................................................................................. 41 
8.4.2 
Safety Endpoints ........................................................................................................................... 41 
8.5 
Analysis Populations .................................................................................................. 42 
8.5.1 
Safety Analysis Population ............................................................................................................ 42 
8.6 
Statistical Methods .................................................................................................... 42 
8.6.1 
Summaries of Baseline Characteristics, Demographics, and Other Analyses .............................. 43 
8.6.1.1 
Demographic and Baseline Characteristics .............................................................................. 43 
8.7 
Interim Analysis ......................................................................................................... 43 

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8.8 
Multiplicity ................................................................................................................ 43 
8.9 
Sample Size and Power Calculations ........................................................................... 43 
8.10 Subgroup Analyses ......................................................................................................... 43 
8.11 Compliance (Treatment Adherence) ................................................................................ 43 
8.12 Extent of Exposure.......................................................................................................... 44 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ..................... 44 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS ......................................................... 44 
10.1 Confidentiality ................................................................................................................ 44 
10.1.1 Confidentiality of Data ..................................................................................................................... 44 
10.1.2 Confidentiality of Subject Records ................................................................................................... 44 
10.1.3 Confidentiality of Investigator Information ..................................................................................... 44 
10.1.4 Confidentiality of Ethics Committee Information ............................................................................ 45 
10.2 Compliance with Financial Disclosure Requirements........................................................ 45 
10.3 Compliance with Law, Audit and Debarment ................................................................... 45 
10.4 Compliance with Trial Registration and Results Posting Requirements ............................. 46 
10.5 Quality Management System .......................................................................................... 46 
10.6 Data Management .......................................................................................................... 47 
10.7 Publications.................................................................................................................... 47 
11. LIST OF REFERENCES ................................................................................................. 48 
12. APPENDICES ............................................................................................................. 53 
12.1. List of Abbreviations and Definition of Terms ................................................................. 53 
12.2. MS Diagnosis criteria ..................................................................................................... 55 
12.3 General Neurological Exam ............................................................................................. 56 
12.4 Predefined Limits of Change Criteria ............................................................................... 59 
12.5 Mapping Between the 11 Categories of Suicidal Ideation and Behavior, the CSSRS, and CDR 
for Programming Standard Tables .......................................................................................... 56 
13.0 SIGNATURES ........................................................................................................... 60 
13.1 Investigator .................................................................................................................... 60 
 
 
 

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LIST OF TABLES 
   
Table 1 Discontinuation Scenarios .......................................................................................... 26 
Table 2  Trial flow chart .......................................................................................................... 26 
Table 3 Evaluating Adverse Events ......................................................................................... 35 
Table 4  Statistical analysis plan .............................................................................................. 39 
Table 5 Analysis Strategy for Safety Parameters .................................................................... 42 
 
 

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1.0 TRIAL OUTLINE 
 
Study Title 
Transcutaneous Electrical Spinal Stimulation (tSCS) for Improving 
Upper Limb Function in People with MS 
Study Registration 
TBD 
Study Category  
Interventional 
Phase 
Pilot study  
Background & 
Rationale 
The ability to efficiently use their hands is critical for maintaining 
activities of daily living (ADLs), a crucial unmet need for people with 
MS (PwMS). Recent clinical trials in patients with spinal cord injury 
have shown excellent safety and provided evidence of efficacy that 
tSCS associated with occupational therapy can improve the upper 
limb (UL) function and the ability to perform ADLs. Therefore, we 
propose to test the efficacy of tSCS in a pilot study in PwMS with 
moderate to severe UL disability. 
Study Design 
Double-blind, parallel, randomized, two arms, sham-controlled 
study in patients with MS and with significant disability of the upper 
limbs treated with tSCS and occupational therapy 
Objective(s) 
To assess the safety and efficacy of tSCS as add-on to standard 
rehabilitation in MS patients with moderate to severe UL disability 
Outcome(s) 
1. Primary endpoint: differences in the nine-hole peg test (9-HPT) 
affected hand in the tSCS treated vs. sham groups by the end of 
treatment (V3 vs V5) 
Secondary endpoints: 
2. Percentage of responders: 20% difference on the 9HPTd (minimal 
clinically important difference (MCID)) from baseline to end of the 
study 
3. Change in the 9HPT dominant and non-dominant hand from 
baseline to end of the study 
4. Change in the Action Research Arm Test (ARAT) from baseline to 
end of the study 
5. Change in the modified Ashworth Scale (mAS) for spasticity 
assessment from baseline to end of the study 
6. Hand strength measured by Grip and Pinch force dynameters 
from baseline to end of the study 
7. Change in the NeuroQOL Upper Extremity function from baseline 
to end of the study 
8. Change in the Modified Fatigue Impact Scale (MFIS) from baseline 
to end of the study 

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9. Change in Global Impression of change (GIC) from baseline to end 
of the study 
Safety and Tolerability 
1. 
presence of serious adverse events  
2. 
Retention rate 
3. 
% sessions attended 
Inclusion / 
Exclusion Criteria 
Inclusion: Patients with MS and moderate to severe UL disability 
defined as 9HPT affected hand ≥ 33.4 sec; 21 to 65 years old  
Exclusion: patients with relevant comorbidities, pacemakers or 
metal implants 
Measurements & 
Procedures 
1. tSCS 
2. Occupational Therapy 
3. Clinical scales and PROs 
Study Product / 
Intervention 
tSCS is a non-invasive electric stimulation system that has shown 
good tolerability and signs of efficacy for improving UL disability 
Controls 
Sham (fictitious stimulation) will be used as control arm 
Number of 
Participants & 
Rationale 
N=60 (30:30) 
Rationale: accepting an alpha risk of 0.05 and a beta risk of 0.1 in a 
two-sided test, 10 subjects are necessary in each group to recognize 
as statistically significant a minimum difference of 10 units on the 
9HPT scale between any pair of groups assuming that 2 groups 
exist. The common deviation is assumed to be 5.5. It has been 
anticipated a drop-out rate of 10%. 
Study Duration: 
24 months 
6 months recruitment, 9 months randomized phase, 6 months OLE, 
3-month analysis and clinical scientific report 
Timelines: 
● First Patient First Visit (FPFV): January 1st, 2025 
● Last Patient Last Visit (LPLV):  December 30th 2026 
Study Schedule: 
Patients in Spain are recruited from the three MS centers (Hospital 
del Mar, Hospital Clínic and Hospital Sant Pau) in Barcelona and 
treated in a single therapy center at Hospital del Mar located closely 
to all of them. Patients in the Netherlands are recruited at the 
Rijndam center, Erasmus Medical Center. 
Run-in period (6 weeks with occupational therapy) 
Double-Blinded period: 6 weeks for safety and efficacy assessments 

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A list of abbreviations used in this document can be found in Appendix 12.3. 
 
 
Open Label Extension (6 weeks) for safety and durability of efficacy 
Study Center: 
Hospital del Mar (HMar); Hospital Clinic of Barcelona (HCB); 
Hospital Sant Pau (HSP), all in Barcelona, Spain; Rijndam center, 
Erasmus Medical Center (EMC) 
Statistical Analysis 
Plan 
The primary and secondary endpoints will be assessed using linear 
mixed-effects models (LME). These models will include the outcome 
measure as the dependent variable, and treatment group, time, and 
their interaction as independent variables, with random intercepts 
for participant and site to account for the longitudinal and clustered 
nature of the data. 
Populations : 1) Intention to treat population; 2) Per protocol 
population: patients that completed 70% of the therapeutic 
sessions 

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2.0 TRIAL DESIGN 
2.1 Trial Design 
This is a double-blinded, parallel, sham-controlled study in PwMS and with significant 
disability of the upper limb (UL). Participants are exposed to a 6-week run-in period with 
standard occupational therapy and then randomized to 6 weeks of tSCS or sham combined 
with ongoing occupational therapy. After completion of the double-blind period, sham-
treatment participants will be offered an additional 6 weeks open-label extension (OLE) 
where they receive active tSCS combined with occupational therapy.  Participants in the 
original active group will be followed with no additional stimulation or occupational therapy 
to assess the durability of effects. The duration of the run-in, active treatment and 
extended follow (6 weeks each) are defined based in the previous results from a similar 
therapy for SCI.  
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures. 
2.2 
Trial Diagram 
The trial design is depicted in Figure 1.  
 
 
 
Figure 1 Trial Design Diagram 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1  
Co- Primary Objective(s) & Hypothesis(es) 
Objectives: 
• Objective 1. To assess the safety and tolerability of tSCS in PwMS. 
• Objective 2. To assess the preliminary efficacy of tSCS on relevant clinical endpoints for 
PwMS, including patient-reported outcomes. This will be assessed by the differences in the 

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nine-hole peg test (9-HPT) affected hand in the tSCS treated vs. sham groups by the end of 
treatment (V3 vs V5) 
Hypothesis: 
We hypothesize that cervical tSCS combined with therapy will be tolerable and feasible in 
PwMS and enhance functional recovery of the upper extremity when compared to 
occupational therapy alone. 
 
3.2  
Key Secondary Objective(s) & Hypothesis(es) 
Objectives:  
 
1. Percentage of responders: 20% difference on the 9HPTd (minimal clinically important difference 
(MCID)) from baseline to end of the study 
2. Change in the 9HPT dominant and non-dominant hand from baseline to end of the study 
3. Change in the Action Research Arm Test (ARAT) from baseline to end of the study 
4. Change in the modified Ashworth Scale (mAS) for spasticity assessment from baseline to end of 
the study 
5. Hand strength measured by Grip and Pinch force dynameters from baseline to end of the study 
6. Change in the NeuroQOL Upper Extremity function from baseline to end of the study 
7. Change in the Modified Fatigue Impact Scale (MFIS) from baseline to end of the study 
8. Change in Global Impression of change (GIC) from baseline to end of the study 
Hypothesis: Our hypothesis is that tSCS treatment of the cervical cord combined with 
occupational therapy is safe and efficacious for treating people with MS with moderate to 
severe upper limb (hands) disability. Recent multi-site clinical trials in patients with spinal 
cord injury (SCI) have shown excellent safety and efficacy of tSCS associated with 
occupational therapy to improve UL functioning (NCT04697472). Therefore, this relevant 
evidence support moving this therapy directly to people with MS (PwMS) with moderate to 
severe UL disability. 
 
3.3.  
Exploratory endpoints 
None 
Hypothesis: NA 
 
3.4. Safety endpoints 
Safety and Tolerability Objectives: 
1. Adverse Events (AEs) and Serious Adverse Events (SAEs): 
All adverse events, regardless of severity or relatedness to the intervention, will be 
collected and documented throughout the study period. This includes both serious 
and non-serious adverse events. Serious adverse events will be defined according to 
ICH-GCP guidelines as any event that results in death, is life-threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, or a congenital anomaly/birth defect. 

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2. Discontinuations and Reasons for Discontinuation: 
Participant retention will be assessed by monitoring the number of participants who 
discontinue the study prior to its completion. The reasons for discontinuation (e.g., 
adverse events, lack of efficacy, personal decision, protocol deviations) will be 
recorded systematically. 
3. Retention Rate: 
The retention rate will be defined as the percentage of participants who complete 
the study intervention and all study visits relative to the total number of participants 
initially randomized. 
4. Attendance Rate: 
The percentage of scheduled intervention sessions that each participant attends will 
be recorded to assess adherence and tolerability. 
Hypothesis: We hypothesize that tSCS will be safe and well tolerated in PwMS, with a low 
incidence of serious adverse events and a high retention rate. 
 
4. BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1  Therapeutic Background 
Multiple sclerosis (MS) is a relapsing 
and/or progressive disease 
characterized by lesions comprised of 
demyelination and axonal loss 
throughout the brain and/or spinal 
cord1. Current disease-modifying 
therapies aim to prevent the 
development of new lesions; 
unfortunately, there are no current 
FDA-approved therapies to promote 
Central Nervous System (CNS) repair 
mechanisms. Thus, strategies to 
promote functional recovery from 
lesion-related deficits in adults with 
multiple sclerosis remain an unmet 
need. 
Electrical spinal cord stimulation is a 
neuromodulation technique that has 
been used to amplify sensorimotor recovery after a wide variety of CNS disorders, including 
MS, traumatic spinal cord injury (SCI), cerebral palsy, dystonia, stroke, and traumatic brain 
injury2. Historically, implantable epidural electrical stimulators were used, but despite initial 
promising results, the requirement of surgically implantable hardware and lack of 
understanding of the mechanism of action limited its use3. Most recently, however, we 
Figure 2:  Transcutaneous electrical spinal stimulation is applied to 
the skin surface over the cervical spinal cord.  In our preliminary 
studies of a person with MS, and our extensive studies of people 
with chronic spinal cord injury, this transcutaneous spinal 
stimulation substantially improves hand strength and function. 
Transcutaneous Spinal 
Stimulation 

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have helped to pioneer new methods of non-invasive transcutaneous spinal cord 
stimulation4, 5 (tSCS; Figure 2).  
 
