High Frequency Impulse Therapy for Neuropathic Pain in NMOSD
Phase: PHASE2
Conditions: Neuromyelitis Optica
Sponsor: Massachusetts General Hospital

 
 
 
Transcutaneous Electrical Nerve Stimulation (TENS) Therapy for Neuropathic Pain in 
NMOSD 
 
Principal Investigator 
Michael Levy, MD, PhD 
55 Fruit St. 
WACC 8th floor 
Boston, MA 02114 
Phone: 617-726-0412  
Email: mlevy11@mgh.harvard.edu  
 
 
 
Protocol Version: 
 
2.1, March 17, 2022 
 
 
 
Original Protocol:               May 3, 3021 
 
 
 
 
 
 
Protocol Revision Record:  
 
Amendment #1: 
 
 
 
Amendment #2: 
 
 
 
Amendment #3: 
 
 
 
 
 
 
 
 

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
Version:  January 28, 25 
 
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Table of Contents 
 
 
1. INTRODUCTION ................................................................................................................................................ 4 
2. TRIAL SCHEME AND OBJECTIVES ............................................................................................................. 6 
2.1. SCHEME ............................................................................................................................................................ 6 
2.2. PRIMARY OBJECTIVE ........................................................................................................................................ 6 
2.3. SECONDARY ..................................................................................................................................................... 6 
3. HYPOTHESES ..................................................................................................................................................... 7 
3.1. PRIMARY .......................................................................................................................................................... 7 
3.2. SECONDARY ..................................................................................................................................................... 7 
4. BACKGROUND AND RATIONALE ................................................................................................................ 8 
4.1. ETIOLOGY AND CURRENT TREATMENT OF CENTRAL NEUROPATHIC PAIN IN PATIENTS WITH NEUROMYELITIS 
OPTICA SPECTRUM DISORDER ......................................................................................................................... 8 
4.2. TENS THERAPY: POTENTIAL APPLICATION TO CENTRAL NEUROPATHIC PAIN .................................................. 9 
5. PATIENT POPULATION ................................................................................................................................. 11 
5.1. INCLUSION CRITERIA ...................................................................................................................................... 11 
5.2. EXCLUSION CRITERIA .................................................................................................................................... 11 
5.3. INCLUSION OF WOMEN AND MINORITIES ....................................................................................................... 13 
5.4. INCLUSION OF CHILDREN ............................................................................................................................... 13 
6. STUDY DESIGN AND TREATMENT PLAN ................................................................................................ 14 
6.1. SUMMARY ...................................................................................................................................................... 14 
6.2. RECRUITMENT ................................................................................................................................................ 14 
6.3. DETERMINATION OF ELIGIBILITY ................................................................................................................... 14 
6.4 RANDOMIZATION AND BLINDING ....................................................................................................................... 14 
6.5. METHODS AND INTERVENTION ...................................................................................................................... 14 
6.6. PATIENT-REPORTED OUTCOMES ....................................................................................... 16 
6.7. CONCOMITANT AND SUPPORTIVE THERAPY ................................................................................................... 16 
6.8. DISCONTINUATION AND WITHDRAWAL OF SUBJECTS .................................................................................... 17 
7. TABLE 3: PATIENT EVENT CALENDAR ................................................................................................... 18 
8. ADVERSE EVENTS .......................................................................................................................................... 19 
8.1. GENERAL .......................................................................................................................... 19 
8.2. REPORTING PROCEDURES ............................................................................................................................... 19 
9. SAFETY MONITORING .................................................................................................................................. 20 
9.1. DATA MANAGEMENT ..................................................................................................................................... 20 
9.2. MONITORING .................................................................................................................................................. 20 
10. ADMINISTRATIVE PROCEDURES .............................................................................................................. 21 
10.1. PROTOCOL AMENDMENTS ................................................................................................ 21 
10.2. INFORMED CONSENT ...................................................................................................................................... 21 
10.3. ETHICS AND GOOD CLINICAL PRACTICE ........................................................................................................ 21 
10.4. REGULATORY AUTHORITIES .......................................................................................................................... 22 
11. STATISTICAL PLAN ........................................................................................................................................ 22 

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
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12. APPENDIX A ...................................................................................................................................................... 24 
13. REFERENCES ................................................................................................................................................... 29 
 
 

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
Version:  January 28, 25 
 
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1. Introduction 
Neuromyelitis optica spectrum disorder (NMOSD) is a chronic relapsing autoimmune disease of 
the central nervous system (CNS) that preferentially targets the optic nerves and spinal cord, 
leading to paralysis, blindness and death. NMOSD is a rare disease that affects approximately 
4,000-8,000 (1-2:100,000 persons in the US) people in the United States, disproportionately 
affects non-Caucasians and females, and has a worldwide prevalence estimated to be 0.52 to 
4.4/100,000. Pain is a severely disabling component of the disease with up to 91% of patients 
reporting central neuropathic pain (CNP) characterized by agonizing burning, shooting or 
tingling sensation in the face, arms, torso and legs. NMOSD lesions in the spinal cord are 
characteristically long and destructive, and pain is more prevalent in NMOSD than in most other 
neurological diseases. Research on the impact of persistent pain on quality of life (QoL) in 
NMOSD has found that those patients with CNP experience more depression, less enjoyment of 
life, and more difficulty with ambulation. Currently, there is no standard of care for CNP 
treatment and off-label use of medications typically used for diabetic peripheral neuropathy are 
often insufficient. NMOSD is a devastating disease and there remains a high unmet need for 
effective treatment of CNP. 
 
