Quell Opioid Reduction and Pain Relief in Patients With Cancer
Phase: NA
Conditions: Pain, Metastatic Breast Cancer, Prostate Cancer, Colorectal Cancer
Sponsor: Scripps Translational Science Institute

Quell Opioid Reduction and Pain Relief in Patients with Cancer   
Scripps Translational Science Institute  
 
Version 3.0 Dated December 16th  2016 
Confidential Document 
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________________________________________________________________________ 
Quell Opioid Reduction and Pain Relief in Patients with Cancer  
________________________________________________________________________ 
 
 
 
 
 
STUDY PROTOCOL 
 
December 16th 2016 
Version 3.0 
 
 
 
 
 
 
 
 
 
 
Funding Provided By: 
NeuroMetrix, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Principal Investigator: 
Toluwalase Ajayi MD  
Scripps Translational Science Institute 
3344 N. Torrey Pines Court, Suite 300 
La Jolla, CA   92037 
858-554-5708 
Fax:  858-546-9272 
 
 
 
Study Co-Investigator:  
Casei Shenoy MD 
Scripps Health 
4311 3rd Ave San Diego CA 
San Diego CA 92103 
 
 
Study Site 
 
Scripps Mercy Cancer Center 
4020 5th Ave 
Unit 401 
San Diego, CA  92103 
United States 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
 

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Table of Contents 
 
 
 
 
 
3 
Abbreviations and Definitions  
 
 
______4 
1. Rationale and Purpose 
 
 
 
 
6 
2. Study Background  
 
 
 
 
6 
 
 
 
3. Study Design   
                      
 
______8 
4. Criteria for Evaluation 
 
 
 
 
9 
5. Subject Selection  
 
 
 
 
 
10 
 
-Inclusion 
 
 
 
 
 
 
 
-Exclusion 
6. Concurrent Medications 
 
 
 
 
10 
7. Study Procedures 
 
 
 
 
 
11 
 
 
8. Evaluation By Visit  
 
 
 
 
12 
9. Data Storage   
 
 
 
_______ 
14 
10. Statistical Analysis  
 
 
 
 
14 
11. Discontinuation and Replacement of Subjects 
 
15 
12. Potential Risks 
 
 
 
 
 
16 
13. Potential Benefits 
 
 
 
 
 
16 
14. Risks/Benefits Ratio  
 
 
______ 
17 
15. Alternative Treatments 
 
 
 
 
17 
16. Payment and Costs  
 
 
 
 
17 
17. Informed Consent 
 
 
 
 
 
17 
18. Confidentiality of Data and Privacy of the Individual 
17 
19. Safety  
 
 
 
 
 
 
18 
 
 
20. Monitoring 
 
 
 
 
 
 
18 
 
 
 
21. Record Retention 
 
 
 
 
 
19 
22. Publication 
 
 
 
 
 
 
19 
23. Facilities and Personnel 
 
 
 
 
19 
-Site Selection 
-Clinical Trial Agreement 
-Personnel Training 
-Center Readiness 
24. References_______________________________________21 
25. Appendix________________________________________24 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations and Definitions 

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ADVERSE EVENT 
Any untoward medical occurrence in a patient or clinical 
investigation.  This study will report events related to data 
collection or loss of privacy. 
 
CRF 
Case report form 
 
CURES 
Controlled Substance Utilization Review and Evaluation   
System 
 
DSMB  
 
 
Data Safety Monitoring Board 
 
EORTC 
 
 
European Organization for Research and Treatment of 
Cancer 
 
HIPAA  
 
 
Health Information Portability and Accountability Act 
GUIDELINES-  
Practice 
 
 
IRB  
 
 
 
Institutional Review Board 
 
MOS  
 
 
Medical Outcomes Study 
 
PGIC  
 
 
Patient Global Impression of Change 
 
SERIOUS  
 
 
Events that result in death, are life threatening, requires or 
ADVERSE EVENT 
Any medical event that is considered serious and may 
jeopardize the patient or may require intervention to prevent 
one of the outcomes listed in the serious definition. 
 
SF-MPQ 
The short form McGill Pain Questionnaire 
 
STSI 
Scripps Translational Science Institute 
 
TENS  
 
 
Transcutaneous Electrical Nerve Stimulator 
 
WINS  
 
 
Wearable Intensive Nerve Stimulation  
 
 
 
 
 
 
1. Rationale and Purpose 
 
Study Abstract: Quell is a class II medical device with FDA 510(k) clearance for the 
symptomatic relief and management of chronic intractable pain, without a prescription. It 
operates by using an electrical stimulator to activate peripheral sensory nerves and trigger 
analgesia. This device has great potential for significantly decreasing opioid use in patients 

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who have chronic pain secondary to serious illnesses and thus improve their quality of life, 
but has not yet been tested for cancer related pain. This study investigates the utility of the 
device in improving pain in patients with cancer while decreasing their overall opioid 
consumption. 
 