 
 
 
 
 
We are using a 10 kHz overlapping frequency to 
apply skin-surface stimulation (Figure 3). This 
high-frequency waveform allows the application 
of 5-fold greater stimulation intensities through 
the skin 6-8, which effectively reaches the spinal cord without causing discomfort4-7, 9. Thus, 
tSCS now permits administration of effective and well-tolerated, high stimulation intensities 
via removable electrodes placed on the skin over the vertebrae. While our tSCS protocols 
are less spatially specific than implanted epidural stimulation, both activate the dorsal 
sensory roots as they enter the spinal cord3, 10-12. Activation of sensory afferent fibers 
provides direct excitation of motor neurons via mono-and poly-synaptic reflexes to improve 
strength and function4-6, 9.  Stimulation likely also activates ascending sensory and other 
interneuron structures within the spinal cord to improve sensation and reduce spasticity 
without the need for surgical implantation5, 6.  
We have demonstrated that our method of tSCS is well-tolerated and promotes significant 
and meaningful recovery of upper extremity function after chronic traumatic spinal cord 
injury4, 6, 13-15.  For example, a prospective, open-label cross-over studies showed that non-
invasive tSCS combined with functional task training improved upper extremity function in 
adults with SCI compared to functional task training alone, even after motor complete 
injury, and when administered up to 12 years after initial injury (Figure 4)4.  
Figure 3: Transcutaneous spinal stimulation 
applied via electrodes placed above and below a 
cervical spinal injury. A 10 kHz carrier frequency 
fills the 1ms stimulus pulses delivered at 30 Hz, 
allowing 5-fold more current to be delivered to the 
skin over the spinal cord and improve hand 
function. 

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Strikingly, these gains were maintained for all 6 participants at least 3-6 months beyond 
stimulation, as long as could be measured. Also notable was the finding that benefits from 
this study extended beyond hand function, as some participants noted improvements in 
bladder function and reduction in spasticity. Improvements in psychological well-being, and 
self-care scores were also captured. 
 
Figure 4. tSCS improves strength and function in 60 people with SCI. Our pivotal of tSCS began with 8 weeks 
of therapy alone (grey data points and lines), followed by 8 weeks of transcutaneous spinal stimulation 
combined with therapy (red data points and lines). While participants either reached a plateau or showed no 
improvement with therapy alone, subsequent tSCS led to significant improvements in strength and sensation, 
with 90% of participants improving in strength or function outcomes. Strength measures included ISNCSCI 
Figure 4:  Stimulation improved hand and 
arm function, which was sustained for 3-6 
months in participants with cervical 
spinal cord injury. All six participants 
improved hand function during 
transcutaneous stimulation paired with 
training. Stimulation combined with 
training led to greater improvements than 
training alone in bilateral (A) pinch force, 
(B) Graded Redefined Assessment of 
Strength, Sensation and Prehension 
(GRASSP test), and (C) GRASSP 
quantitative prehension. Improvements 
that occurred during stimulation paired 
with training were maintained for at least 
3 to 6 months of follow-up.   *: p < 0.05; 
NS: p > 0.05. 

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Upper Extremity Motor Score (UEMS), hand grasp force, and finger-tip pinch force. Sensory outcomes were 
ISNCSCI Sensory Score, Upper Extremity Sensory Score (UESS) and monofilament finger-tip sensation in the 
GRASSP test.  
We then led a pivotal, multi-site trial of 60 participants with traumatic SCI and 
demonstrated the safety and efficacy of tSCS for arm and hand function in chronic 
tetraplegia5 (Figure 4). Following 8 weeks of tSCS combined with hand therapy, 90% of 
participants improved in either strength or function outcomes. Seventy-two percent of 
participants improved in both strength and function (the primary endpoint). Sensation also 
improved following tSCS by more than 9 points on the gold-standard clinical ISNCSCI total 
sensory score, compared to an equal number of sessions of therapy alone. These results are 
currently under review by the FDA following a do-novo submission by ONWARD Medical, 
for potential device approval in early 2024. 
We are beginning to test tSCS for people with multiple sclerosis (PwMS) and observing 
impressive results in our first participant (see preliminary data below). Although the lesions 
in MS are distributed throughout the brain and spinal cord, there is strong evidence to 
suggest that spinal stimulation, and tSCS in particular, will be similarly effective for PwMS as 
those with SCI4-7, 9, 16, stroke17, and children with cerebral palsy18-20, based on the 
mechanisms of action of tSCS. 
Evidence is accumulating that the combination of tSCS and intensive functional task training 
(therapy) promotes recovery via the following mechanisms (outlined in Figure 5). tSCS 
directly activates sensory afferent pathways via the dorsal or posterior spinal roots3, 10-12. 
Sensory afferent activation then provides trans-synaptic, sub-threshold excitatory input to 
the lower motor neurons within the spinal cord21. This sub-threshold input is believed to 
raise the motor neuron’s baseline level of excitability, which allows spinal cord motor 
neuron pools to be activated by the remaining, but weak, descending motor pathways from 
the brain22. Thus, by raising the lower motor neuron’s level of excitability to a sufficient 
sub-threshold level, descending volitional control of movement can be restored23. 
Continued active participation in rehabilitation training can then promote further 
reorganization of the spinal networks and strengthen the remaining intact but weak 
synaptic connections24-26.  

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The mechanisms of tSCS suggest it may be very effective for persons with multiple sclerosis. 
Multiple Sclerosis (MS) is a chronic, inflammatory demyelinating condition characterized by 
multiple lesions disseminated throughout the brain and spinal cord. Thus, weakness may 
occur due to inadequate motor output from the brain, similar to stroke and cerebral palsy. 
Weakness in MS may also result from axon conduction failure in signals passing through the 
spinal cord, as in spinal cord injury.  
There are notable similarities between MS and SCI as well as dissimilarities. Chronic spinal 
cord lesions in each condition are characterized by demyelination, axonal loss, and 
chronically activated microglia27, 28. The list of resulting symptoms and functional 
impairments are remarkably similar: motor weakness, sensory impairment, spasticity, 
neuropathic pain, and neurogenic bowel/bladder are highly prevalent in both conditions29, 
30. Therefore, similar to SCI, we hypothesize that spinal stimulation in people with MS has 
the potential to bring lower motor neurons closer to the threshold, allowing weak but 
descending input from the brain to initiate movement (Figure 5).  
Although most of the research on SCS has been conducted in humans, the beneficial effect 
of tSCS in animal models of SCI and MS has also been demonstrated. SCS has shown the 
ability to restore the functioning of spinal cord circuits that were disconnected from central 
control with functional (locomotor and pain reduction) improvements in the animals31-34. In 
experimental autoimmune encephalomyelitis, SCS reduces CNS inflammation35 and 
promotes the release of neuroprotective genes such as BDNF36.  
Although transcutaneous spinal cord stimulation has not been well-studied in PwMS, 
electric stimulation has been applied peripherally to the nerve supply of weak muscles (e.g., 
foot extensors) to restore function and prevent muscle atrophy in PwMS37-39. Existing data 
Figure 5. A schematic of the mechanism by which spinal cord stimulation enables voluntary movement after 
damage to descending motor tracts from SCI or MS. 1. In the intact nervous system, a voluntary effort can readily 
elevate the level of excitability of the lower motor neuron to exceed the motor threshold and activate a muscle 
contraction; 2. Following nervous system injury or demyelination, descending motor tracts from the brain are less 
effective in allowing an individual to initiate movement. There is some electrical activity from remaining intact fibers, 
but the level of excitability is insufficient to reach motor threshold. Hence, no movement occurs; 3. In the case of 
nervous system injury or demyelination + electrical stimulation, spinal stimulation raises the level of excitability to a 
sub-threshold level; this can enable the weak but remaining descending input from the brain to exceed the motor 
threshold. Voluntary movement is restored and enables participation in therapy which leads to further neuroplasticity.  

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on epidural spinal cord stimulation in MS also shows promise: a 2021 systematic review 
concluded that spinal cord stimulation was likely efficacious for MS-related motor 
impairment, neuropathic pain, and neurogenic bladder, although all available studies used 
only surgically implanted devices and were only retrospective in nature40.  
Less is known about the efficacy of transcutaneous SCS in MS, which highlights the novelty 
of our proposal. One prior study demonstrated that the application of single-session 
transcutaneous lumbar spinal cord stimulation without therapy is feasible in MS and 
demonstrated short-term improvements in mobility, postural control and spasticity41. An 
important proof-of-concept study in MS, functional gains from this single session of 
transcutaneous lumbar spinal cord stimulation lasted 2 hours post-intervention.  
To our knowledge, the proposed study will be the first to investigate the ability of repeated 
transcutaneous cervical spinal cord stimulation combined with occupational therapy on 
longer-term recovery of upper extremity function, which is identified as a high priority by 
the MS community42, 43.  
An alternative to electrical spinal cord stimulation is transcranial magnetic stimulation 
(TMS), which has shown some promise in PwMS44. Here, however, we propose to use tSCS 
instead of TMS based on the wider efficacy demonstrated in SCI by tSCS, the latest 
improvement of the tSCS technology to non-invasively activate the spinal cord without pain 
or discomfort. We believe that the direct effects of spinal cord electric stimulation on 
sensory axons which in turn enable movement is the ideal treatment for PwMS, given their 
partial preservation of  cortical and spinal cord circuits. Our encouraging preliminary data, 
combined with the demonstrated safety and efficacy of tSCS in SCI, compels us to test non-
invasive spinal stimulation as a treatment to improve hand function for PwMS.   
This application aims to conduct a pilot clinical trial to demonstrate the safety and 
preliminary efficacy of tSCS and to inform the design of pivotal trials aimed at obtaining 
regulatory approval for the indication of treating people with MS with moderate to severe 
upper limb disability. We model this approach after our recent proof-of-concept4, 6 and 
then multi-site clinical trial 5 in people with SCI where we have demonstrated the safety 
and efficacy of tSCS combined with intensive occupational therapy to improve upper 
extremity functioning  The results of this pivotal trial, combined with our strong preliminary 
data, supports moving this therapy directly to PwMS with moderate to severe upper limb 
disability. 
 
Preliminary Results 
Preliminary data from a participant with secondary progressive MS, EDSS 8.0 (indicating 
high baseline disability) provides confidence that transcutaneous spinal cord stimulation will 
benefit patients with MS. This participant required caregiver assistance for many activities 
of daily living (ADLs), including transfers, dressing, grooming, bathing and feeding, due to 
bilateral (left>right) upper extremity weakness. Prior to enrollment in our preliminary study, 
this participant had been working with a local occupational therapist but had transitioned to 
monthly maintenance therapy visits after reaching a plateau in functional recovery.  

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17 
Upon enrollment in our study, this participant with MS underwent two assessment visits 
one week apart, during which their baseline function was assessed. Subsequently, they 
completed 10 intervention visits consisting of transcutaneous spinal cord stimulation (tSCS) 
combined with 
occupational 
therapy for hand 
and arm function as 
previously 
described1.  
Treatments 
occurred 3 times per 
week for 60-minutes 
each session. 
 
Following 10 visits 
tSCS and 
occupational 
therapy, the 
participant 
improved 
substantially in hand 
strength, upper extremity function, and spasticity. Specifically, grip force, lateral pinch 
force, and tip pinch force increased by 55-100% in both hands due to the intervention 
(Figure 6 and 7).  
 
Due to muscle weakness and spasticity, this participant's gross upper limb movements, 
coordination, and finger opening were severely restricted. The hand and arm function and 
dexterity progressively improved throughout 10 sessions of tSCS combined with hand and 
arm therapy (Figure 7). 
 
Figure 7. Starting from the very first 
session, tSCS combined with hand and 
arm therapy gradually enhanced gross 
upper extremity movements, pinch 
and grip performance, and hand 
dexterity.  
From left to right, (a) limited movement 
and dexterity at baseline/first few 
sessions and (b) gradual improvement 
in right upper limb coordination; left 
gross manual dexterity; and left arm 
range of motion; and reduction in left 
flexor spasticity by tSCS combined with 
therapy. 
 
Figure 6. Transcutaneous spinal cord stimulation (tSCS) + occupational therapy 
led to notable improvements in strength. The average improvement of grip force in 
the right and left hand were 55%, lateral pinch force was 86%, and tip pinch force was 
100% following 10 intervention sessions. Grip force, lateral pinch force, and tip pinch 
force were measured by precise digital dynamometers. 
Figure 7. Patient with SPMS hand performance before (A) and after (B) tSCS therapy. 