Transcutaneous electrical nerve stimulation (TENS) therapy is a non-invasive pain modifying 
intervention that utilizes transcutaneous electrical stimulation of ascending (sensory) fibers with 
the intent of re-organizing maladaptive signaling pathways. This neuromodulatory therapy has 
been investigated for treatment of persistent peripheral neuropathic pain in several conditions 
including chemotherapy-induced neuropathy, post-herpetic neuralgia and post-surgical 
neuropathic pain with promising results. Patients report sustained relief after undergoing daily 
treatment sessions for 10 consecutive weekdays.  
 
Recently we completed a sham-controlled trial using a TENS unit called Scrambler in NMOSD 
patients showing a meaningful reduction in neuropathic pain compared to controls. The 
Scrambler device must be operated in an office by a professional technician, thereby limiting its 
usefulness to the wider NMOSD population. The Quell transcutaneous electrical nerve 
stimulation device delivers varying electric pulses non-invasively to reduce pain.  It is a small, 
wearable device that utilizes regularly-changing electric pulses to stimulate nerves such that the 
experience of pain is blocked.  Because the Quell Flex is programmable remotely, a sham-
controlled trial can be conducted while keeping the patient blinded to the trial arm. 
 
For patients with NMOSD and other conditions that cause pain originating in the central nervous 
system, non-obtrusive, non-pharmacological devices might prove a viable alternative to pain 
medications. Pharmaceutical treatments for pain such as opioids have led to addiction and life-
style changes with unacceptable side effects. Cost and side effects are concerns with other 
pharmacologic therapies for pain. In addition, in efforts to control pain, many patients are 
prescribed multiple medications, and then have to cope with the complexities and hazards of 
polypharmacy.  Most importantly, none of the pharmaceutical treatments for pain in NMOSD 
have been proven effective in a trial. 
 
 
 

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
Version:  January 28, 25 
 
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If we could show among a significant patient cohort that a safe and effective at-home 
nonpharmacological pain therapy is available for patients with NMOSD, it would be life altering 
for a great many – not only those with NMOSD, but also with related neuroimmune disorders 
and other conditions with central neuropathic pain.  
The goal of this project is to provide an effective, non-invasive treatment for neuropathic pain in 
NMOSD that can be safely employed at home. Many NMOSD patients have such chronic pain 
and/or disability that frequent visits to the clinic for therapy is difficult, if not impossible, in the 
best of times. Secondly, safe at-home treatments that offer continuous relief of pain (and 
potentially other co-occurring symptoms) can improve quality of life immensely during this, and 
likely future times of social distancing, when leaving home is dangerous, especially for a 
population on lifelong immune suppressants.  Also, an at-home therapeutic option will save both 
time and money for patients. 
 
 

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
Version:  January 28, 25 
 
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2. Trial Scheme and Objectives 
2.1. 
Scheme 
Patients will be randomized 1:1 to receive treatment daily for 4 consecutive weeks versus sham, 
followed by an open-label phase for additional 4 consecutive weeks. 
2.2. 
Primary Objective 
The primary objective is to determine the difference in the Numerical Pain Scale score between 
the baseline screening call and at week 4 in the treatment group compared with the same 
difference in the placebo or sham group. 
 
The Numerical Pain Scale is an 11-point scale (0-10) that includes guides to assist in the 
determination of the pain level. 
2.3. 
Secondary 
Six secondary objectives are intended to collect additional information about the potential benefit 
of QUELL FLEX: 
 
A. The difference in pain scores at the end of the open label phase compared to the end 
of the initial blinded phase.  
B. A change in the “worst” pain score in the treatment arm vs. the sham arm between the 
baseline screening call and week 4; and the change in the “worst” pain from baseline 
to week 8 for all subjects. 
C. A change in the “average” pain score in the treatment arm vs. the sham arm between 
the baseline screening call and week 4; and the change in the “average” pain from 
baseline to week 8 for all subjects. 
D. The number of patients who withdraw because of poor compliance. We expect a 
higher withdrawal and non-compliance rate in the sham group.  
E. Quality of life surveys will be conducted before and after the treatment phase and at 
the end of the study to determine if the QUELL FLEX treatment impacts overall 
quality of life. 
F. Reduction in pain medication use over the course of the study. 
 