Hypothesis: We hypothesize that Quell and its associated mobile application will decrease 
the overall opioid consumption of our test population while providing pain relief as self-
reported by the study participants.   
 
Purpose of the Study Protocol: To study effects Quell has on opioid consumption and pain 
relief in patients with cancer. 
 
Rational: The prevalence of pain is high in patients with advanced chronic illness such as 
cancer. Despite increasing interest in, and efforts to improve its management, pain remains 
poorly controlled in nearly half of all patients with cancer, with little change in the past 20 
years. (1). The prevalence of cancer-related pain has ranged from 14% to 100% depending 
on what surveys are evaluated, (2) and the incidence of pain has been shown to be similar 
across stages of disease. (3). Further, it has been shown that previously healthy people can 
be severely debilitated with poor quality of life during or even after curative treatments 
leave them with continued pain (4,5). Opioids are the mainstay of the medical management 
of moderate to severe pain and are used, in addition to appropriate adjuvants, by 
oncologists and palliative medicine physicians to help manage cancer related pain. 
However, given the associated side effects and the stigma of opioids both on the part of the 
patients and some providers, these medications do not always adequately relieve the 
patient’s pain. Neuropathic pain in particular, is a challenge because while opioids and 
their adjuvants do help, there is no clear consistent medication that is proven effective 
above the rest (6). 
 
Quell is a novel Wearable Intensive Nerve Stimulation (WINS) device that has FDA 
clearance for treatment of chronic pain continuously, including during sleep. Its mechanism 
of action is based on Transcutaneous Electrical Nerve Stimulation (TENS). It utilizes a 
precise high power electrical stimulator to activate peripheral sensory nerves and trigger 
analgesia. Though this device has efficacy for chronic and neuropathic pain (7), it has yet 
to be tested in this highly needed patient population, and has immense potential to 
significantly improve their quality of life.  
 
 
 
 
 
2. Study Background 
 
In 2015, 14.5 million Americans were living with a recent or remote history of cancer. 
(8,9). Pain is among the most, if not the most distressing sequelae of cancer and its 
associated treatments, and remains poorly managed worldwide. The devastation of living 
with uncontrolled pain has a significant effect on quality of life, physical functioning, and 
psychological distress.  
 

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Cancer related pain develops from complex interactions among cancer cells, the immune 
system, and the peripheral and central nervous systems (10,11). Cancer cells and the local 
immune cells produce a wide range of substances that stimulate the pain receptors. Once 
pain receptors are stimulated, impulses are transmitted first by afferent Ad fibers and then 
by separate slower C fibers. These fibers end in cell bodies in the dorsal root or trigeminal 
ganglion, which then interact with neurons in the central nervous system cells in the spinal 
cord. These cells synapse to the contralateral thalamus from which impulses are transmitted 
to regions of the cortex via somatosensory pathways. Visceral pain arising from 
nociceptors in internal organs is mostly transmitted by C fibers. It is often less well 
localized and less sharp than somatic pain, and is triggered by direct irritation from the 
tumor, distention.  
 
The subjective nature of cancer pain derives in part from the perception of pain. The 
perception of pain is known to vary depending on factors such as anxiety, depression, 
distraction, etc. These factors have no direct relationship to the pain receptors, or the 
painful stimulus caused by the interplay between the cancer cells and immune cells. 
However, the fact that these factors impact the pain overall, indicates the presence of 
additional mechanisms that alter pain transduction and perception (12). One mechanism is 
the descending inhibition from midbrain and higher regions that contain high concentration 
of opioid receptors. Various neurotransmitters are involved in mediating this pain 
inhibition pathway including GABA and serotonin, but most important are the endogenous 
opioids, explaining why synthetic opioids work so well to inhibit pain (13).  
 
The pain gate theory states that activation of sensory nerves (Aβ fibers) closes a “pain gate” 
in the spinal cord that inhibits the transmission of pain signals carried by nociceptive 
afferents (C and Aδ fibers) to the brain (14). Although it is activated by localized peripheral 
nerve stimulation, the descending pain inhibition system has analgesic effects that may 
extend beyond the stimulation site to provide broad pain relief (15-19). 
 