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18 
 
 
These hand strength gains were mirrored by improvements in upper extremity function 
measured by the Action Research Arm Test, a measure of upper extremity coordination, 
dexterity, and functioning2, 9-Hole Peg Test (9HPT), a measure of finger dexterity3, and Box 
& Blocks Test, a measure of gross manual dexterity4 (Figure 8). 
Note that due to fatigue and physical limitations, this participant was unable to complete 
the 9HPT, and therefore their score is recorded as the total number of pegs placed in 90 
seconds. This reflects the participant’s significant baseline disability. Even their left upper 
extremity, which was more severely impaired at baseline, demonstrated gains following as 
few as 10 tSCS intervention sessions. At baseline, the participant was unable to transfer any 
blocks during the Box & Blocks test or place any pegs during 9HPT with their left upper limb; 
however, after 10 intervention sessions, they developed the ability to independently 
perform these tasks using their left upper extremity. Importantly, the intervention also led 
to subjective improvements in upper extremity function, as evidence by increased scores on 
the Quality of Life in Neurological Disorders (NeuroQoL) Upper Extremity Function Short 
Form Questionnaire5 (Figure 8d), a patient-reported outcome developed with support from 
the National Institute of Neurologic Disorders and Stroke to assess health-related quality of 
life in individuals with neurologic conditions, including MS. 
The participant also experienced a reduction in spasticity following only 10 sessions of tSCS 
+ hand therapy (Figure 9). The Modified Ashworth Scale score evaluates spasticity in 16 
Figure 8. Dexterity, functional movement capacity, and coordination of the upper extremities showed rapid 
and clinically meaningful improvements after 10 sessions with Transcutaneous Spinal Cord Stimulation 
(tSCS) combined with occupational therapy. The functionality of the hand and arm were tested by the Action 
Research Arm Test (ARAT, a measure of upper extremity coordination, dexterity, and functioning), 9-Hole Peg Test 
(a measure of finger dexterity), and Box & Blocks Test (a measure of gross manual dexterity Our participant showed 
an improvement exceeding the 15-20% threshold. While the MCID for the ARAT and Box and Blocks Test has not 
been established for MS. Notably, our participant's improvements in both tests surpassed these benchmarks by only 
10 sessions with tSCS. Patient-reported upper extremity function was also captured by Quality of Life in 
Neurological Disorders (NeuroQoL) Upper Extremity Function Questionnaire (a self-report of health-related quality of 
life in for adults with neurological disorders).  

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19 
joint movements of the upper extremities. Muscle resistance during each movement is 
scored on a scale of 0-4, where 0 is not spasticity, and 4 is complete rigidity. For simplicity of 
presentation, we sum the scores for all 16 movement, for a range of 0-64 points1 . We 
observed a 3-6 point reduction in spasticity in both upper limbs (Figure 8). The participant 
reported that reduced spasticity led to improvement in daily activities and a reduction in 
their spasticity-related shoulder pain. 
Most importantly, all outcomes were measured in the absence of tSCS.  Therefore, the 
measured functional gains persisted after only 10 sessions of tSCS, suggesting they will 
easily translate to better function during daily activities outside of stimulation and 
therapy sessions.   
In addition to the above improvements, the participant reported high satisfaction with the 
treatment, and felt sessions were 
painless and easy to tolerate (figure 10).  
After the 10 intervention sessions were completed, the participant provided the following 
positive feedback: 
 “My left hand was curled all the time before I started stimulation sessions. 
Now, I am able to extend my fingers without needing a stretch.” 
“My left shoulder was bothering me a lot. Now, the pain is gone, which is a 
big benefit of spinal cord stimulation.” 
Figure 10. Participant found transcutaneous spinal cord stimulation tolerable, painless, and highly 
satisfactory. Participant answered the acceptability of intervention questionnaire after 10 sessions of therapy + 
transcutaneous spinal cord stimulation. The questionnaire consisted of 7 questions relating to tolerability and 
acceptability of the intervention, answered on a Likert scale, as shown above. 
Figure 9. Notable reduction in upper 
extremity spasticity facilitated the participant’s 
daily activities and alleviated their spasticity-
related shoulder pain. Lower scores indicate 
less spasticity/better outcome. MAS; Modified 
Ashworth Scale. 

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20 
“I can raise my right arm much easier than before and can touch the top of 
my head now, which was not possible before. I can also raise and extend my 
left arm higher than before.” 
  
Positive feedback was also noted by the participant’s local occupational therapist post-
intervention. Throughout the pilot trial, the participant did not participate in any sessions 
with this local therapist. However, after the pilot trial intervention was completed, this local 
therapist (who had no connection to the study or study team) re-evaluated this participant 
and noted the following positive effects: 
“ (the participant) demonstrated significant improvement in functional use of 
right hand today, as well as ADL and progress towards goals. She also 
demonstrates gains in psychological wellness, including motivation, initiation 
and self-efficacy.”  
 
We are very encouraged by the significant gains after only 10 intervention sessions in this 
participant and anticipate continued improvement with further sessions. Importantly, these 
gains were seen in a participant who had been undergoing occupational therapy (without 
tSCS) in the community but who had plateaued in their progress. The proposed randomized 
clinical trial is needed to rigorously test whether tSCS combined with therapy can lead to 
functional gains when directly compared to occupational therapy alone in PwMS.  
 

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21 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Current disease-modifying therapies aim to prevent the development of new lesions; 
unfortunately, there are no current FDA-approved therapies to promote Central Nervous 
System (CNS) repair mechanisms. Thus, strategies to promote functional recovery from 
lesion-related deficits in adults with multiple sclerosis remain an unmet need. This proposal 
seeks to remedy this significant gap in MS care. 
4.2.2  Rationale for Stimulation Protocols Selection/Regimen 
The tSCS non-invasive spinal stimulation utilizes two modulated frequencies: (1) base 
frequency and (2) overlapping frequency. The base frequency is 30 Hz, whereby 1ms pulses 
are delivered 30 times per second Figure 12 right).  Within each pulse, an overlapping 
frequency of 10kHz is deployed to permit about 5-fold more current to be delivered for the 
same level of cutaneous sensation under the electrodes. This 10 kHz overlapping frequency 
is adapted from kilohertz-frequency muscle stimulation, permitting high-amplitude 
stimulation on the skin surface without discomfort. Thus, stimulation applied on the surface 
of the skin can reach the spinal cord dorsal roots to activate spinal networks. The rationale 
for the 10 kHz overlapping frequency is that high-frequency waveforms can selectively block 
unmyelinated C-fibers in the skin50, 51, and stimulation may penetrate more deeply due to 
the lowering of the tissue impedance 4, 6, 52. We have observed substantial improvements in 
hand and arm function without inducing discomfort under the electrodes in our studies of 
more than 70 people with spinal cord injury4-6. 
4.2.2.1 Rationale for the Use of Sham 
In order to assess the efficacy of the therapy in clinical outcomes, comparison between 
active and sham treatment is required. Using sham or placebo for 6 weeks is accepted for 
patients with MS. In order to encourage participation and fulfill patients’ expectations, 
sham treated patients will be offered an additional 6 weeks open-label extension (OLE) 
where they receive active tSCS combined with occupational therapy. 
4.2.2.2 Rationale for Healthy Control 
No healthy control group is required. 
4.2.2.2  
Starting Stimulation Protocols for This Trial 
The base frequency is 30 Hz, whereby 1ms pulses are delivered 30 times per second Figure 
12 right).  Within each pulse, an overlapping frequency of 10kHz is deployed to permit 
about 5-fold more current to be delivered for the same level of cutaneous sensation under 
the electrodes. 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
Primary endpoints: the 9HPT is the accepted outcome for UL assessment in MS. 
Secondary endpoints: In addition to the 9HPT, the ARAT, MAS, NeuroQOL, MFIS, and GIC 
are standard scales used in patients with MS 
 
4.2.3.2 Safety Endpoints 
The safety and tolerability of tSCS will be assessed throughout the study via Adverse Event 
reporting, and vital signs will be assessed at every trial visit.  

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22 
4.3 
Benefit/Risk 
Participants in this study are patients with MS with severe disability involving UL (and most 
likely with severe lower limb disability, being restricted to a wheelchair) or having 
significant ambulation limitations). tSCS is not invasive, is well tolerated and is a minimal-
risk device. As a result, the risk/benefit should be highly beneficial for the participants. 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Patients with MS (McDonald criteria 2017) with moderate to severe upper-limb disability 
defined as 9HPT in the dominant hand/functional hand > 33.3 sec (range: 33.3-240 sec) 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be between 21 to 65 years of age (inclusive) on the day of signing informed consent.  
2. Have MS (McDonald criteria 2017) with moderate to severe upper-limb disability 
defined as 9HPT in the dominant hand/functional hand > 33.3 sec (range: 33.3-240 
sec) 
3. Any type of disease modifying therapy is allowed and should be stable in the last 3 
months. 
4. Not having received corticosteroids previous month. 
5. Each subject must sign the informed consent form, in accordance with local 
requirements, after the scope and nature of the investigation have been explained 
to the subject, and before Screening assessments. 
6. Based on the investigator's judgment, the subject should: 
a. Be able to speak, read, and understand the language of the trial staff and the 
informed consent form; 
b. Possess the ability to respond verbally to questions, follow instructions, and 
complete study assessments. 
c. Be able to adhere to the stimulation protocol and visit schedules. 
7. Women of child-bearing potential* must have a negative urine pregnancy test 
before the inclusion in the study and agree to use highly effective contraceptive 
methods during the study. Highly effective contraceptive methods will include 
intrauterine device, implant, patch or pill, bilateral tubal occlusion, vasectomized 
partner and sexual abstinence. 
* A woman will be considered of childbearing potential, following menarche and until 
becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A 
postmenopausal state is defined as 0 menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone level in the postmenopausal range 
may be used to confirm a post- menopausal state in women not using hormonal 

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23 
contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single follicle stimulating hormone measurement is insufficient. 
 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject has: 
1. Any condition or therapy impairing trial participation and assessments 
2. The presence of a relapse or use of IV steroids for any reason 3 months prior to 
screening visit. 
3. Severe systemic diseases or history of cancer or hereditary familiar cancer. 
4. Clinically relevant concomitant disease: cardiac, gastrointestinal, hepatic, pulmonary, 
neurological, renal or other major disease. 
5. Pregnant or breastfeeding women. 
6. Drug or alcohol abuse. 
7. Patients with active systemic bacterial, viral or fungal infections, or known to have AIDS 
or to test positive for HIV antibody at screening. 
8. Ongoing known bacterial, viral or fungal infection (with the exception of onychomycosis 
and dermatomycosis), positive hepatitis B surface antigen or hepatitis C antibody tests 
at screening. 
9. Patients with a known history of syphilis or tuberculosis or test positive for syphilis 
(positive rapid plasma regain, RPR) or tuberculosis (positive skin test) at screening. 
Active or latent tuberculosis (TB). 
10. Dementia or severe psychiatric, cognitive or behavioral problems or other comorbidity 
that may interfere with the compliance to the protocol. 
11. Any other clinically relevant medical or surgical condition, which, in the opinion of the 
investigator, would put the subject at risk by participating in the study. 
12. Participation in other experimental studies within the previous 90 days prior to 
screening visit. 
13. Patients having a pacemaker or other metal implants. 
5.2 
Trial Treatment(s) 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations. 
5.2.1  Therapeutic regimen Selection: tSCS stimulation protocols 
The tSCS non-invasive spinal stimulation utilizes two modulated frequencies: (1) base 
frequency and (2) overlapping frequency. The base frequency is 30 Hz, whereby 1ms pulses 
are delivered 30 times per second Figure 12 right).  Within each pulse, an overlapping 
frequency of 10kHz is deployed to permit about 5-fold more current to be delivered for the 
same level of cutaneous sensation under the electrodes. This 10 kHz overlapping frequency 
is adapted from kilohertz-frequency muscle stimulation, permitting high-amplitude 
stimulation on the skin surface without discomfort. Thus, stimulation applied on the surface 

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24 
of the skin can reach the spinal cord dorsal roots to activate spinal networks. The rationale 
for the 10 kHz overlapping frequency is that high-frequency waveforms can selectively block 
unmyelinated C-fibers in the skin6, 7, and stimulation may penetrate more deeply due to the 
lowering of the tissue impedance 1, 8, 9. We have observed substantial improvements in hand 
and arm function without inducing discomfort under the electrodes in our studies of more 
than 70 people with spinal cord injury1, 8, 10. 
 
 
Figure 12: (Left) SpineX device attached to two skin-surface electrodes for a child with 
cerebral palsy. (Right) Stimulation waveform with 10 kHz carrier frequency superimposed 
on each 1ms pulse, delivered 30 times per second to activate the spinal cord without 
discomfort from the surface of the skin.  
 
Based on the protocol11, stimulation waveforms are configured as monophasic or biphasic 
based on the configuration that leads to the most robust facilitation of arm and hand 
movements. The intensity of the stimulation is increased gradually (e.g., 5 mA steps) until 
the increase in muscle tone began to interfere with movement coordination or is judged 
uncomfortable by the participant. Treatment is performed with amplitudes of stimulation 
just below the motor threshold and adjusted as needed for the remainder of the therapy 
sessions as in prior studies1, 8, 10.  
 