 

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
Version:  January 28, 25 
 
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3. Hypotheses 
3.1. Primary 
• QUELL FLEX therapy reduces pain scores in NMO patients on the Numerical Pain Scale 
at the week 4 study visit compared to baseline/screening visit, and this reduction is 
significantly greater compared to the reduction due to sham treatment during the same 
time period. Power for this study is calculated based on our previous study using a TENS 
unit (Scrambler) in the same patient population.  
3.2. 
Secondary 
• QUELL FLEX therapy is an acceptable treatment measured by compliance and patient 
survey. 
• Patients who were randomized initially to the sham arm will show a reduction in pain 
score after crossing over into the open label arm. In contrast, the patients in the treatment 
arm will not necessarily show additional benefit after rolling over in the open label arm.  
• The “average” and “worst” pain scores will decline in the treatment arm and not 
necessarily in the sham arm. 
• As pain is a primary driver of quality of life, quality of life will improve with treatment 
compared to sham.  
• Patients for whom QUELL FLEX works well may choose to reduce their intake of pain 
medications. 
 
 

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
Version:  January 28, 25 
 
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4. Background and Rationale 
4.1. Etiology and current treatment of central neuropathic pain in patients with 
neuromyelitis optica spectrum disorder 
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central 
nervous system (CNS) that preferentially causes recurrent inflammatory attacks in the optic 
nerves and spinal cord, leading to blindness, paralysis and death. Despite these devastating 
consequences of the disease, patients have reported that pain is among the most prevalent and 
debilitating symptoms. 
 In particular, 
central 
neuropathic pain 
(CNP) is 
pervasive, severe, 
intractable to 
treatment, and 
affects 62-91% of 
patients with 
NMOSD. CNP is 
described as 
agonizing 
burning, stabbing, 
shooting, 
tingling or 
squeezing 
sensation that is distressing, persistent and incapacitating. While the severity of CNP in NMOSD 
is not well-understood, its presence is a direct consequence of targeted immune-mediated 
destruction of the spinal cord and occurs at and below the spinal cord lesion level, and may be a 
result of damage to ascending sensory pathways where there is inadequate stimulation of 
peripheral sensory nerve endings.  Ascending (sensory) pathways are nerves that go upward from 
the spinal cord toward the brain carrying sensory information from the body to the brain. In 
contrast, descending (motor) pathways are nerve pathways that go down the spinal cord and 
allow the brain to control movement of the body below the head (Figure 1). As a consequence of 
ongoing spontaneous activity arising in the periphery, surviving neurons develop increased 
background activity, enlarged receptive fields and increased responses to ascending nerve 
impulses, including normally harmless tactile stimulation. 
 
Figure 1. Cross-section of the spinal cord depicting spinal tracts.  
 
 
 
                 From: 

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
Version:  January 28, 25 
 
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4.2. 
TENS Therapy: potential application to central neuropathic pain 
4.2.1. Rationale for nerve-based treatments  
Scrambler Therapy is a new, non-invasive technology with Food 
and Drug Administration (FDA) 510(k) approval, "Scrambler ST 
5 TENS Device," (K081255) granted in February 2009. It uses 
cutaneous electrostimulation that simulates normal nerve action 
potentials. The impulses are transmitted via surface electrodes 
placed surrounding the pain area along the same nerve pathways, 
done by following the dermatomes and avoiding areas that hurt 
(Figure 2). The device synthesizes 16 different types of nerve 
action potentials similar to the endogenous kinds, strings them 
into sequences, and directly stimulates the nerves. These different 
waveforms are dynamically assembled into strings of information 
that are recognized by the CNS and replace pain with “no-pain” 
information. Neuroplasticity enables these new signals to replace the old, inappropriate 
amplification of pain signals. Scrambler therapy provides 16 continuously changing variable 
nonlinear waveforms, or a “scrambled” signal, thus making it different from transcutaneous 
electrical nerve stimulation (TENS), which provides an on-off, biphasic waveform. TENS is 
thought to block the pain signal rather than replace it with new information, which translates into 
often short-lived results that are not as practical for persistent pain. Data in Scrambler therapy, 
on the other hand, suggests that patients can have significantly reduced pain or be pain-free for 
up to 3 months following a series of treatments, and that follow-up treatments may require fewer 
sessions for continued relief, including limited data from randomized controlled trials. The exact 
mechanism by which Scrambler Therapy relieves pain is under investigation. 
 
OH DEAR.  THE ENDNOTES ARE ALL MESSED UP. 
 
4.2.2. Data on Scrambler therapy 
In 2018, the Johns Hopkins Neuromyelitis Optica Clinic conducted a sham-controlled 
randomized trial of Scrambler treatment over 10 consecutive days in 22 NMOSD patients to 
determine efficacy, acceptability, feasibility and duration of in-clinic therapy. We measured 
changes in pain with the numerical rating scale and analyzed change in pain levels and related 
symptoms at time of treatment and again at 30 and 60 days.  The findings showed significant 
pain reduction and quality of life improvements, including reduction of anxiety and depression, 
up to 30 days.  Scrambler has been used in other patients with central neuropathic pain including 
a brainstem lesion and transverse myelitis. 
 