High frequency nerve stimulation, such as with a WINS device, induces an elevation in 
enkephalins that act through the δ-opioid receptor (20,21). Synthetic opioids mostly act 
through μ and k-opioid receptors. All three of these receptors are involved in descending 
pain inhibition. 
 
Clinical researchers have reported good clinical success with cutaneous electrical 
stimulation using 16 different electrical currents, assembled into packages, and transmitted 
to the existing nerves using modified electrocardiogram pads for 30 minutes a day (22,23).  
 
TENS is characterized by a number of electrical parameters including the stimulation pulse 
shape, amplitude, duration, pattern, and frequency (24). Although all the parameters can 
be adjusted in an attempt to achieve maximal analgesia, only pulse intensity (24,25-27) has 
a clear influence. Stimulation at an intensity below the level of sensory perception does not 
provide pain relief, and the degree of analgesia is correlated to the stimulation intensity 
(28). 
 
Quell is a wearable, automated electrical nerve stimulator designed for people with pain, 
that includes technology to provide convenience while optimizing pain relief. It consists of 
four components: a therapy pod, an electrode array, a band, and a mobile app. The therapy 

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pod, which contains the electronics, is placed in the band and then an electrode array is 
attached by snapping it to the therapy pod. The electrode array consists of 4 hydrogel pads 
that provide a large (60 cm2) interface between the stimulator and the patient’s sensory 
nerves. The hydrogel typically lasts 2 weeks or 100 hours of use, and is formulated to 
reduce skin irritation. The band is placed on the upper calf where therapy is initiated by 
pressing the button. The reason for placement on the upper calf is that this area has a high 
density of cutaneous sensory innervation that enables robust stimulation of Aβ fibers. 
When placed on the upper calf, the electrode array is circumferential and will stimulate 
sensory dermatomes S2- L4 providing a broad neural input to trigger analgesia through the 
descending pain inhibition system.  
 
A calibration procedure is used to estimate the optimal therapeutic stimulation intensity 
(within the recommended range) for each patient. This is accomplished by an algorithm 
that automatically determines an intensity within the recommended therapeutic range that 
is appropriate for the patient. Once calibrated, all subsequent therapy is automatically 
delivered at the required intensity. The patient has the option of manually adjusting 
intensity at any time and the device incorporates these changes in subsequent therapy 
sessions. Quell automatically compensates for nerve desensitization by adaptively 
increasing the intensity over the course of the one-hour therapy session. The device enables 
long- term unattended therapy, such as overnight, by automatically restarting hour-long 
therapy sessions every other hour as long as the device remains on the leg. It also monitors 
the amount of time it is on the same region of skin and alerts the patient to ventilate the 
area to reduce the risk of irritation. Finally, Quell has embedded intelligence to determine 
if the patient is sleeping and automatically reduces the intensity to provide overnight pain 
relief without disturbing sleep.  
 
The therapy pod is powered by a Lithium-Ion battery that provides 30-40 hours of therapy 
(4-7 days of typical use) if fully charged. The battery can be recharged in 2-3 hours by 
plugging the device into an AC adapter. 
 
 
 
 
 
 
 
3. Study Design 
 
The study is a single site, double blinded, placebo controlled randomized clinical trial. 40 
subjects will be selected based on the inclusion criteria stated below and then randomized 
to either the intervention group or the placebo control group. Prior to the start of this study, 
a Controlled Substance Utilization Review and Evaluation (CURES) reports will be 
acquired to establish baseline number of opioid prescriptions for each subject. Subjects will 
track how consistently they are using pain medications, both opioids and non-opioids, 
during the two weeks prior to the start of the study. They will also provide twice daily 
recordings of their pain intensity via a mobile application. At the end of this two-week 
period, each subject will be fitted with a Quell or a sham device, including initial calibration 
to the subject’s comfort level as described in the background section. 

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The sham device is identical to Quell in all aspects with one exception. While Quell 
delivers 1 hour of continuous stimulation during a therapy session, the sham device delivers 
three 2-minute periods of stimulation at 0, 28 and 58 minutes within the therapeutic session. 
This limited stimulation should have little to no analgesic effect but should suggest to the 
subject that they are receiving therapy.  
 
Neither the principal investigator, nor the co-investigator or the subject will know if they 
are given a sham device or the actual Quell device. The study coordinators will be the only 
ones who will be aware of which intervention subjects receive. At the end of the study, 
subjects will be asked if they thought they had the sham or actual device. Both the principal 
and the co-investigator will be asked to identify which subjects they thought had Quell vs 
the sham device, prior to analysis of the data. 
 