 
5.2.2  Timing of Therapeutic Regimen Administration 
The treatment will be administered 6 weeks in conjunction with standard occupational 
therapy. 
5.2.3 Trial Blinding/Masking 
Patient and physician will be blinded. For participants who randomize to the sham 
stimulation condition, the presence of active stimulation treatment will be concealed by 
using a sham stimulation that begins with the same stimulation waveforms and amplitudes 
used for treatment, but gradually reduces the stimulation current to zero over the first two 
minutes of each session.  All participants will be instructed that they will most likely 
accommodate to the stimulation and not perceive it after several minutes.  The treating 
researcher will be unaware of the patient allocation. An independent investigator informed 
of the therapeutic arm will prepare the device to administer treating stimulation or sham 

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25 
and will record such assignment for each treating visit in a secured file not available for the 
treating researcher. 
5.3 
Randomization 
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS). There are 2 treatment arms: stim 
and sham. Subjects will be assigned randomly in a 1:1 ratio to either tSCS or sham.  
5.4 
Stratification 
Randomization will be stratified by center. 
5.5 Concomitant Treatments (Allowed) 
Patients will be allowed to take their therapy prescribed for MS and any other comorbidity. 
Treatments specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study. If there is a clinical indication for any treatment specifically prohibited during 
the trial, discontinuation from trial therapy may be required.  The investigator should 
discuss any questions regarding this with the Principal Investigator.  The final decision on 
any supportive therapy rests with the investigator and/or the subject's primary physician. 
However, the decision to continue the subject on trial therapy requires the mutual 
agreement of the investigator and the subject. 
5.6 
Rescue Treatments & Supportive Care 
No rescue or supportive treatments are specified to be used in this trial. 
5.7 
Diet/Activity/Other Considerations 
Not required. 
5.7.1 Diet 
Subjects should maintain their usual diet throughout the duration of the trial. 
5.7.2 Use of Alcohol, Caffeine, and Tobacco 
The site should advise subjects that alcohol should NOT be consumed during the study. The 
site should advise subjects to limit their alcohol intake as follows: 
Refrain from consuming any alcohol for at least 24 hours prior to the study.  
The site should advise subjects to limit their tobacco use as follows:  
Refrain from the equivalent of >15 cigarettes a day during the study, and 
Refrain from smoking during the study 
5.7.3 Activity 
NA 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be withdrawn by the investigator if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal procedures are provided in Section 7.1.4 – Other Procedures. 
Table 1 provides reasons why a subject must be discontinued from treatment but may 
continue to be monitored in the trial, as well as reasons why a subject must be discontinued 
from treatment and the trial. 

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26 
Table 1 Discontinuation Scenarios 
Reason for Discontinuation Scenario 
Action 
The subject or legal representative (such as a parent or 
legal guardian) withdraws consent. 
Discontinuation from 
Treatment and Trial 
The subject has a medical condition or personal 
circumstance which, in the opinion of the investigator, 
places the subject at unnecessary risk through 
continued participation in the trial or does not allow 
the subject to adhere to the requirements of the 
protocol. 
Discontinuation from 
Treatment and Trial 
The subject is no longer able to participate in the trial or 
is not compliant with trial-related procedures. 
Discontinuation from 
Treatment and Trial 
The subject takes a prohibited treatment during the 
trial.  
This deviation should be 
documented and consulted 
regarding the management of 
the subject. 
Subjects who report suicidal ideation with intent, with 
or without a plan or method (i.e., a positive response to 
items 4 or 5 in the assessment of suicidal ideation on 
the C-SSRS) or suicidal behavior may meet 
discontinuation criteria.   
Please refer to Section 
7.1.2.2.11, 7.2.3.2 and the ECI 
guidance document for details. 
Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she 
shall not be allowed to restart treatment. 
5.9 
Subject Replacement Strategy 
No subject replacement is intended. 
5.10 Beginning and End of the Trial 
The overall trial begins when the first subject signs the informed consent form. The overall 
trial ends when the last subject completes the last study-related phone-call or visit, 
discontinues from the trial, or is lost to follow-up (i.e., the subject is unable to be contacted 
by the investigator). 
5.11 Clinical Criteria for Early Trial Termination 
There are no pre-specified criteria for terminating the trial early. 
6.0 TRIAL FLOW CHART 
Table 2  Trial flow chart 
Visit Number 
1 
2 
3-6 
7 
Visit Title 
Screening Randomization 
Baseline 
Double 
blinded 
assessment 
OLE 

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Scheduled Week/Day 
Day 0 
Day 42 
Days 42-61-
84 
Day 
126 
Scheduling Window by Days: 
+2 
+3 
+3 
+5 
Administrative Procedures 
 
 
 
 
Informed Consent – Subject 
X 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
Subject Identification Card 
X 
 
 
 
Medical History 
X 
 
 
 
Prior Medication Review 
X 
 
 
 
Randomization 
 
X 
 
 
Monitor Trial Device Compliance 
 
X 
 
 
Clinical Procedures/Assessments 
 
 
 
 
9HPT 
 
X 
X 
X 
ARAT 
 
X 
X 
X 
mAS 
 
X 
X 
X 
NeuroQOL 
 
X 
X 
X 
MFIS 
 
X 
X 
X 
GIC 
 
X 
X 
X 
Safety 
 
X 
X 
X 
 
7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The investigator or qualified designee must obtain documented consent from each 
potential subject or each subject’s legally acceptable representative prior to participating in 
a clinical trial. Documented consent from each subject (referred to as subject consent) will 
also be obtained by the investigator or qualified designee. 
7.1.1.1.1 General Informed Consent 
Consent will be documented by the subject’s dated signature on a consent form along with 
the dated signature of the person conducting the consent discussion.  
A copy of the respective signed and dated consent forms (subject consents) will be given to 
the subject and subject before participation in the trial. 
The initial subject informed consent forms, any subsequent revised written informed 
consent forms and any written information provided to the subject will receive the Ethic 
Committee of the Hospital del Mar approval/favorable opinion in advance of use. The 

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28 
subjects will be informed in a timely manner if new information becomes available that may 
be relevant to their willingness to continue participation in the trial.  The communication of 
this information will be provided and documented via a revised consent form(s) or 
addendum to the original consent form(s) that captures the subject’s dated signature. 
Relevant clinical or MRI findings will be disclosed to the patient and refer for appropriate 
care. 
Specifics about a trial and the trial population will be added to the consent form template(s) 
at the protocol level.  Informed consent(s) will adhere to the ethics Committee 
requirements, applicable laws and regulations. 
7.1.1.2 Inclusion/Exclusion Criteria 
If it is determined that the subject does not meet the inclusion/exclusion criteria at visits, 
the subject will be withdrawn from the study.  
7.1.1.3 Subject Identification Card 
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site (Hospital del Mar) contact information 
(including direct telephone numbers) to be utilized in the event of an emergency.  The 
investigator or qualified designee will provide the subject with a Subject Identification Card 
immediately after the subject provides written informed consent. 
7.1.1.4 Medical History 
A medical history will be obtained by the investigator or qualified designee. 
7.1.1.5 Prior and Concomitant Treatments Review 
7.1.1.5.1 Prior Treatments 
The investigator or qualified designee will review any prior therapeutic drug or 
neurostimulation use, in advance to visit 2, and record prior treatment taken by the subject 
within 30 days before starting the trial.  
7.1.1.5.2 Concomitant Treatments 
The investigator or qualified designee will record treatment(s), if any, taken by the subject 
during the trial. Any changes to treatment(s) (i.e., dose, frequency) will also be recorded. If 
the subject reports taking any prohibited treatments during the study, this will be recorded 
as a study deviation. Concomitant treatments will not be changed during the study, without 
first consulting the investigator, except in cases of medical emergencies or other obvious 
exceptions. Please see Section 5.5 for more details. 
7.1.1.6 Assignment of Screening Number 
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  
Each subject will be assigned only one screening number.  Screening numbers must not be 
re-used for different subjects. 
7.1.1.7 Assignment of Treatment/Randomization Number 
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number. The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization. Once a treatment/randomization 
number is assigned to a subject, it can never be re-assigned to another subject. 

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29 
A single subject cannot be assigned more than 1 treatment/randomization numb 
7.1.1.8 Trial Compliance (Treatment) 
During stimulation visits, administration of tSCS therapy will be witnessed by the 
investigator and/or trial staff. Accounting of trial treatment will be conducted as specified in 
the Trial Flow Chart.  
7.1.1.9 Interactive Voice Response System/Integrated Web Response System 
The investigator or designee will call/log into IVRS/IWRS as specified in the Trial Flow Chart. 
Upon confirmation of a subject’s eligibility at Visit 2, the investigator or designee will call 
IVRS or log into IWRS to randomize the subject. Subjects who do not meet eligibility criteria 
at Visit 4 will be screen-failed in IVRS/IWRS. For all randomized subjects, the investigator or 
designee will continue to call/log into IVRS/IWRS as per the Trial Flow Chart. For completed 
or discontinued subjects, the investigator or designee will make the final call/web action 
into IVRS/IWRS at their last trial visit. For additional information, please refer to Section 5.3. 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Physical Assessments/Examinations 
7.1.2.1.1 Neurological Examination (Neuro Exam) 
A complete physical examination (PE), including a neurological exam, will be performed by a 
primary investigator or sub-investigator. This examination will also be performed in the 
event of early discontinuation. The following body systems should be included in these 
exams: 
7.1.2.1.3 Vital Signs 
Body Temperature:  Body temperature will be measured with an oral or tympanic 
thermometer. The same method (e.g., oral, or tympanic, ºC) should be used for all 
measurements for each individual subject and should be the same for all subjects 
throughout the trial. 
Heart Rate (HR), Blood Pressure (BP) and Respiratory Rate (RR):  Subjects should be resting 
for at least 10 minutes prior to having vital sign measurements obtained. The same 
position should be used for all measurements for each individual subject and should be the 
same for all subjects throughout the trial. The correct size of the blood pressure cuff and 
the correct positioning on the subject’s arm is essential to increase the accuracy of blood 
pressure measurements. The same method (e.g., manual, or automated) should be used for 
all measurements for each individual subject and should be the same for all subjects 
throughout the study. 
Vital signs will be assessed also after the tSCS sessions for identifying any adverse effect.  
7.1.2.1.4 Body Height/Weight 
Height (cm/in) and body weight (kg/lbs.) will be collected and recorded. Measurements 
should be recorded to the nearest centimeter/inch and kilogram/pound. Body weight data 
will be collected without shoes and with heavy clothing (such as coats) removed. Body 
weight should be performed on the same scale for the same individual throughout the 
study. 

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30 
7.1.2.2 Neurological and Cognitive exam 
At baseline and by end of the visit 2 (stimulation) a neurological exam (as defined in section 
12.6) will be administered for identifying CNS related adverse events.  
7.1.2.2.2 Measurements of Upper-Limb Function 
The Nine-hole peg test (9HPT) has been validated as the assessment of the hand function 
for MS46, with 15 to 20% defined as the minimal clinically important difference. In order to 
capture the upper-limb functioning we will include the Action Research Arm Test for motor 
function. The smallest real difference/minimal detectable change is defined as 5.7 points for 
the ARAT54 and 5.5 points for the Box and Blocks Test in stroke55. The Asworth scale will 
be used for assessing spasticity and the NeuroQOL Upper Extremity function as a PRO 
relevant for upper-limb dysfunction. In addition we will include a validated scale for fatigue 
in MS such as the MFIS and a global scale such as GIC for identifying additional effects of 
PROs. 
7.1.3 Laboratory Procedures/Assessments 
No laboratory procedures are planned. 
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws from participation in the trial during visit 2 (before 
completing the three planned stimulations), all applicable activities scheduled for the end of 
visit 2, as outlined in Section 6.0 Trial Flow Chart, will be performed at the time of 
discontinuation.  Any adverse events which are present at the time of 
discontinuation/withdrawal will be followed in accordance with the safety requirements 
outlined in Section 7.2 - Assessing and Recording Adverse Events 
7.1.4.2 Blinding/Unblinding 
When the investigator or sub-investigator needs to identify the treatment arm used by a 
subject in case of emergency e.g., the occurrence of serious adverse experiences, he/she 
will contact the emergency unblinding call center by telephone and make a request for 
emergency unblinding.  As requested by the investigator or sub-investigator the emergency 
unblinding call center will provide the information to him/her promptly and report 
unblinding.  The emergency unblinding call center will make a record promptly however, 
the investigator or sub-investigator must enter the intensity of the adverse experiences 
observed, their relation to study arm, the reason thereof, etc., in the medical chart etc., 
before unblinding is performed. Additionally, the investigator must go into the IVRS system 
and perform the unblind in the IVRS system to update arm disposition.  If the emergency 
unblinding call center is not available for a given site in this trial, IVRS/IWRS should be used 
for emergency unblinding in the event that this is required for subject safety. 
If unblinding has occurred, the circumstances around the unblinding (e.g., date and reason) 
must be documented promptly, and principal investigator notified as soon as possible.  Only 
the principal investigator or delegate and the respective subject’s code should be 
unblinded.  Trial site personnel directly associated with the conduct of the trial should not 
be unblinded. 
7.1.4.3 Domiciling 
NA 