Because of the positive effects of Scrambler therapy on NMOSD patients, and because of the 
complications inherent in accessing said therapy, we became interested in following that study 
with one assessing portable devices using similar methodology. 
 
 
Figure 2. A picture of the machine with 
electrode placement. Permission from 
Thomas Smith, MD

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
Version:  January 28, 25 
 
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4.2.3. Data on Quell Relief 
 
In a study for Quell TENS on back pain, the following results were reported:  
“After six weeks, those in the Experimental group reported lower “worst” pain scores and less 
overall interference than those in the Control group (p<0.025). After three months those 
assigned to the Experimental group (hfTENS device) reported significantly less pain (worst, 
least, average, now) than those in the Control condition (p<0.01; Table 3). Pre-post 
comparisons on average pain intensity on the BPI showed significant groups differences 
(Experimental=1.24; Control=-0.03; t=2.74; p<0.01) with 31.0% of the Experimental group 
showing ≥2.0 differences vs. 12.9% among the Control group. Those in the Experimental group 
also reported less overall pain-related interference (general activity, mood, walking ability, work, 
relation with others, sleep, and enjoyment of life) compared with the Control group (p<0.025). 
Also, subjects assigned to use the hfTENS reported reduced pain catastrophizing scores 
compared with the Controls (p<0.025). No differences were noted between groups on the self-
report questionnaires assessing disability (PDI) and anxiety and depression (HADS). Both 
groups demonstrated a reduction in the use of prescription pain medication, but no differences 
were found between groups.”   
 

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
Version:  January 28, 25 
 
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5. Patient Population 
5.1. Inclusion Criteria 
5.1.1. Men and women 18 years of age or older diagnosed with NMOSD per the 2015 
NMOSD criteria 
5.1.2. Patients must be positive for the aquaporin-4 antibody in serum  
5.1.3. Presence of persistent neuropathic pain (>3 months) rated at a level of 4 or higher on 
the Numerical Pain Scale 
5.1.4. Patients must be stable in their disease, such that they have had no spinal cord 
relapses within 6 months prior to enrollment 
5.1.5. Patients must be on a stable medication regimen that may include anti-epileptic, 
antidepressant, or non-steroidal anti-inflammatory medications, with no adjustments 
to the regimen within 30 days of enrollment 
5.1.6. Pain must be localized to a spinal cord lesion  
5.1.7. Patient understands the study regimen, its requirements, risks, and discomforts, and is 
able and willing to sign an informed consent form 
5.1.8. Patients must own and be able to operate an iOS or Android smartphone with internet 
connection 
5.2. Exclusion Criteria 
5.2.1. Patients who are cognitively or mentally incompetent  
 
5.2.2. Patients whose primary complaint is numbness/tingling 
5.2.3. Any of the following: pregnant women, nursing women, women of childbearing 
potential or their sexual partners who are unwilling to employ adequate contraception 

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
Version:  January 28, 25 
 
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(condoms, diaphragm, birth control pills, injections, intrauterine device [IUD], 
surgical sterilization, subcutaneous implants, abstinence, etc.). 
5.2.4. Use of an investigational agent for pain control concurrently or within the past 30 
days 
5.2.5. History of an allergic reaction or previous intolerance to transcutaneous electronic 
nerve stimulation or to latex 
5.2.6. Patients with implantable drug delivery systems, e.g. Medtronic Synchromed. 
5.2.7. Patients with heart stents or metal implants such as pacemakers, automatic 
defibrillators, cochlear implants, aneurysm clips, vena cava clips and skull plates 
(Metal implants for orthopedic repair, e.g. pins, clips, plates, cages, joint 
replacements are allowed) 
5.2.8. Patients with a known history of myocardial infarction or ischemic heart disease 
within the past six months 
5.2.9. Patient who have had surgery to treat a pain-related condition in the last 6 months 
5.2.10. Prior celiac plexus block, or other neurolytic pain control treatment, within 1 month 
5.2.11. Other identified causes of painful parasthesias existing prior to chemotherapy (e.g., 
carpal tunnel syndrome, B12 deficiency, AIDS, monoclonal gammopathy, diabetes, 
heavy metal poisoning amyloidosis, syphilis, hyperthyroidism or hypothyroidism, 
inherited neuropathy, etc.) that might be responsible for the patient’s current 
neuropathic symptoms 
5.2.12. Skin conditions such as open sores that would prevent proper application of the 
electrodes 
5.2.13. Patients with an ongoing concomitant central neurologic disorder or history of 
epilepsy, brain damage, or symptomatic brain metastases  
5.2.14. Other medical or other condition(s) that in the opinion of the investigators might 
compromise the objectives of the study 
 