Once the study subjects have started using the device, we will also be able to monitor and 
track their sleep wirelessly via the mobile application as long as they are wearing the 
device. Subjects will receive weekly check in’s to monitor the functionality of the device 
and to help troubleshoot any issues with the device for the duration of subject participation 
in the study. These check-ins will take place in person, by phone, and or per subject’s usual 
outpatient oncology visits. Each subject will use their device for 8 weeks, during which 
they will continue to track their pain, sleep and frequency of pain medication use as stated 
above. Study investigators will receive automated alerts via email to ensure that study are 
participants using their devices and that the devices are powered on at regular intervals for 
the duration of the study. 
 
Both Quell and the sham device communicate via Bluetooth with the same mobile 
application. This application provides the subjects with a dashboard of device information, 
trending data on device usage, and sleep quality. This same information will be synced to 
a cloud so that investigators involved in the study can collect this data remotely, as well as 
monitor adherence with the device.  
 
Total duration of subject participation will be 10 weeks.  
 
 
4. Criteria for Evaluation 
 
Primary Efficacy Endpoint  
 
The primary endpoint is a reduction in daily opioid use assessed at weeks 2, 4, 6, 8 and 10 
of the study as recorded by the subject in their analgesia diary.  This diary will be a 
preformatted paper form given to each subject at the start of the study, and will include the 
name and dosage of all the analgesic pain medications prescribed to the subject, as well as 
any over the counter pain medications the subject will be using. The subjects will be asked 
to log what times they take their pain medication each day. This diary will then be reviewed 
and logged into our secure database at each of the clinic visits as stated above. Per previous 
studies with a similar design, a 20-30% change in opioid consumption is clinically relevant. 
This end point is chosen as the overall goal of this study is to provide a novel way for 
patients with cancer to have optimal pain control while reducing their overall opioid use.  

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Secondary Endpoints  
 
Change in pain intensity via the mobile app and as described by the subject using the Short-
form McGill Pain Questionnaire-2 SF-MPQ-2 and the Patient Global Impression of 
Change (PGIC). The pain intensity scores will be measured twice daily using the mobile 
application and the SF-MPQ-2 will be completed during weeks 0,2,4,6 and 10 of the study. 
The PGIC will come completed at week 10. 
 
These tools were chosen because a treatment should demonstrate a statistically and a 
clinically significant effect. Well-researched cutoff method suggests, that a 30% reduction 
of pain can be considered clinically significant (29). This level corresponds with a 2 points 
on a 0 to 10 pain intensity numerical rating scale (30). The Short-form McGill Pain 
Questionnaire (SF-MPQ-2) assesses the major symptoms of both neuropathic and 
nociceptive pain and can be used in studies of epidemiology, natural history, 
pathophysiologic mechanisms, and treatment response. Numerous studies have 
demonstrated its reliability, validity, and responsiveness in diverse samples of subjects with 
acute and chronic pain. Subjects rate their pain in sensory and affective terms and use a 
visual analog scale. The self-report measure Patient Global Impression of Change reflects 
a subject's belief about the efficacy of treatment. It is well studied and widely used in 
chronic pain clinical trials. PGIC is a 7-point scale depicting a subject's rating of overall 
improvement of a treatment intervention. Subjects rate their change as “very much 
improved,” “much improved,” “minimally improved,” “no change,” “minimally worse,” 
“much worse,” or “very much worse.” 
 
Changes in quality of life as measured by the Functional Assessment of Cancer The 
EORTC Quality of Life C-15- PAL measurement scale assessed at time of enrollment 
(week 0) week 6 and week 10 of the study. This is a validated questionnaire developed to 
assess the quality of life of palliative care cancer subjects. 
 
Additional analysis includes changes in objective sleep measures using the mobile 
application and also The Sleep Scale developed for the Medical Outcomes Study. We will 
also look at the other characteristics of the pain that are automatically monitored with 
Quell/Sham device and its mobile application such as activity level.  
 
5. Subject Selection 
 
Study Population 
40 Subjects with a diagnosis of metastatic cancer of any type, with cancer related pain on 
active chemotherapy treatment, who meet the inclusion and exclusion criteria will be 
selected for participation in this study 
 
General Inclusion Criteria:  
1. Male or Female greater than or equal to 18 year of age at visit one.   
2. Documented diagnosis of metastatic cancer, who has cancer/chemotherapy related 
pain, with a prognosis of 6 month or greater as determined by the primary 
oncologist. 

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3. Visual evidence that subject owns a smart phone and is able to use basic mobile 
applications such as downloading an app, opening the app, and performing one 
simple task within the app. 
4. Subject speaks and reads English fluently.  
5. Subject able to understand and grant informed consent.  
6. Live in an area with cellular data connectivity available as provided by the subject. 
7. Documented adherence with clinic follow up visits per medical records. 
8. Subject using at least one opioid medication on a daily basis. 
 