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31 
7.1.4.4 Calibration of Critical Equipment 
Not required for the SCONE device. 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Visits 
Each visit should be performed as noted in the Trial Flow Chart. For visits that require 
additional explanations, please see those specific visits below. 
7.1.5.1.1 Visit 1: Screening 
At Visit 1, subjects who provide informed consent will undergo a series of diagnostic and 
safety assessments to determine if they are eligible for the trial. A designated subject must 
also consent to participate and will be asked to complete certain assessments throughout 
the trial. Subjects planning to undergo elective procedures during the study (known prior to 
trial start) should not proceed until such procedures have been completed. 
At the screening visit, medical history, use of drugs, alcohol, caffeine, smoking will be 
recorded. If the subject fulfills the inclusion criteria and signs the informed consent, the 
patient will then be exposed to a 6-week run-in period with standard occupational therapy. 
7.1.5.1.2 Visit 2: Baseline 
Patients will be randomized to either treatment or sham stimulation and assigned a code. 
Before starting stimulation, the researcher will conduct a vital signs and neurological 
examination. Then, the patient will be subjected to the first tSCS stimulations (a 30 min 
stimulations).  
7.1.5.1.3 Visit 3-5: Stimulation Visits 
At each visit the patient will be reassessed for vital signs. After the completion of each 
session period. 9HPT will be assessed the last day of stimulation for each session period. 
7.1.5.1.2 Visit 13, 14 and 29: end of DBP, onset and end of OLE 
During such visits, vital signs, and neurological exam and 9HPT will be conducted. 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation 
subject administered a medical device treatment and which does not necessarily have to 
have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol 
specified procedure, whether considered related to the medicinal product or protocol 
specified procedure. Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 

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32 
Product includes any device, diagnostic agent, pharmaceutical product, biological product, 
or protocol-specified procedure, whether investigational (including sham or active 
comparator treatment) or marketed, manufactured by, licensed by, provided by, or 
distributed by the vendor for human use. 
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
inadequate therapeutic regimen (whether accidental or intentional), from abuse and from 
withdrawal. 
Electronic reporting procedures can be found in the electronic data capture (EDC) entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent). 
7.2.1 Definition of an Over-treatment for this Protocol and Reporting of Over-treatment  
In this trial, an over-treatment is any therapeutic regimen of higher intensity or of longer 
duration than the specified therapeutic regimen to be administered in a calendar day 
(accidental or intentional). If an adverse event(s) is associated with (“results from”) the 
over-treatment, the adverse event(s) is reported as a serious adverse event, even if no 
other seriousness criteria are met. If the therapeutic regimen meeting the protocol 
definition of over-treatment is taken without any associated clinical symptoms or abnormal 
laboratory results, the over-treatment is reported as a non-serious Event of Clinical Interest 
(ECI), using the terminology “accidental or intentional over-treatment without adverse 
effect.” 
All reports of over-treatment with and without an adverse event must be reported by the 
investigator within 24 hours either by electronic media or paper. Electronic reporting 
procedures can be found in the electronic data capturing (EDC) entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent). 
7.2.2 Reporting of Pregnancy and Lactation 
Female participants may screen for this study if: 
• 
They are surgically sterile [have had a hysterectomy (uterus removed), bilateral 
oophorectomy (ovaries removed), or tubal ligation at least 6 months prior] 
• 
They are of post-menopausal age and have not had a menstrual period for 12 
months 
• 
They have a vasectomized partner (performed at least 6 months prior) who has 
been documented to no longer produce sperm 
• 
They are using a highly effective method of contraception to avoid pregnancy 
throughout the study and for 30 days after you complete this study. 
Examples of acceptable forms of highly effective contraception include: 
1. 
Established use of oral, injected or implanted hormonal methods of contraception 
plus use of a condom for your male partner. 
2. 
Placement of an intrauterine device (IUD) or intrauterine system (IUS) plus use of a 
condom for your male partner. 
3. 
True abstinence: When this is in line with your preferred and usual lifestyle 
NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation 
methods), condoms alone or double barrier are not acceptable methods of contraception. 

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33 
Male participants must ensure a condom is used for all sexual intercourse as well as 
following the acceptable methods of contraception listed above for your female partner 
and ensuring that they are used for the entire duration of the study, and for at least 90 days 
after you complete this study.  
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
7.2.3 Immediate Reporting of Adverse Events  
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any therapeutic regimen or during 
any use of the product that: 
● Results in death; 
● Is life threatening; 
● Results in persistent or significant disability/incapacity; 
● Results in or prolongs an existing inpatient hospitalization;  
● Is a congenital anomaly/birth defect;  
● Is another important medical event. 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable in the same timeframe as SAEs to 
meet certain local requirements. Therefore, these events are considered serious for 
collection purposes. 
● Is a cancer; 
● Is associated with an overdose. 
Refer to Table 3 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment, any serious 
adverse event, or follow up to a serious adverse event, including death due to any cause, 
that occurs to any subject must be reported within 24 hours for weekly days or 72 days over 
the weekend if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, sham treatment or a procedure. The 24 hours for the site starts when 
the site becomes aware of the SAE. SAEs not reported will be considered a major protocol 
deviation.  
For the time beginning at treatment allocation through 14 days following cessation of 
treatment, any serious adverse event, or follow up to a serious adverse event, including 
death due to any cause, whether or not related to the product, must be reported within 24 
hours either by electronic media or paper. Electronic reporting procedures can be found in 
the EDC data entry guidelines. Paper reporting procedures can be found in the Investigator 
Trial File Binder (or equivalent). 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the product that is brought to the attention of the investigator at 
any time outside of the time specified in the previous paragraph also must be reported 
immediately. 

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34 
All subjects with serious adverse events must be followed up for outcome. 
7.2.3.2 . Events of Clinical Interest (during the stimulation visit 2 (in the 1h after each 
stimulation) 
1. Agitation – daytime or nighttime 
2. Confusion or cognitive impairment - daytime or nighttime 
Regarding items #1 and 2 above, agitation, confusion or cognitive impairment should be 
considered an ECI if in the investigator’s opinion an acute worsening from baseline has 
occurred, or there is an unusual or atypical presentation of symptoms for a given subject.  
7.2.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 3. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 3 for instructions in evaluating adverse events. 
7.2.5 Management and Reporting of Adverse Events 
All adverse events (AEs), regardless of their severity or relationship to the investigational 
product, will be systematically assessed, recorded, and reported as follows: 
• 
Detection: Investigators will actively monitor participants for any signs or symptoms 
of adverse events during study visits and treatment sessions. 
• 
Assessment: A qualified physician investigator will assess each AE for severity, 
seriousness, causality, and expectedness according to protocol guidelines and 
regulatory standards (ICH-GCP). 
• 
Reporting: 
o All serious adverse events (SAEs) must be reported to the sponsor within 24 
hours of awareness via the electronic data capture (EDC) system or by paper 
form if needed. 
o Non-serious AEs will be documented in the case report forms (CRFs) and 
summarized during regular safety reviews. 
• 
Follow-up: All AEs will be followed until resolution, stabilization, or until an 
adequate explanation is available. 
• 
Pregnancy and lactation: Although not considered AEs, any pregnancy or lactation 
event during the study must also be reported promptly according to protocol 
procedures. 
These procedures are designed to ensure participant safety and regulatory compliance 
throughout the study. 
 

 
Page 35 of 60 
 
   
 
 
Table 3 Evaluating Adverse Events 
Maximum 
Intensity 
Mild 
awareness of sign or symptom, but easily tolerated (for pediatric trials, awareness of symptom, but 
easily tolerated) 
Moderate 
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like 
something is wrong) 
Severe 
incapacitating with inability to work or do usual activity (extremely distressed or unable to do usual 
activities) 
Seriousness A serious adverse event (SAE) is any adverse event occurring at any Therapeutic regimen or during any use of  
product that: 
†Results in death; or 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event 
as it occurred [Note: This does not include an adverse event that, had it occurred in a more severe form, might have 
caused death.]; or 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal 
life functions); or 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, 
regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation.   
(Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not worsened is not a 
serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Hospital 
del Mar neurosciences product and is documented in the patient’s medical history.); or 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis); or 
Is a cancer (although not serious per ICH definition, is reportable within 24 hours to meet certain local 
requirements); or 
Is associated with an over-treatment (whether accidental or intentional).  Any adverse event associated with an 
over-treatment is considered a serious adverse event for collection purposes. An over-treatment that is not 

 
Page 36 of 60 
 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 
24 hours. 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization 
may be considered a serious adverse event when, based upon appropriate medical judgment, the event may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and 
units 
Action 
Taken  
Did the adverse event cause the product to be discontinued? 
Relationship 
to  
Product 
Did the product cause the adverse event?   The determination of the likelihood that the product caused the 
adverse event will be provided by an investigator who is a qualified physician.  The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done.  This initialed document must be retained for the required 
regulatory time frame.  The criteria below are intended as reference guidelines to assist the investigator in 
assessing the likelihood of a relationship between the test drug and the adverse event based upon the available 
information 
The following components are to be used to assess the relationship between the product and the AE; the greater 
the correlation with the components and their respective elements (in number and/or intensity), the more likely 
the p product caused the adverse event: 
Exposure 
Is there evidence that the subject was actually exposed to the product such as:  reliable history, 
acceptable compliance assessment (pill count, diary, etc.), expected pharmacological effect, or 
measurement of drug/metabolite in bodily specimen? 
Time Course Did  the  AE  follow in  a reasonable temporal  sequence from administration of the  product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with 
investigational medicinal products)? 
Likely Cause Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors 
 

 
Page 37 of 60 
 
Relationship 
to the 
Product 
(continued)  
The following components are to be used to assess the relationship between the product and the AE 
(continued) 
Dechallenge Was the  
 product discontinued or dose/exposure/frequency reduced? 
      If yes, did the AE resolve or improve? 
           If yes, this is a positive dechallenge.  If not, this is a negative dechallenge. 
(Note:  This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the 
AE resolved/improved despite continuation of the product; (3) the trial is a single-Therapeutic 
regimen drug trial); or (4)  
product(s) is/are only used one time.) 
Rechallenge Was the subject re-exposed to the  product in this trial? 
      If yes, did the AE recur or worsen? 
          If yes, this is a positive rechallenge.  If not, this is a negative rechallenge. 
(Note:  This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, 
or (2) the trial is a single-Therapeutic regimen drug trial); or (3)  
product(s) is/are used only one time.) 
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH 
MAY HAVE BEEN CAUSED BY THE PRODUCT, OR IF RE-EXPOSURE TO THE PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE. 
 
Consistency 
with Trial  
Treatment  
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the  
product or drug class pharmacology or toxicology? 
The assessment of the relationship will be reported on the case report forms /worksheets by an investigator who is a qualified 
physician according to his/her best clinical judgment, including consideration of the above elements. 
Record one of the 
following: 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of 
a  

 
Page 38 of 60 
 
product relationship). 
Yes, there is a reasonable 
possibility of  
 product relationship. 
There is evidence of exposure to the  
 product.  The temporal sequence of the AE onset relative to the administration of the  
 product is reasonable.  The AE is more likely explained by the  
 product than by another cause.  
No, there is not a 
reasonable possibility of  
 product relationship 
Subject did not receive the  
 product OR temporal sequence of the AE onset relative to administration of the  
 product is not reasonable OR the AE is more likely explained by another cause than the  
 product.  (Also entered for a subject with over-treatment without an associated AE.) 
 