5.2.15. Pain is primarily due to prior spinal fusion procedure or pain is in an area where there 
was previously a spinal fusion procedure 

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
Version:  January 28, 25 
 
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5.2.16. History of an allergic reaction or previous intolerance to hydrogel adhesive used in 
TENS devices 
5.2.17. Patients with implantable spinal cord stimulators 
5.3. 
Inclusion of Women and Minorities 
This interventional clinical trial will involve the recruitment of 46 participants with central 
neuropathic pain resulting from neuromyelitis optica spectrum disorder (NMOSD). There are no 
restrictions related to sex, race or ethnicity for trial inclusion. NMOSD disproportionately affects 
women and minorities. Given that the ratio by sex of those diagnosed with NMOSD is 6.5-9 
females for every 1 male, the expectation is that at least 80% of participants will be women.  
5.4. Inclusion of Children 
This study includes women and men with central neuropathic pain caused by neuromyelitis 
optica spectrum disorder (NMOSD) who are of age 18 years or older. Because previous trials 
have involved those aged 18 and older, children under the age of 18 will not be included. Most 
patients are diagnosed with NMOSD in their 30’s and 40’s, and it is the expectation that this will 
impact recruitment very little.  
 
 

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
Version:  January 28, 25 
 
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6. Study Design and Treatment Plan 
6.1. 
Summary 
Building on the recent successful phase II study using Scrambler TENS among NMOSD 
patients, we propose bringing a non-invasive neuromodulation technology to a larger NMOSD 
population with the important distinction that we will study self-administered take-home QUELL 
FLEX units on this cohort of patients for the reasons outlined above. 
6.2. 
Recruitment 
We plan to recruit 46 consecutive patients with NMOSD (23 per arm) with a diagnosis of 
NMOSD based on the 2015 international consensus diagnostic criteria and the presence of 
neuropathic pain. Trial information will be made available through clinicaltrials.gov. 
6.3. 
Determination of Eligibility 
Eligibility for participation will be reviewed and confirmed by a member of the study staff.  
Upon successful eligibility, the patient will be eligible for registration into the study, at which 
time a study-specific subject ID/number will be assigned.   
 
For patients who reach the study team from outside of the Mass General NMO Clinic, a member 
of the patient’s care team will be consulted to confirm that s/he believes that the participant is 
appropriate for protocol participation. 
 
Study intervention cannot begin until the patient is successfully registered and consented.  
6.4 Randomization and Blinding 
Randomization would be done in blocks of 4 (e.g. 2 placebo and 2 treatment assignments) 
assigned at random at the beginning of the study for each 4 patients enrolled in the study 
consecutively. This ensures that it is not possible to predict the arm assignment of patients as we 
unblind them in groups of 4 at the conclusion of each patient’s participation in the study. 
 
Blinding keys, including the arm assignment of the patient, will be sealed in envelopes and not 
opened until unblinding occurs for the 4-patient-block.  
6.5. Methods and Intervention 
6.5.1. QUELL FLEX Transcutaneous Electrical Nerve Stimulation Therapy 
The locations of symptoms will be assessed remotely by telemedicine and remote MRI review. If 
patient has pain areas referable to more than one lesion, treatment will be done on the area that is 
most bothersome to the patient.  
6.5.1.1. Treatment Days 
 
1. Prior to initiation of Quell therapy, patients will be asked to rate their pain on the 
Numerical Pain Scale and will complete a Short Form-36 Health Inventory (SF-36).  
2. All training on the use of the device will be conducted remotely through Zoom.  