Exclusion Criteria: 
1. Subject has a cardiac pacemaker, implanted defibrillator or other implanted 
electronic device.  
2. Inability to complete subjective data as required; e.g. on mobile application and 
questionnaires. 
3. Does not live in an area with suitable cellular data connectivity. 
4. Has infrequent scheduled clinic visits. 
 
Subject Recruitment 
Subjects will be recruited from the Scripps Mercy Oncology Clinic, San Diego California.   
 
6. Concurrent Medications  
All subjects should be maintained on their same oncology treatment protocol as directed 
by the primary oncologists during the study as they were prior to the onset of the study. 
Any changes in medication type, doses and frequency should be discussed with the treating 
physician and documented.    
 
7. Study Procedures 
 
7.1 Enrollment 
Subjects meeting eligibility criteria will be screened by the primary investigator and 
treating oncologist. Subjects will be introduced to the study during their scheduled 
oncology and or palliative care visit. Study information will be made available to the 
subjects. Those interested in the study will be provided with the informed consent, enrolled 
in the study and provided with the materials necessary for participation in the study.   
 
7.2 Measures of Adherence and Treatment 
By using the mobile application, subjects will automatically be keeping a diary that time 
stamps each entry of pain intensity. Further, the mobile application communicates with 
Quell and the sham device via Bluetooth and thus also monitors the usage of the device. 
The questionnaires as stated above will be completed either at the clinic visits as detailed 
below, or if the subject cannot make it to the clinic visit, the questionnaire will be 
completed over the phone by the study investigators. The results of these questionnaires 
will be stored in a HIPAA compliant central data hub. 
 
7.3 Data collection 
After informed consent has occurred, all subjects will be asked questions regarding socio-
demographics, age, ethnic background, gender, height, weight, medical and related family 
history (ie. cancer, psychiatric diseases, substance misuse and abuse). Additionally, they 

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will be educated on how to input their pain intensity into the mobile application; and 
separately how to record their pain medication use using a paper analgesic dairy.  
 
Quality of life assessment will be conducted in person at the enrollment visit (week zero), 
and again at weeks 6 and 10.  
 
Assessments entered into the mobile application including, pain assessments and sleep 
monitoring will sync wirelessly through cloud data base and will only be accessed by 
approved personal directly involved in the study.  Anonymized data will be stored in a 
HIPAA compliant central data hub.  
 
7.3.1 Concomitant Medications 
All concomitant medications and concurrent therapies will be documented at screening and 
each scheduled clinic visit. A CURES report will be retrospectively generated for one 
month at time of enrollment, then every four weeks for the duration of the study.  
 
7.3.2 Socio-Demographics 
Demographic information (date of birth, gender, ethnicity, race) will be recorded at 
screening 
 
7.3.3 Medical History 
Relevant medical history, including history of current disease, pertinent family history, and 
information regarding underlying diseases will be recorded at Screening. 
 
7.3.4 Vital Signs 
Body temperature, blood pressure, pulse and respirations will be performed during their 
regular scheduled visits and recorded as part of this study. If study visits occur outside of 
scheduled clinic visits, vital signs will not be performed or recorded.   
 
7.3.5 Adverse events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation 
to study drug will be recorded on the case report form (CRF). 
 
7.3.6 Study Visits  
Investigators will attempt to schedule study visits so that they coincide with subject’s 
oncology visits in order to not add any additional burden. If these dual visits cannot be 
scheduled and study visit needs to occur in person, subject will receive compensation for 
time and travel. 
 
8.  Evaluations by Visit  
 
8.1 
Visit 1 (Week 0) 
1. 
Review the study with the subject and obtain written informed consent and   HIPAA 
authorization. 
2. 
Assign the subject a unique screening number. 
3. 
Record demographics data. 
4. 
Record medical history, including a history of diagnosis date, and prior treatments. 

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5. 
Record concomitant medications. 
6. 
Perform and record vital signs. 
7. 
Download and set up mobile application on subject’s phone. 
8. 
Educate subject on how to use mobile application. 
9. 
Have subject demonstrate knowledge of how to use application. 
10. 
Perform and record the SF-MPQ-2, opioid assessment and Quality of life 
Assessment.  
11.  
Provide them with their analgesic diary and educate them on how to use it 
12. 
Schedule subject for visit 2 weeks. 
 