  
 
Page 39 of 60 
 
7.2.5 Investigator Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to the Ethical Committee of Hospital del Mar and 
investigators in accordance with all applicable global laws and regulations, i.e., per ICH 
Topic E6 (R1) Guidelines for Good Clinical Practice. 
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
Linear mixed-effects models will be used to test the association between treatment arm 
and all primary and secondary endpoints. These models will include an outcome measure as 
the dependent variable, treatment assignment, time of measurement, and their interaction 
as independent variables and a random intercept for participant and site to account for the 
longitudinal and clustered nature of the data. If imbalances exist in baseline characteristics 
between treatment groups, sensitivity analyses will be conducted by including the covariate 
in the mixed-effects models as an independent variable to determine the impact it may 
have on the desired association. For the primary outcome, the interaction between 
treatment assignment and the 6 weeks follow-up will be assessed, with statistical 
significance indicating a difference in the change in 9-HPT is present between treatment 
groups at V5.  All other time points and outcome measures will be treated as secondary.  
These analyses will be conducted following the intention to treat principle. Additional 
exploratory analyses will be conducted on the per protocol population defined as those who 
completed at least 70% of therapeutic sessions.  
Table 4  Statistical analysis plan 
Study Design Overview 
Transcutaneous Electrical Spinal Stimulation (tSCS) for Improving 
Upper Limb Function in People with MS 
Treatment Assignment 
Active stimulation: tSCS 
Sham: stimulations using a non-active electric stimulation 
Analysis Populations 
Intention to treat  
Per Protocol 
Primary Endpoint(s) 
Differences in the nine-hole peg test (9-HPT) affected hand in the 
tSCS treated vs. sham groups by the end of treatment (V3 vs V5) 
Key Secondary 
Endpoints 
1. Percentage of responders: 20% difference on the 9HPTd 
(minimal clinically important difference (MCID)) from baseline to 
end of the study 
2. Change in the 9HPT dominant and non-dominant hand from 
baseline to end of the study 
3. Change in the Action Research Arm Test (ARAT) from baseline 
to end of the study 
4. Change in the modified Ashworth Scale (mAS) for spasticity 
assessment from baseline to end of the study 

  
 
Page 40 of 60 
 
5. Hand strength measured by Grip and Pinch force dynameters 
(Figure 10) 
6. Change in the NeuroQOL Upper Extremity function from 
baseline to end of the study 
7. Change in the Modified Fatigue Impact Scale (MFIS) from 
baseline to end of the study 
8. Change in Global Impression of change (GIC) from baseline to 
end of the study 
 
Exploratory endpoints 
 
Statistical Methods for 
Key Efficacy Analyses 
Linear mixed-effects models will be used to test the association 
between treatment arm and all primary and secondary 
endpoints. 
Statistical Methods for 
Key Safety Analyses 
Descriptive statistics 
Interim Analyses 
No interim analysis for efficacy or safety is planned for this study. 
Multiplicity 
Not planned 
Sample Size and Power  Sample size: n=60  
For a large, standardized effect size (Cohen’s d=0.8), with a 
sample size of 52 (26 in each arm) we would have greater than 
80% power to detect a significant difference in 9HPT between 
treatment arms using a two-sample t-test and a two-sided 
significance level of 0.05. Assuming a common standard 
deviation of 5.5, this corresponds to a difference of 4.4 units 
between treatment groups. Allowing for a conservative attrition 
rate of 15% (our previous trial in SCI with a similar design had 
10% attrition4-6), we plan on enrolling 60 participants.  
Furthermore, as our proposed analysis is a linear mixed-effects 
model, we anticipate greater efficiency resulting in a slightly 
higher power. Reimbursement of travel expenses will be used to 
promote retention. 
8.2 Responsibility for Analyses 
The statistical analysis of the data obtained from this study will be the responsibility of the 
Principal Investigator (Pablo Villoslada, HMar) and the biostatistician of the study (Agustin 
Conesa, HMar).  
8.3 
Hypotheses 
Objectives and hypotheses of the study are stated in Section 3. 

  
 
Page 41 of 60 
 
8.4 
Analysis Endpoints 
Key efficacy and safety endpoints that will be evaluated for within- and/or between-tSCS 
protocols are listed below, followed by the descriptions of the derivations of selected 
endpoints.  
8.4.1. Efficacy Endpoints 
Rationale for the key efficacy endpoints is given in Section 4.2.3.1 and an initial description 
of the efficacy measures is included in Section 7.1.2.2. In general, if a baseline value exists 
for a particular efficacy measure, then the change from baseline in that value will be 
evaluated.  
Primary Endpoint 
Differences in the nine-hole peg test (9-HPT) affected hand in the tSCS treated vs. sham 
groups by the end of treatment (V3 vs V5) 
Secondary Endpoint 
1. 
Percentage of responders: 20% difference on the 9HPTd (minimal clinically 
important difference (MCID)) from baseline to end of the study 
2. 
Change in the 9HPT dominant and non-dominant hand from baseline to end of the 
study 
3. 
Change in the Action Research Arm Test (ARAT) from baseline to end of the study 
4. 
Change in the modified Ashworth Scale (mAS) for spasticity assessment from 
baseline to end of the study 
5. 
Hand strength measured by Grip and Pinch force dynameters (Figure 10) 
6. 
Change in the NeuroQOL Upper Extremity function from baseline to end of the study 
7. 
Change in the Modified Fatigue Impact Scale (MFIS) from baseline to end of the 
study 
8. 
Change in Global Impression of change (GIC) from baseline to end of the study 
8.4.2 Safety Endpoints 
Presence of serious adverse events (together with items of special attention) 
An initial description of the safety measures is included in Sections 7.1.2.1, 7.1.2.2.10 and 
7.1.3. Safety and tolerability will be assessed by statistical and clinical review of the 
following data collected throughout the study:  adverse experiences (AEs), and treatment-
emergent suicidality. The primary time for safety analyses is Visit 2; Safety endpoints are 
classified into 2 tiers (see Statistical Methods for Key Safety Analyses in Section 8.1 for Tier 
definitions). 
Tier 1 Safety Endpoints include (the proportion of subjects with): 
1. Any AE 
2. Any Serious AE 
3. Any treatment-Related AE 
4. Any Serious and treatment-Related AE  
5. Discontinuation due to AE 
Tier 2 Safety Endpoints include: 
1. Specific AEs, SOC AEs or PDLCs which have incidence in all 3 subjects.  

  
 
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8.5 
Analysis Populations 
8.5.1 Safety Analysis Population 
The safety population will be used for the analysis of safety data in this study. The safety 
population consists of all subjects who received at least 1 stimulation protocol of trial 
treatment. Subjects will be included in the treatment group corresponding to the trial 
treatment they received for the analysis of safety data using the safety population. Subjects 
who take incorrect trial treatment for the entire treatment period will be included in the 
treatment group corresponding to the trial treatment received.  
At least 1 vital sign measurement obtained after at least 1 stimulation protocol of trial 
treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required. 
8.6 
Statistical Methods 
Safety and tolerability will be assessed by statistical and clinical review of the following data 
collected throughout the study: adverse experiences (AEs). Safety will be evaluated with 
doses combined; selected safety analyses will be performed for doses separately. 
The analysis of safety results will follow a tiered approach (Table 5). The tiers differ with 
respect to the analyses that will be performed. Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p-values and 95% confidence 
intervals provided for between-group comparisons. Other safety parameters will be 
considered as Tier 2 or Tier 3. Tier 2 parameters will be assessed via point estimates with 
95% confidence intervals provided for between-group comparisons.  
Membership in Tier 1 requires that at least 4 subjects in any treatment group exhibit the 
event; all other adverse experiences and predefined limits of change will belong to Tier 2. 
Summary statistics for baseline, on-treatment, and change from baseline values will be 
provided by the treatment group in table format.    
See Table 5 for a classification of safety endpoints as Tier 1, or 2 and the corresponding 
analysis strategy for each endpoint. 
 
Table 5 Analysis Strategy for Safety Parameters 
Safety 
Tier 
Safety Endpoint† 
p-Value§ 
95% CI for 
Treatment  
Compariso
n§ 
Descriptiv
e Statistics 
Tier 1 
Any AE 
 
X 
X 
 
Any Serious AE 
 
X 
X 
 
Any Drug-Related AE 
 
X 
X 
 
Any Serious and Drug-Related AE 
Discontinuation due to AE 
 
X 
X 
X 
X 
 
Specific AEs, SOCs, or PDLCs (incidence 
≥4 subjects in 1 of the treatment 
groups) 
 
X 
X 

  
 
Page 43 of 60 
 
Tier 2 
Specific AEs, SOCs or PDLCs ‡ 
(incidence <4 subjects in all the 
treatment groups) 
 
 
X 
 
 
 
 
 
2 Adverse Event (AE) references refer to both Clinical and Laboratory AEs. 
3 Includes only those endpoints not pre-specified as Tier 1 or not already 
pre-specified as Tier-2 endpoint 
4 P-value and CI for safety endpoints based upon Miettinen & Nurminen 
method 
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X = 
results will be provided. 
 
 
8.6.1 Summaries of Baseline Characteristics, Demographics, and Other Analyses 
8.6.1.1 Demographic and Baseline Characteristics 
Demographic variables (e.g., age, gender, race), baseline characteristics, primary and 
secondary diagnoses, and prior and concomitant therapies will be summarized by 
treatment either by descriptive statistics or categorical tables. 
8.7 
Interim Analysis 
No interim analyses for efficacy or safety are planned for this study  
8.8 
Multiplicity 
Not planned. 
8.9 
Sample Size and Power Calculations 
Sample size 
Sample size: n=60  
Power for the primary hypothesis 
For a large, standardized effect size (Cohen’s d=0.8), with a sample size of 52 (26 in each 
arm) we would have greater than 80% power to detect a significant difference in 9HPT 
between treatment arms using a two-sample t-test and a two-sided significance level of 
0.05. Assuming a common standard deviation of 5.5, this corresponds to a difference of 4.4 
units between treatment groups. Allowing for a conservative attrition rate of 15% (our 
previous trial in SCI with a similar design had 10% attrition4-6), we plan on enrolling 60 
participants.  Furthermore, as our proposed analysis is a linear mixed-effects model, we 
anticipate greater efficiency resulting in a slightly higher power. Reimbursement of travel 
expenses will be used to promote retention. 
8.10 Subgroup Analyses  
An exploratory sex-stratified analysis will be conducted to assess potential differences in 
safety and efficacy outcomes between male and female participants. Although the study 
is not powered to detect sex-specific effects, this analysis aims to provide additional 
insights into potential sex-related variations in treatment response.8.11 Compliance 
(Treatment Adherence) 
Summary statistics will be provided on percent compliance by treatment for all subjects 
included. 

  
 
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8.12 Extent of Exposure 
The total number of days each subject received a particular total daily stimulation protocol 
will be identified and then summarized (as subject counts and percentages)  
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
No drugs are being tested in this study 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
10.1.1 Confidentiality of Data 
By signing this protocol, the investigator affirms that information furnished to the 
investigator will be maintained in confidence, and such information will be divulged to the 
institutional review board, ethics review committee (IRB/ERC) or similar or expert 
committee, affiliated institution, and employees, only under an appropriate understanding 
of confidentiality with such board or committee, affiliated institution, and employees.  Data 
generated by this trial will be considered confidential by the investigator, except to the 
extent that it is included in a publication as provided in the Publications section of this 
protocol. 
10.1.2 Confidentiality of Subject Records 
By signing this protocol, the investigator agrees that the Ethical Committee, or regulatory 
authority representatives may consult and/or copy trial documents to verify 
worksheet/case report form data.  By signing the consent form, the subject agrees to this 
process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission. 
By signing this protocol, the investigator agrees to treat all subject data used and disclosed 
in connection with this trial in accordance with all applicable privacy laws, rules, and 
regulations. 
10.1.3 Confidentiality of Investigator Information 
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all sub-investigators and trial site 
personnel, may be used and disclosed for trial management purposes, as part of a 
regulatory submissions, and as required by law. This information may include: 
1. name, address, telephone number and e-mail address; 
2. hospital or clinic address and telephone number; 
3. curriculum vitae or other summary of qualifications and credentials; and 
4. other professional documentation. 
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators. By signing this protocol, the investigator expressly consents to these uses and 
disclosures. 

  
 
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10.1.4 Confidentiality of Ethics Committee Information 
The principal investigator is required to record the name and address of the Ethics 
Committee that reviews and approves this trial. 
10.2 Compliance with Financial Disclosure Requirements 
The investigator/subinvestigator(s) agree to provide his/her financial interests to allow for 
the submission of complete and accurate certification and disclosure statements. The 
investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form.  
10.2.1 Compliance with Ethical Principles and Medical Device Regulation 
This study will be conducted in accordance with the ethical principles outlined in the 
Declaration of Helsinki, as adopted by the 75th World Medical Assembly, Helsinki, Finland, 
October 2024, and any subsequent revisions. 
In addition, the study will comply with all applicable regulatory requirements, including the 
Regulation (EU) 2017/745 on medical devices, specifically concerning clinical investigations 
involving medical devices. 
The protocol, informed consent forms, and any other relevant study documentation will be 
reviewed and approved by an independent Ethics Committee prior to initiation. All 
participants will provide written informed consent before any study-related procedures are 
performed. 
10.3 Compliance with Law, Audit and Debarment 
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of 
Good Clinical Practice (e.g., International Conference on Harmonization (ICH) of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: all 
applicable federal, state, and local laws, rules and regulations relating to the conduct of the 
clinical trial. 
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations, is provided in Section 12.1 Hospital del Mar 
Neurosciences Code of Conduct for Clinical Trials. 
The investigator also agrees to allow monitoring, audits, Ethics Committee review and 
regulatory authority inspection of trial-related documents and procedures and provide for 
direct access to all trial-related source data and documents. 
The investigator agrees not to seek reimbursement from subjects, their insurance providers 
or from government programs for procedures included as part of the trial reimbursed to the 
investigator. 
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state, and local 
laws, rules, and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
regulatory agencies. 
Trial documentation will be promptly and fully disclosed by the investigator upon request 
and shall be made available at the trial site upon request for inspection, copying, review 

  
 
Page 46 of 60 
 
and audit at reasonable times from any regulatory authorities.  The investigator agrees to 
promptly take any reasonable steps that are requested because of an audit to cure 
deficiencies in the trial documentation and worksheets/case report forms. 
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  
This documentation includes, but is not limited to, the protocol, worksheets/case report 
forms, advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities, consent forms, investigator’s curricula vitae, 
monitor visit logs, laboratory reference ranges, laboratory certification or quality control 
procedures and laboratory director curriculum vitae. By signing this protocol, the 
investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol 
database lock. All trial documents shall be made available if required by relevant regulatory 
authorities. The investigator must consult with and obtain written approval prior to 
destroying trial and/or subject files.   
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed. 
10.4 Compliance with Trial Registration and Results Posting Requirements 
The principal investigator of the trial is solely responsible for determining whether the trial 
and its results are subject to the requirements for submission to EUDRA  
(http://eudragmdp.ema.europa.eu) or ClinicalTrials.org (http://www.clinicaltrials.gov) 
or other local registries. Hospital del Mar researchers will review this protocol and submit 
the information necessary to fulfill these requirements. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
EMA clinical trials directive or other locally mandated registries are that of the investigators 
and agrees not to submit any information about this trial or its results to those registries. 
10.5 Quality Management System 
By signing this protocol, the principal investigator agrees to be responsible for 
implementing and maintaining a quality management system with written development 
procedures and functional area standard operating procedures (SOPs) to ensure that trials 
are conducted and data are generated, documented, and reported in compliance with the 
protocol, accepted standards of Good Clinical Practice, and all applicable federal, state, and 
local laws, rules and regulations relating to the conduct of the clinical trial. 