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
Version:  January 28, 25 
 
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3. Patients will be shipped a QUELL FLEX device. It will either be a functional QUELL 
FLEX device for the treatment arm or a non-functional QUELL FLEX device in the sham 
arm. All of the lights, charging equipment, and app connectivity will be the same. The 
only difference is that the non-functional sham devices will administer an electrical 
current for only 2 minutes each at the top of a treatment hour, at 30 minutes and at 58 
minutes, as opposed to for the full hour when the device is engaged. 
4. Patients will be informed that we are conducting a number of different treatment 
paradigms – some of them have high frequency waves that are not perceptible, and some 
have lower frequency waves that may be transiently perceptible. In addition, we will re-
inform them there is a sham arm.  
5. The electrodes will be placed on patients on the back in the dermatome of the most 
painful area. The intensity of the stimulus is increased until the patient can first feel some 
sensation associated with the electrodes. Script: “Tell me when you feel something.” 
6. Stimulation intensity will be increased until a maximum threshold is tolerated without 
being painful.  
7. Once the intensity is at its maximum setting, the study coordinator will evaluate the level 
of pain. If the patient feels a constant burn, single sting or feeling of discomfort, the 
electrodes will be repositioned. The exact electrode positioning will depend on the 
delimitation of the surface pain area, and analgesic response of the patient.  
8. Once satisfactory electrode placement and stimulus intensity is determined, therapy is 
maintained for at least an hour per day for 4 weeks (both treatment and sham groups).  
9. Patients will report pain scores weekly throughout experimental period while on a zoom 
call with the trial researcher. Patients will again complete all measurement tools and pain 
ranking at end of treatment. 
10. At the conclusion of the 4-week experimental arm, all patients will be shipped a new 
QUELL FLEX device for use in the 4-week open label phase. This one will be 
functional. The experimental QUELL FLEX devices will be returned in the same 
shipping box to the study team. Study staff will administer the SF-36 Quality of Life 
questionnaire. 
11. In the 4-week open label phase, patients will continue to use the device with the 
electrodes in the same position. Weekly pain scores will be documented as before as well 
as the SF-36 Quality of Life questionnaire at the conclusion of the 4-week open label 
period.  
12. At the conclusion of the 4-week open label period for the 4-patient block, blinding will be 
unsealed and reported to the patients. They will then have the opportunity to keep the 
functional QUELL FLEX if they wish.  
13. Four and eight weeks after the completion of the open label phase, patients will be called 
for a wellness check and asked to rate their pain again. 
14. Adverse Events will be monitored and documented weekly. 
6.5.1.2. Treatment follow-up:  
Patients will be contacted by Zoom weekly during the experimental and open-label phases to 
check in on them, and will be asked weekly to report their pain score. At the conclusion of the 
experimental phase and at the end of the study, patients will be asked again to complete the Short 
Form-36 Health Inventory (SF-36).   

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
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Patient-Reported Outcomes 
6.6.1. General 
 
The numerical pain scale will be administered verbally during each study visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study staff will ask both average and worst pain experienced in the week prior to each study 
visit, using the same Numerical Rating Scale.  Additionally, she will ask if and for how long 
relief lasted after QUELL FLEX use on average over the week. 
 
 
 
 
6.6.2. Measurement tools: description and rationale for use 
The Numerical Pain Scale used to collect input prior to initiation, and at end of treatment, has 
been validated in dozens of persistent pain conditions and is the most widely used tool in both 
Scrambler therapy and NMOSD research to date. SF-36 is a patient-reported survey of overall 
patient health-related quality of life and has been widely used for QoL assessment in chronic 
conditions, including in NMOSD research.  
 
NOTE:  Please see questionnaires in Appendix A. 
6.7. Concomitant and Supportive Therapy 
The concomitant medications and therapies deemed necessary for the supportive care and safety 
of the subject are allowed, provided their use is documented in the medical records.  
 
The use of other concurrent investigational drugs or devices for management of pain is not 
allowed unless approved by the Principal Investigator. 

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
Version:  January 28, 25 
 
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6.8. Discontinuation and Withdrawal of Subjects 
All patients who initiate protocol intervention will be included in the overall evaluation of 
tolerability and acceptability (intent-to-treat analysis). All reasons for discontinuation of therapy 
will be clearly documented in the record.  
 
Unless the subject refuses, follow-up will continue for the planned duration following the study 
intervention.   
6.8.1. Discontinuation of Intervention 
The reasons for discontinuation of protocol treatment include: 
 
• 
Non-compliance with the study protocol; including, but not limited to not using the 
device more than 75% of the study duration.  
• 
Unacceptable major reaction to electrical stimulation or other major adverse events 
• 
Intercurrent illness or condition that would, in the judgment of the treating investigator, 
affect assessment of clinical status to a significant degree or require discontinuation of 
study intervention. 
• 
At subject’s own request. Note: The reason for discontinuation from the study must be 
documented. The patients will be included in the overall evaluation of tolerability and 
acceptability (intent-to-treat analysis) if any protocol intervention was administered prior 
to withdrawal. 
• 
Study is closed or cancelled for any reason. 
6.8.2. Withdrawal from Study 
The reasons for withdrawal from the study include: 
 
• 
Subject withdraws consent for follow-up. 
• 
Subject is lost to follow-up. 
• 
Study is terminated for any reason. 
 
 

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
Version:  January 28, 25 
 
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7. Table 3: Patient Event Calendar  
Phase 
Baseline  
Screening/Consent 
Experimental 
(Weeks) 
Open Label 
(Weeks) 
Follow-up (weeks) 
Time Point 
(days) 
Within 2 weeks 
1 
2 
3 
4 
5 
6 
7 
8 
12 
16 
Exam/Tests
* 
Consent, MRI 
review, Q# 
AE and weekly 
pain score 
assessment, Q 
AE and weekly pain 
score assessment, Q 
AE and pain 
score 
assessment 
AE and pain 
score 
assessment 
#Q: Questionnaire (SF-36) 
 
 
 

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8. Adverse Events 
In over 4000 patients treated and reported to the FDA for approval, published and in-press 
studies, no significant adverse events have been reported with Scrambler and related TENS units.  
8.1.  General 
Adverse events will be monitored and documented weekly and at termination of final treatment.  
Any serious adverse events or study violations will be immediately reported to the Primary 
Investigator and Partners Institutional Review Board (IRB). Study deviations and other adverse 
events will additionally be reported to the PI immediately, and to the IRB within the IRB’s 
specified time frame. Given that the device has been cleared for marketing for the proposed 
use,28 no Investigational Device Exemption is needed through the FDA.  
 