8.2 
Visit 2 (Week 2) 
1. 
Record any Adverse Experiences as needed.  
2. 
Review Mobile Application Pain assessment. 
3.  
Review documentation of analgesic use. 
4.  
Perform and record vital signs.  
5. 
Give subject Quell/Sham device, make sure subject properly calibrates.  
6. 
Educate subject on how to use the device and to adjust intensity if needed and 
communicate that stimulation should feel “strong but comfortable”.  
7. 
Schedule follow up phone calls for subject to help trouble shoot and field questions 
on the device. 
8.  
Perform and record the SF-MPQ-2. 
9. 
Perform and record the results of the MOS Sleep Scale. 
10. 
Schedule follow up visit for 2 weeks. 
 
8.3 
Visit 3 (Week 4) 
1. 
Record any Adverse Experiences/troubleshoot any questions or concerns. 
2.  
Review mobile application for adherence use. 
3. 
Record changes to concomitant medications. 
4. 
Perform and record vital signs. 
5. 
Review Mobile Application Pain and Sleep assessment. 
6.  
Review documentation of analgesic medication use. 
7. 
Perform and record the SF-MPQ-2. 
8. 
Schedule follow up visit for 2 weeks. 
 
8.4 
Visit 4 (Week 6) 
1. 
Record any Adverse Experiences/troubleshoot any questions or concerns.  
2. 
Record changes to concomitant medications. 
3. 
Review mobile application for adherence use. 
4. 
Perform and record vital signs. 
5. 
Review Mobile Application Pain and Sleep assessment. 
6.  
Review documentation of analgesic medication use. 
7.  
Perform and record Quality of life Assessment and SF-MPQ-2. 
8. 
Perform and record the results of the MOS Sleep Scale. 
9.  
Schedule check in phone calls as needed. 
10.  
Schedule follow up appointment in 4 weeks. 
 
8.5 
Visit 5 (Week 8) 
1. 
Over the phone unless otherwise scheduled to come into clinic. 

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2. 
If over the phone only; Review documentation of analgesic use. 
3. 
If scheduled to come in; visit 5 will mirror Visit 3 (Week 4). 
 
8.6 
Visit 6 (Week 10) 
1. 
Record any Adverse Experiences/troubleshoot any questions or concerns. 
2. 
Record changes to concomitant medications. 
3. 
Review mobile application for adherence of use. 
4. 
Perform and record vital signs. 
5. 
Review Mobile Application Pain and Sleep assessment. 
6.  
Review documentation of analgesic medication use. 
7.  
Perform and record SF-MPQ-2 and Quality of life Assessment. 
8.  
Collect Quell/Sham device and delete mobile application from subject’s phone. 
9. 
Administer the PGIC, the MOS Sleep Scale survey and record the results.  
10.  
Provide subject with results of any preliminary data analysis pertinent to their 
involvement in the study.  
11. 
Address any remaining question or concerns regarding subject’s participation in the 
study.  
 
8.7 
Early Withdrawal Visit 
1. 
Record any Adverse Experiences/troubleshoot any questions or concerns  
2. 
Record changes to concomitant medications. 
3. 
Review mobile application for adherence of use. 
4. 
Perform and record vital signs. 
5. 
Review Mobile Application Pain and Sleep assessment. 
6.  
Review documentation of analgesic medication use. 
7. 
Perform and record SF-MPQ-2 and Quality of life survey 
8. 
Collect Quell/Sham device and delete mobile application from subject’s phone 
9. 
Administer the PGIC. 
10.  
Provide subject with results of any preliminary data analysis pertinent to their 
involvement in the study.  
11. 
Address any remaining question or concerns regarding subject’s participation in the 
study.  
  
9.  Data Storage  
 
All data will be transmitted and stored to HIPAA compliant encrypted standards.  
 
Future research: 
 
Subject information will be kept for at least 2 years after completion of this study and up 
to 20 years for future research that has not yet been planned. Future research using the data 
will first be approved by Scripps IRB.   After 2031, the code that links the sample to the 
subject’s traditionally-identifying information will be destroyed.  Related de-identified 
health information will be kept indefinitely for future research studies at Scripps in secure 
databases. 
 
10.  Statistical Analysis 
 

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A biostatistician will perform all data analysis. The sample size (20 participants per group) 
achieves 80% power to find a 20% (absolute) difference in mean percent change in opioid 
consumption between the two groups with an estimated standard deviation of mean percent 
change of 22% and 90% power with an estimated standard deviation of 19% in both groups 
using a two-sided two-sample t-test with a significance level (alpha) of 0.05. 
 