  
 
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10.6 Data Management 
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data. By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature. By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate. Detailed information regarding Data Management procedures for this 
protocol will be provided separately. 
10.7 Publications 
This trial may be intended for publication, even if terminated prematurely. Publication may 
include any or all the following: posting of a synopsis online, abstract and/or presentation at 
a scientific conference, or publication of a full manuscript. The principal investigator will 
work with the authors to submit a manuscript describing trial results within 12 months after 
the last data become available, which may take up to several months after the last subject 
visit in some cases such as vaccine trials. Hospital del Mar researchers will post a synopsis of 
trial results for approved products on EUDRA or Clinicaltrials.gov by 12 months after the last 
subject's last visit for the primary outcome, 12 months after the decision to discontinue 
development, or product marketing (dispensed, administered, delivered, or promoted), 
whichever is later. 
These timelines may be extended for products that are not yet marketed, if additional time 
is needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality 
agreement. When a manuscript is submitted to a biomedical journal, the policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript. If the manuscript is subsequently accepted for publication, the researchers 
will allow the journal, if it so desires, to post on its website the key sections of the protocol 
that are relevant to evaluating the trial, specifically those sections describing the trial 
objectives and hypotheses, the subject inclusion and exclusion criteria, the trial design and 
procedures, the efficacy and safety measures, the statistical analysis plan, and any 
amendments relating to those sections.  
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or 
revising it critically for important intellectual content; and 3) final approval of the version to 
be published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be considered to determine authorship if contributions have also been 
made to all three of the preceding authorship criteria. Although publication planning may 
begin before conducting the trial, final decisions on authorship and the order of authors’ 
names will be made based on participation and actual contributions to the trial and writing, 
as discussed above. The first author is responsible for defending the integrity of the data, 
method(s) of data analysis and the scientific content of the manuscript. 
 
 

  
 
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11. LIST OF REFERENCES 
1. 
Wallin MT, Culpepper WJ, Campbell JD, et al. The prevalence of MS in the United 
States: A population-based estimate using health claims data. Neurology 2019;92:e1029-
e1040. 
2. 
Waltz JM, Andreesen WH, Hunt DP. Spinal cord stimulation and motor disorders. 
Pacing Clin Electrophysiol 1987;10:180-204. 
3. 
Barss TS, Parhizi B, Porter J, Mushahwar VK. Neural Substrates of Transcutaneous 
Spinal Cord Stimulation: Neuromodulation across Multiple Segments of the Spinal Cord. J 
Clin Med 2022;11. 
4. 
Inanici F, Brighton LN, Samejima S, Hofstetter CP, Moritz CT. Transcutaneous Spinal 
Cord Stimulation Restores Hand and Arm Function After Spinal Cord Injury. IEEE Trans 
Neural Syst Rehabil Eng 2021;29:310-319. 
5. 
Moritz C, Field-Fote EC, Tefertiller C, et al. Non-invasive spinal cord electrical 
stimulation for arm and hand function in chronic tetraplegia: a safety and efficacy trial. Nat 
Med 2024;30:1276-1283. 
6. 
Inanici F, Samejima S, Gad P, Edgerton VR, Hofstetter CP, Moritz CT. Transcutaneous 
Electrical Spinal Stimulation Promotes Long-Term Recovery of Upper Extremity Function in 
Chronic Tetraplegia. IEEE Trans Neural Syst Rehabil Eng 2018;26:1272-1278. 
7. 
Samejima S, Caskey CD, Inanici F, et al. Multisite Transcutaneous Spinal Stimulation 
for Walking and Autonomic Recovery in Motor-Incomplete Tetraplegia: A Single-Subject 
Design. Phys Ther 2022;102. 
8. 
Estes S, Zarkou A, Hope JM, Suri C, Field-Fote EC. Combined Transcutaneous Spinal 
Stimulation and Locomotor Training to Improve Walking Function and Reduce Spasticity in 
Subacute Spinal Cord Injury: A Randomized Study of Clinical Feasibility and Efficacy. J Clin 
Med 2021;10. 
9. 
Gad P, Lee S, Terrafranca N, et al. Non-Invasive Activation of Cervical Spinal 
Networks after Severe Paralysis. J Neurotrauma 2018;35:2145-2158. 
10. 
Hofstoetter US, Freundl B, Binder H, Minassian K. Common neural structures 
activated by epidural and transcutaneous lumbar spinal cord stimulation: Elicitation of 
posterior root-muscle reflexes. PLoS One 2018;13:e0192013. 
11. 
Capogrosso M, Wenger N, Raspopovic S, et al. A computational model for epidural 
electrical stimulation of spinal sensorimotor circuits. J Neurosci 2013;33:19326-19340. 
12. 
de Freitas RM, Capogrosso M, Nomura T, Milosevic M. Preferential activation of 
proprioceptive and cutaneous sensory fibers compared to motor fibers during cervical 
transcutaneous spinal cord stimulation: a computational study. J Neural Eng 2022;19. 
13. 
Moritz CT. Now is the Critical Time for Engineered Neuroplasticity. 
Neurotherapeutics 2018;15:628-634. 

  
 
Page 49 of 60 
 
14. 
Ievins A, Moritz CT. Therapeutic Stimulation for Restoration of Function After Spinal 
Cord Injury. Physiology (Bethesda) 2017;32:391-398. 
15. 
Samejima S, Henderson R, Pradarelli J, Mondello SE, Moritz CT. Activity-dependent 
plasticity and spinal cord stimulation for motor recovery following spinal cord injury. Exp 
Neurol 2022;357:114178. 
16. 
Tefertiller C, Rozwod M, VandeGriend E, Bartelt P, Sevigny M, Smith AC. 
Transcutaneous Electrical Spinal Cord Stimulation to Promote Recovery in Chronic Spinal 
Cord Injury. Front Rehabil Sci 2021;2. 
17. 
Powell MP, Verma N, Sorensen E, et al. Epidural stimulation of the cervical spinal 
cord for post-stroke upper-limb paresis. Nat Med 2023;29:689-699. 
18. 
Gad P, Hastings S, Zhong H, Seth G, Kandhari S, Edgerton VR. Transcutaneous Spinal 
Neuromodulation Reorganizes Neural Networks in Patients with Cerebral Palsy. 
Neurotherapeutics 2021;18:1953-1962. 
19. 
Sachdeva R, Girshin K, Shirkhani Y, Gad P, Edgerton VR. Combining spinal 
neuromodulation and activity based neurorehabilitation therapy improves sensorimotor 
function in cerebral palsy. Front Rehabil Sci 2023;4:1216281. 
20. 
Hastings S, Zhong H, Feinstein R, et al. A pilot study combining noninvasive spinal 
neuromodulation and activity-based neurorehabilitation therapy in children with cerebral 
palsy. Nat Commun 2022;13:5660. 
21. 
Milosevic M, Masugi Y, Sasaki A, Sayenko DG, Nakazawa K. On the reflex 
mechanisms of cervical transcutaneous spinal cord stimulation in human subjects. J 
Neurophysiol 2019;121:1672-1679. 
22. 
Benavides FD, Jo HJ, Lundell H, Edgerton VR, Gerasimenko Y, Perez MA. Cortical 
and Subcortical Effects of Transcutaneous Spinal Cord Stimulation in Humans with 
Tetraplegia. J Neurosci 2020;40:2633-2643. 
23. 
Edgerton VR, Roy RR. A new age for rehabilitation. Eur J Phys Rehabil Med 
2012;48:99-109. 
24. 
Kleim JA, Jones TA. Principles of experience-dependent neural plasticity: implications 
for rehabilitation after brain damage. J Speech Lang Hear Res 2008;51:S225-239. 
25. 
Cai LL, Courtine G, Fong AJ, Burdick JW, Roy RR, Edgerton VR. Plasticity of 
functional connectivity in the adult spinal cord. Philos Trans R Soc Lond B Biol Sci 
2006;361:1635-1646. 
26. 
Behrman AL, Ardolino EM, Harkema SJ. Activity-Based Therapy: From Basic 
Science to Clinical Application for Recovery After Spinal Cord Injury. J Neurol Phys Ther 
2017;41 Suppl 3:S39-s45. 
27. 
Papastefanaki F, Matsas R. From demyelination to remyelination: the road toward 
therapies for spinal cord injury. Glia 2015;63:1101-1125. 

  
 
Page 50 of 60 
 
28. 
Kuhlmann T, Moccia M, Coetzee T, et al. Multiple sclerosis progression: time for a 
new mechanism-driven framework. Lancet Neurol 2023;22:78-88. 
29. 
Kister I, Bacon TE, Chamot E, et al. Natural history of multiple sclerosis symptoms. 
Int J MS Care 2013;15:146-158. 
30. 
Jensen MP, Truitt AR, Schomer KG, Yorkston KM, Baylor C, Molton IR. Frequency 
and age effects of secondary health conditions in individuals with spinal cord injury: a scoping 
review. Spinal Cord 2013;51:882-892. 
31. 
Mokhtari T, Ren Q, Li N, Wang F, Bi Y, Hu L. Transcutaneous Electrical Nerve 
Stimulation in Relieving Neuropathic Pain: Basic Mechanisms and Clinical Applications. Curr 
Pain Headache Rep 2020;24:14. 
32. 
Choi EH, Gattas S, Brown NJ, et al. Epidural electrical stimulation for spinal cord 
injury. Neural Regen Res 2021;16:2367-2375. 
33. 
Eisdorfer JT, Smit RD, Keefe KM, Lemay MA, Smith GM, Spence AJ. Epidural 
Electrical Stimulation: A Review of Plasticity Mechanisms That Are Hypothesized to Underlie 
Enhanced Recovery From Spinal Cord Injury With Stimulation. Front Mol Neurosci 
2020;13:163. 
34. 
Seanez I, Capogrosso M. Motor improvements enabled by spinal cord stimulation 
combined with physical training after spinal cord injury: review of experimental evidence in 
animals and humans. Bioelectron Med 2021;7:16. 
35. 
Madsen PM, Sloley SS, Vitores AA, Carballosa-Gautam MM, Brambilla R, Hentall 
ID. Prolonged stimulation of a brainstem raphe region attenuates experimental autoimmune 
encephalomyelitis. Neuroscience 2017;346:395-402. 
36. 
Stevanovic I, Mancic B, Ilic T, et al. Theta burst stimulation influence the expression 
of BDNF in the spinal cord on the experimental autoimmune encephalomyelitis. Folia 
Neuropathol 2019;57:129-145. 
37. 
Abboud H, Hill E, Siddiqui J, Serra A, Walter B. Neuromodulation in multiple 
sclerosis. Mult Scler 2017;23:1663-1676. 
38. 
Street T, Taylor P, Swain I. Effectiveness of functional electrical stimulation on 
walking speed, functional walking category, and clinically meaningful changes for people with 
multiple sclerosis. Archives of physical medicine and rehabilitation 2015;96:667-672. 
39. 
Hammond ER, Recio AC, Sadowsky CL, Becker D. Functional electrical stimulation 
as a component of activity-based restorative therapy may preserve function in persons with 
multiple sclerosis. J Spinal Cord Med 2015;38:68-75. 
40. 
Rapisarda A, Ioannoni E, Izzo A, D'Ercole M, Montano N. Is There a Place for Spinal 
Cord Stimulation in the Management of Patients with Multiple Sclerosis? A Systematic 
Review of the Literature. Minim Invasive Surg 2021;2021:9969010. 