Even though this trial includes a blinded experimental phase, given the low risk of adverse 
events imposed by the trial, it does not rise to the level of requiring a data safety monitoring 
board.  
 
Information about all intervention-related adverse events, including those volunteered by the 
subject, discovered by investigator/study personnel questioning, or detected through physical 
examination, or other means, will be collected, followed, and reported appropriately.   
8.2 Reporting Procedures 
All intervention-related adverse events will be captured on the appropriate source documents or 
in a designated database.  
 
The same applies to any adverse event classified as a “serious adverse event;” these will also 
only be reported if intervention-/study-related.   
 
Any unexpected intervention-related adverse events and serious adverse events will be reported 
to the IRB per current institutional standards. If an adverse event requires modification of the 
informed consent, these modifications will be provided to the IRB with the report of the adverse 
event. If an adverse event requires modification to the study protocol, these modifications will be 
provided to the IRB as soon as is possible.  
 
 

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9. Safety Monitoring 
9.1. Data Management 
All information will be collected by study staff through zoom conversations with patients.  She 
will maintain all responses on computer programs using only de-identified patient numbers. 
 
All study data will be reviewed for completeness and accuracy by the Principal Investigator.  
9.2.Monitoring  
Each week, patients will communicate with the study coordinator to check in and report adverse 
effects. At the start of the study, at the end of the experimental phase and at the conclusion of the 
study, quality of life surveys will be conducted by Zoom. Four and eight weeks after the study is 
completed, patients will be contacted to report their pain scores.  
 
 

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10. Administrative Procedures 
10.1. 
Protocol Amendments 
Any changes to the protocol will be made in the form of an amendment and must be approved by 
the IRB before implementation. The Principal Investigator (or his designee) is responsible for the 
coordination and development of all protocol amendments.  
10.2. 
Informed Consent 
Human subjects will be recruited through the Mass General NMOSD Clinic. This clinical trial 
will be posted through clinicaltrials.org and on The NMO Clinic’s Facebook page. Those 
patients who seek participation from outside of the Massachusetts General Brigham network are  
eligible to be screened. On-line consent forms will be provided to interested patients after an 
initial intake phone call. The consent form RedCap (or other approved IRB platform) link will be 
emailed to the patient and then discussed with the study coordinator over a Zoom call. The 
Principal Investigator or the study coordinator will explain to each patient the nature of the study, 
its purpose, procedures involved, expected duration, potential risks and benefits. Each patient 
will be informed that participation in the study is voluntary, that he/she may withdraw from the 
study at any time, and that withdrawal of consent will not affect his/her subsequent medical 
treatment. This informed consent will be given by means of an on-line statement and has been 
approved by the IRB. No patient will enter the study before her informed consent has been 
obtained. In accordance with the Health Insurance Portability and Accountability Act (HIPAA), 
the informed consent document (or a separate document to be given in conjunction with the 
consent document) will include a participant authorization to release medical information to the 
study sponsor and supporting agencies and/or allow these bodies, a regulatory authority, or 
Institutional Review Board access to subjects’ medical information that includes all hospital 
records relevant to the study, including subjects’ medical history.  The PI or study coordinator 
will file the signed consent forms. 
10.3. 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and Good Clinical Practice, as 
described in: 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations). 
3. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 
1964, amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
 
The investigator agrees to adhere to the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice. 

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Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
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10.4. 
Regulatory Authorities 
10.4.1. Institutional Review Board 
Information regarding study conduct and progress will be reported to the Institutional Review 
Board (IRB) per the current institutional standards. 
11. Statistical Plan  
11.1.Acceptability 
Counts and percentages will be used to assess acceptability based on adherence to treatment 
schedule. We will report the number and percent of patients in each group who are able to 
complete all treatments. A chi-square test for independence of group by dichotomous outcome 
will be performed to assess differences between the two groups. In the event that the expected 
frequencies are < 5, Fisher’s exact test will be performed. While no serious adverse events have 
been reported with use of Scrambler or other TENS therapies in the NMOSD patient population, 
the numbers and percent observed for each group will be reported. 
11.2. Efficacy  
Change in pain score will be calculated by subtracting the patient’s week 4 score from his or her 
baseline value prior to treatment initiation. Change in scores will be summarized using means 
and standard deviations provided the resulting distribution is symmetric, otherwise medians and 
interquartile ranges will be used. Provided the resulting distribution of pain scores is roughly 
normal, we will use a two-sample t-test to compare the QUELL FLEX and sham groups. 
Previous studies suggest that the average pain value at baseline is at least 4 on the 0-10 
numerical rating scale with a standard deviation of the original pain value expected to fall in the 
range of 1-1.5 in this patient population. As such, a conservative estimate of the standard 
deviation would be approximately 20%. With 19 patients in each arm and under these 
assumptions, we will have the ability to detect a change of 2.0 points in the QUELL FLEX 
group with power of 0.90. If the change score distribution is highly skewed, Wilcoxon’s signed 
rank test will be utilized instead.  
To account for ~20% dropout rate, we will add 4 subjects to each arm for a total of 23 subjects 
per arm. We included a dropout rate of ~20% based on previous studies with this device. We will 
run a sensitivity analysis to determine if the drop-out rate in either arm had an impact on the trial 
results 
A 20% reduction in pain has been previously determined to be a clinically meaningful 
improvement, we will report the number and percent of patients from each group who achieve 
this benchmark. 
11.3.Quality of Life 
As a sub-aim, we will investigate whether a decrease in pain impacts QoL (SF-36) over time by 
correlating the change in pain scores to the change in each variable between initiation of 