Descriptive statistics will be calculated for baseline characteristics of both study groups 
and to assess the effectiveness of the randomization.  Repeated measures analysis will be 
used to assess changes in opioid medication use, pain assessments, and quality of life 
mesaures over time in the intervention group compared to the control group. Mid study 
analysis will be conducted with all data amassed around week 6 of all subjects enrolled.  
 
11. 
Discontinuation and Replacement of Study Participants  
 
11.1 
Early Discontinuation of Quell/Sham Device  
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  The 
following is a list of possible reasons for study treatment discontinuation:  
• 
Subject withdrawal of consent (or assent) 
• 
Subject is not compliant with study procedures 
• 
Adverse event that in the opinion of the investigator would be in the best interest 
of the subject to discontinue study treatment 
• 
Protocol violation requiring discontinuation of study treatment 
• 
Lost to follow-up 
• 
Sponsor request for early termination of study 
 
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.   
 
All subjects who discontinue study treatment should come in for an early discontinuation 
visit as soon as possible and then should be encouraged to complete all remaining 
scheduled visits and procedures. 
 
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. Reasonable attempts will be made by the 
investigator to provide a reason for subject withdrawals.  The reason for the subject’s 
withdrawal from the study will be specified in the subject’s source documents. 
 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.  As noted above, subjects who discontinue study treatment 
early (i.e., they withdraw prior to Visit 6) should have an early discontinuation visit. Refer 
to Section 8 for early termination visit.  Subjects who withdraw after Visit 4 but prior to 
Visit 6 should be encouraged to come in for a final visit (and the procedures to be followed 
would include those for their next scheduled visit).   
 
11.2 
Replacement of Subjects 

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Subjects who withdraw from the study treatment will not be replaced, as long some data 
has been collected from the device. This withdraw will be accounted for in our data 
analysis. Should subjects withdraw from the study without ever using the device, their 
device will be collected and they will be replaced with a new participant.  
 
11.3 Protocol Violations  
A protocol violation occurs when the subject, investigator, or Sponsor fails to adhere to 
significant protocol requirements affecting the inclusion, exclusion, subject safety and 
primary endpoint criteria.  Protocol violations for this study include, but are not limited to, 
the following: 
• 
Failure to meet inclusion/exclusion criteria 
• 
Use of a prohibited concomitant medication 
• 
Include other specific examples as appropriate for the study (non-adherence with 
study drug regimen, etc.) 
 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The Sponsor will determine if a protocol violation will result in 
withdrawal of a subject. 
 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a 
Sponsor representative and the Investigator. A copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files. 
 
12. Potential Risks  
 
Risk from the device: 
Transcutaneous electrical nerve stimulation therapy is considered mostly safe. On rare 
occasions, an electrical current will be too intense for a subject, causing irritation on the 
skin. On very rare cases, some subjects have reported some calf muscle cramping with 
prolonged use.  
 
Some subjects with skin allergies may react to the electrode pads used with the units. 
People with pacemakers, infusion pumps, defibrillators, and similar devices should not be 
exposed to the electrical currents produced by transcutaneous electrical nerve stimulation. 
 
Psychological or Social Risks Associated with Loss of Privacy: 
 
In spite of all the safety measures that we will use, we cannot guarantee that the subject’s 
identity will never become known. Every effort will be made to secure the information 
stored on the mobile application and the information uploaded into the cloud database. In 
order to maintain subject confidentiality, only a site number, subject number and subject 
initials will identify all study subjects on any documentation submitted to the Sponsor.   
 
13. Potential Benefits 
 
Subjects enrolled in this study have the potential to have their pain adequately managed 
while down titrating their overall opioid use. There may be no direct benefit to the subject 

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for participating in this study.  Knowledge gained by conducting this study may lead to the 
identification of mechanisms that may lead to improved detection and treatment of subjects 
with cancer related pain. 
 
 
14. Risk-Benefit Ratio 
 
There is minimal risk of physical harm with any of the devices used. As with any electronic 
means of communication, no matter how secure, there is always a risk of a data breach.  
 
15. Alternative Treatment(s) 
 
This study involves the addition of a drug free wearable pain device. Subjects may refuse 
participation in this study and this will not influence their care in any way. 
 
16. Subject Payment/Costs 
 
Subjects will be paid per study visit. Additionally, should they choose, they can keep the 
Quell device as well as 6 months worth of electrodes. Subjects who were assigned the sham 
device will be given the option of using and keeping the Quell device.   
 
17. Informed Consent 
 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations. 
 
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and provide the documents to the Sponsor or designee for approval prior to submission to 
the IRB.   
 
The consent form generated by the Investigator must be acceptable to the Sponsor and be 
approved by the IRB. 
 