  
 
Page 51 of 60 
 
41. 
Hofstoetter US, Freundl B, Lackner P, Binder H. Transcutaneous Spinal Cord 
Stimulation Enhances Walking Performance and Reduces Spasticity in Individuals with 
Multiple Sclerosis. Brain Sci 2021;11. 
42. 
Zackowski KM, Freeman J, Brichetto G, et al. Prioritizing progressive MS 
rehabilitation research: A call from the International Progressive MS Alliance. Mult Scler 
2021;27:989-1001. 
43. 
Bebo BF, Jr., Allegretta M, Landsman D, et al. Pathways to cures for multiple sclerosis: 
A research roadmap. Mult Scler 2022;28:331-345. 
44. 
Fawaz SI, Izumi SI, Hamada SM, et al. Role of Cervical Spinal Magnetic Stimulation 
in Improving Posture and Functional Ambulation of Patients with Relapsing Remitting 
Multiple Sclerosis. Rehabil Res Pract 2022;2022:6009104. 
45. 
Lyle RC. A performance test for assessment of upper limb function in physical 
rehabilitation treatment and research. Int J Rehabil Res 1981;4:483-492. 
46. 
Feys P, Lamers I, Francis G, et al. The Nine-Hole Peg Test as a manual dexterity 
performance measure for multiple sclerosis. Mult Scler 2017;23:711-720. 
47. 
Mathiowetz V, Volland G, Kashman N, Weber K. Adult norms for the Box and Block 
Test of manual dexterity. Am J Occup Ther 1985;39:386-391. 
48. 
Cella D, Lai JS, Nowinski CJ, et al. Neuro-QOL: brief measures of health-related 
quality of life for clinical research in neurology. Neurology 2012;78:1860-1867. 
49. 
French B, Leathley M, Sutton C, et al. A systematic review of repetitive functional task 
practice with modelling of resource use, costs and effectiveness. Health Technol Assess 
2008;12:iii, ix-x, 1-117. 
50. 
Ward AR, Robertson VJ, Makowski RJ. Optimal frequencies for electric stimulation 
using medium-frequency alternating current. Archives of physical medicine and rehabilitation 
2002;83:1024-1027. 
51. 
Joseph L, Butera RJ. High-frequency stimulation selectively blocks different types of 
fibers in frog sciatic nerve. IEEE Trans Neural Syst Rehabil Eng 2011;19:550-557. 
52. 
Medina LE, Grill WM. Volume conductor model of transcutaneous electrical 
stimulation with kilohertz signals. J Neural Eng 2014;11:066012. 
53. 
Gelenitis K, Santamaria A, Pradarelli J, et al. Non-invasive Transcutaneous Spinal 
Cord Stimulation Programming Recommendations for the Treatment of Upper Extremity 
Impairment in Tetraplegia. Neuromodulation 2024. 
54. 
van der Lee JH, Beckerman H, Lankhorst GJ, Bouter LM. The responsiveness of the 
Action Research Arm test and the Fugl-Meyer Assessment scale in chronic stroke patients. J 
Rehabil Med 2001;33:110-113. 

  
 
Page 52 of 60 
 
55. 
Chen HM, Chen CC, Hsueh IP, Huang SL, Hsieh CL. Test-retest reproducibility and 
smallest real difference of 5 hand function tests in patients with stroke. Neurorehabil Neural 
Repair 2009;23:435-440. 
 
 

  
 
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12. APPENDICES 
 
12.1. List of Abbreviations and Definition of Terms 
 
AE 
Adverse Experience 
ASaT 
All Subjects as Treated 
βhCG 
Beta-Human Chorionic Gonadotropin 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Scale 
DEGs 
Data Entry Guidelines 
ALS 
Amyotrophic Lateral Sclerosis 
ECI 
Events of Clinical Interest 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FSH 
Follicle-stimulating Hormone 
TPS 
Transcranial Pulse Stimulation 
GCP 
Good Clinical Practice 
HR 
Heart Rate 
 
IA 
Interim Analysis 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Review Committee 
IRB 
Institutional Review Board 
kg 
Kilogram 
NCS 
Not Clinically Significant 
PDLC 
Pre-Defined Limit of Change. 
PE 
Physical Examination 

  
 
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SAC 
Scientific Advisory Committee 
SAE 
Serious Adverse Experience 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SES 
Standardized Effect Size 
SOC 
System Organ Class 
 
SOP 
Standard Operating Procedure 
SAP 
Statistical Analysis Plan 
ULN 
Upper Limit of Normal 

  
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12.2. MS Diagnosis Criteria 
The diagnosis of MS according to the McDonald criteria requires:  
Clinical Presentation 
Additional data needed for MS diagnosis 
Two or more attacks; objective clinical 
evidence of two or more lesions 
None 
Two or more attacks; objective clinical 
evidence of 1 lesion 
Dissemination in space, demonstrated by: 
• MRI or, 
• Two or more MRI-detected lesions 
consistent with MS plus positive CSF 
or, 
• Further clinical attack at a different 
site later 
One attack; objective clinical evidence for 
two or more lesions 
Dissemination in time, demonstrated by: 
• MRI or, 
• Second clinical attack 
One attack; objective clinical evidence of 
one lesion (monosymptomatic 
presentation; CIS) 
Dissemination in space, demonstrated by: 
• MRI or, 
• Two or more MRI-detected lesions 
consistent with MS plus positive CSF 
and 
Dissemination in time, demonstrated by: 
• MRI or, 
• Second clinical attack 
Insidious neurologic progression suggestive 
of MS (PPMS) 
1-year disease progression (retrospectively 
or prospectively objectively determined) 
and two of the following: 
• Positive brain MRI (nine T2 lesions 
or four or more T2 lesions with 
positive VEP) 
• Positive spinal cord MRI (two focal 
T2 lesions) 
• Positive CSF 
 

  
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12.3 
General Neurological Exam 
The General Neurological Examination will be performed at the timepoint(s) specified in the 
protocol flow chart. 
Note to the investigator: If at any time abnormalities are observed in the General 
Neurological Exam, the Investigator should do additional examinations as needed based 
on his or her medical judgment. 
The General Neurological Examination includes all of the modules listed below, with the 
exception of Module 1, and is intended to be a general screening examination and 
sufficient for this study and subject population. 
MODULE 2 – CRANIAL NERVE ASSESSMENT 
A. II – Visual Fields and acuity 
B. II, III – Pupil Size and Reactivity 
C. III, IV, VI – Extraocular Movements (range of motion, smooth pursuit, saccades, 
nystagmus) 
1. Observe for nystagmus during eye movements, increased nystagmus at the end of 
gaze or other oculomotor changes (mild nystagmus at extremes of gaze is normal). 
Note direction of nystagmus 
D. V – Facial Sensation, Jaw Strength 
E. VII – Muscles of Facial Expression (wrinkle brow, squeeze eyes shut, smile) 
F. VIII – Auditory Acuity (assessed using a bed-side screening test eg by rubbing fingers on 
each side of subject’s head or by whispering numbers) 
G. IX – Gag reflex 
H. X – Swallow  
I. XI – Shoulder shrug 
J. Tongue Protrusion (midline) 
Score: left and right (except for G, H, J) 
Grade: NORMAL or IMPAIRED and describe abnormality 
MODULE 3 - MOTOR SYSTEM 
A. Muscle Tone 
1. Ask the volunteer to relax. 
2. Flex and extend the volunteer’s elbows and knees (bilaterally). 
3. There is a small, continuous resistance to passive movement. 
4. Observe for involuntary movements (eg, tremor, tics, fasciculations). Observe for 
resistance to passive movement; observe for decreased (flaccid) or increased 
(rigid/spastic) tone. 
Score:  left and right 
Grade: NORMAL, INCREASED or DECREASED 
B. Muscle Strength 

  
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1. Ask the subject to stand up from sitting without using hands Grade: NORMAL, 
IMPAIRED and describe abnormality 
2. Test proximal limb strength by having the volunteer flex and extend the knees and 
elbows against your resistance. 
Test bilaterally and compare 1 side to the other. 
Score:  left and right 
Grade: 5/5: normal; 4/5: movement against resistance impaired; 3/5: movement 
against gravity but not against resistance; 2/5: visible movement but not against 
gravity; 1/5: visible contraction; 0/5: no visible activity 
3. Test distal limb strength by having the volunteer conduct dorsiflexion and plantar 
flexion of the volunteer’s feet; finger abduction and handgrip strength against your 
resistance. 
Test bilaterally and compare 1 side to the other. 
Score:  left and right 
Grade: 5/5: normal; 4/5: movement against resistance impaired; 3/5: movement 
against gravity but not against resistance; 2/5: visible movement but not against 
gravity; 1/5: visible contraction; 0/5: no visible activity 
C. Pronator Drift 
1. Ask the volunteer to hold both arms straight forward with, palms up and eyes closed 
for ~10-15 seconds as tolerated; watch for how well the arm position is maintained. 
2. Instruct the volunteer to keep both arms still while you tap them briskly downward. 
The volunteer should normally be able to maintain extension and supination. 
Inability to maintain extension and supination (and drift into pronation) indicates an 
upper motor neuron deficit. 
Score:  left and right 
Grade: NORMAL or IMPAIRED and describe abnormality 
MODULE 4 - REFLEXES 
A. Biceps 
B. Knee 
Note: Other deep tendon reflexes may be tested at Investigator's discretion (eg elbow, wrist 
or Achilles tendon) 
Score: left and right 
Grade: NORMAL, INCREASED, DECREASED or ABSENT 
C. Babinski 
Score: left and right 
Grade: NORMAL or ABNORMAL 
MODULE 5 - COORDINATION AND GAIT 
A. Rapid, Rhythmic Alternating Movements 

  
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1. Testing each hand separately, ask the volunteer to tap the distal thumb with the tip 
of each finger, in sequence, as fast as possible.  
Score: left and right 
Grade: NORMAL or IMPAIRED 
Reminder: If the rapid alternate movements are disturbed, the subject will be 
asked to strike his hand on the thigh, raise the hand, turn it over and 
then strike the back of the hand down on the same place.  (This test is 
impaired in cerebellar disease, extra pyramidal disease and upper MN 
weakness.) 
B. Point-to-Point Movements 
1. Ask the volunteer to touch your index finger and their nose alternately several 
times. Move your finger about as the volunteer performs this task. 
Score: left and right 
Grade: NORMAL or IMPAIRED 
Reminder: If the point-to-point testing is disturbed, the subject will be asked to 
place 1 heel on the opposite knee and then run it down the shin to the 
big toe. Repeat this for both sides. (Impaired tests indicate cerebellar 
disease.) 
C. Romberg 
1. Ask the volunteer to stand with both feet together and eyes closed for 20 to 30 
seconds without support. 
2. Be prepared to catch the volunteer if they are unstable. 
Grade: NORMAL or IMPAIRED 
D. Gait 
1. Ask the volunteer to walk across the room, turn and come back (assess posture, 
balance, swinging of arms and movement of the legs). 
Grade: NORMAL or IMPAIRED and describe abnormality 
2. Ask the volunteer to walk heel-to-toe in a straight line (tandem gait). 
Grade: NORMAL or IMPAIRED and describe abnormality 
MODULE 6 - SENSORY 
A. Light touch sense:  cotton wisp on skin of forearms and legs, bilaterally. 
B. Pin prick: safety pin touched lightly to skin of forearms and legs, bilaterally. 
C. Temperature: warm or cool object touched to skin of forearms and legs, bilaterally. 
D. Vibration:  tuning fork vibration detection in hands, feet bilaterally. E. Position sense:  
perception of thumb and toe movement, bilaterally. 
F. Stereognosis: (identify common objects placed in hand, eg, coin, key). 
Score: left and right 
Grade: NORMAL OR IMPAIRED and describe abnormality (for each A to F) 

  
Page 59 of 60 
 
 
12.4 Predefined Limits of Change Criteria  
Predefined Limits of Change Criteria for Vital Signs, Weight, and Temperature 
Measurement 
Criteria 
Systolic blood   
pressure 
≥180 mm Hg and ≥20 mm Hg increase from 
baseline 
< 90 mm Hg and > 20 mm Hg decrease from 
baseline 
Diastolic blood   
pressure 
≥105 mm Hg and ≥15 mm Hg increase from 
baseline 
< 50 mm Hg and > 15 mm Hg decrease from 
baseline 
Pulse 
≥120 bpm and ≥15 bpm increase from baseline 
< 50 bpm and > 15 bpm decrease from baseline 
Orthostatic blood 
pressure 
>20 mm Hg systolic sitting to standing after 
treatment  
(but not in baseline) 
Weight 
≥7 % increase from baseline 
≥7 % decrease from baseline 
Temperature 
≥101°F and ≥2°F increase from baseline (≥38.3°C 
and ≥1°C increase from baseline) 
 
 
 
 
 

  
Page 60 of 60 
 
13.0 SIGNATURES 
13.1 Investigator 
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data 
in accordance with the protocol and, in particular, I agree to report any serious adverse 
events as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to 
handle all clinical supplies and collect and handle all clinical specimens in accordance with 
the protocol.  I understand that information that identifies me will be used and disclosed as 
described in the protocol, and that such information may be transferred to countries that 
do not have laws protecting such information.  Since the information in this protocol and 
the referenced Investigator’s Brochure is confidential, I understand that its disclosure to any 
third parties, other than those involved in approval, supervision, or conduct of the trial is 
prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure, or access by third parties. 
TYPED NAME 
 
TITLE 
 
SIGNATURE 
 
DATE SIGNED