TENS for Neuropathic Pain in NMOSD 
 
Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
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treatment through the use of single variable regression. As an additional exploratory analysis we 
will categorize patients as having improved pain (> 20% point change on NPS scale) or not. We 
will then test for a relationship between improved pain and QoL, with the hypothesis that 
patients with less pain will be less likely to experience anxiety and depressive symptoms.  
11.4.Reporting and Exclusions 
Patients who sign a consent form, but do not initiate protocol intervention for any reason (e.g., 
patients who are screen failures), will be replaced and will not count towards our accrual goal. 
 
 

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Principal Investigator:  Michael Levy, MD, PhD 
 
 
 
 
 
 
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12. APPENDIX A 
 

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13. REFERENCES 
 
 
1. Oh J, Levy M. Neuromyelitis optica: an antibody-mediated disorder of the central 
nervous system. Neurol Res Int. 2012;2012:460825.  
 
2. Mealy MA, Boscoe A, Caro J, Levy M. Assessment of Patients with Neuromyelitis 
Optica Spectrum Disorder Using the EQ-5D. Int J MS Care. 2019 May-Jun;21(3):129-
134. 
 
3. Qian P, Lancia S, Alvarez E, Klawiter E, Cross A, Naismith R. Association of 
neuromyelitis optica with severe and intractable pain. Archives of Neurology 
2012;69(11). 
 
4. Zhao S, Mutch K, Elsone L, Nurmikko T, Jacob A. Neuropathic pain in neuromyelitis 
optica affects activities of daily living and quality of life. Multiple Sclerosis Journal 
2014;20(12).  
 
5. Mealy MA, Kozachik SL, Levy M. Review of Treatment for Central Spinal Neuropathic 
Pain and Its Effect on Quality of Life: Implications for Neuromyelitis Optica Spectrum 
Disorder. Pain Manag Nurs. 2019 Dec;20(6):580-591. 
 
6. Mealy M, Kozachik S, Cook L, Totonis L, Salazar R, Allen J, Nolan M, Smith T, Levy 
M. Scrambler therapy improves pain in neuromyelitis optica. Neurology 2020;94. 
 
7. https://www.quellrelief.com/wp-content/uploads/2020/08/01_Web.pdf 
 
8. D’Amato S, Mealy M, Erdek M, Kozachik S, Smith T. Scrambler therapy for the 
treatment of chronic central pain: a case report. A&A Practice 2018;10(12) 
 
9. Mealy M, Newsome S, Smith T. Case Report: Scrambler therapy for treatment-resistant 
central neuropathic pain in a patient with transverse myelitis. International Journal of MS 
Care 2019;21(2). 
 
10. Kapural L, Yu C, Doust MW, Gliner BE, Vallejo R, Sitzman BT, Amirdelfan K, Morgan 
DM, Brown LL, Yearwood TL, Bundschu R, Burton AW, Yang T, Benyamin R, Burgher 
AH. Novel 10-kHz High-frequency Therapy (HF10 Therapy) Is Superior to Traditional 
Low-frequency Spinal Cord Stimulation for the Treatment of Chronic Back and Leg 
Pain: The SENZA-RCT Randomized Controlled Trial. Anesthesiology. 2015 
Oct;123(4):851-60. 
 
11. Krebs EE, Gravely A, Nugent S, et al. Effect of Opioid vs Nonopioid Medications on 
Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis 
Pain: The SPACE Randomized Clinical Trial. JAMA. 2018;319(9):872-882. 
 

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12. Amirdelfan, et al. Non-Invasive High Frequency Impulse Therapy for Chronic Low Back 
Pain: A Multi-center, Randomized, Cham-controlled Trial. 2018 
 
13. TBD1: Jamison, R, Wan L et al. Outcome of a High Frequency Transcutaneous Electrical 
Nerve Stimulator (hfTENS) Device for Low Back Pain: A Randomized Controlled Trial