The study personnel that have been trained on this study protocol by the sponsor 
(investigator, designated co-investigator or research coordinator) will obtain informed 
consent for this study.  Subjects will be given ample time to read and understand the 
consent form in their native language. Subjects will have an opportunity to ask the 
investigator and or coordinator questions and have all questions answered before signing.  
Once the subject has signed the informed consent, a copy will be given to them.  The 
original consent will be filed at the study site. 
 
18. Confidentiality of Data/Privacy of Individuals 
 
Scripps Translational Science Institute affirms the subject’s right to protection against 
invasion of privacy.  Data files are stored on a password-protected computer/database and 
will be accessible only to the above listed investigators and research staff.  Subject’s data 

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will be assigned and identified by a unique code.  Traditional identifying information such 
as name, address, phone, medical record number, etc will not be included in the database.  
Only the investigators and the research staff will have the link that can match the code to 
identifying information.  Study files will be kept in secure locations at each study site.   
 
19.  Safety 
 
Adverse Events:   
 
Any event that occurs during the study period and is considered to be directly related to the 
study procedures will be considered an adverse event.  All possible events will be reported 
to Scripps Translational Science Institute.  Loss of privacy would also be considered a 
reportable adverse event.   
 
Serious Adverse Events: 
 
We do not anticipate any serious adverse events related to this study.  However, events that 
fit the definition of a serious adverse event according to ICH guidelines must be reported 
to STSI within 24 hours.  
 
Such events include any untoward medical occurrence that is life threatening, results in 
death, requires hospitalization or prolongation of existing hospitalization, and/or results in 
persistent or significant disability/incapacity.  Medical Events that may not be immediately 
life threatening or result in death or hospitalization should also be considered serious when 
they jeopardize the subject or require intervention to prevent one of the other outcomes 
listed in the serious definition. 
 
The study Principal Investigator at Scripps will review adverse events and serious adverse 
events directly related to loss of privacy.  This study does not have a Data Safety 
Monitoring Board. 
 
20. Monitoring 
 
STSI will monitor the study throughout its duration.  The study monitor will visit the site 
at appropriate intervals to review investigational data for accuracy and completeness and 
to ensure adherence with the protocol.  The investigator/site will permit access to all 
documents and records maintained on the subjects in the study.  Source documents will be 
reviewed to ensure all subjects have properly signed and dated the informed 
consent/HIPAA forms. All information will be reviewed to ensure eligibility criteria as per 
the protocol, and supporting source data will be verified. The Investigator and/or research 
coordinator must be available for monitoring visits. STSI will collect the appropriate 
regulatory documentation from each clinical site according to ICH/GCP guidelines.  
Regulatory document records at the site will also be reviewed periodically during 
monitoring visits for accuracy and completeness.   
 
*Enrollment may not begin at the study site until all required documentation is collected, 
key study personnel are trained and written approval from STSI is given to start enrollment. 
 

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21.  Record Retention 
 
Research records will be kept for at least 2 years after study completion.  Scripps will 
continue to store and use the subject information for up to 20 years.  In 2031, the code that 
links the subject to the identifying health and trait information will be destroyed.  The data 
and related de-identified health and trait information may be kept indefinitely.  Record 
retention must also comply with any specific requirements of the local reviewing IRB. (i.e. 
Scripps- must keep HIPAA form for at least 6 years after study completion)   
 
Records will ultimately be kept at the research site until STSI has given written permission 
to destroy the records.  If record retention cannot be maintained by the participating sites, 
STSI must be notified and storage will be provided. 
 
22.  Publication 
 
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996.  
 
23.  Facilities and Personnel 
 
Site Selection 
 
Investigators and participating centers will be selected at institutions with access to an 
established IRB or equivalent that meets on a regular basis. An interest in participating in 
the study and willingness to support monitoring and auditing procedures will be 
prerequisites.  Other considerations include the center’s ability to execute the study 
protocol and a prospective subject population that will meet the protocol criteria.  
 
Clinical Trial Agreement 
 
A Clinical Trial Agreement must be signed by all parties named in the Clinical Trial 
Agreement and returned to Scripps Translational Science Institute prior to the 
commencement of any study activities. 
 
Personnel Training 
 
Center personnel (investigators, coordinators, and other key clinical staff) will be trained 
by the sponsor on the study protocol and study activities relevant to their role prior to 
conducting any study activities.  Training will also include but is not limited to smartphone 
device setup and continual use, case report form (CRF) completion, and use of an electronic 
data capture program. 
 
It is the responsibility of the study site investigator to ensure that there are ample staff to 
complete the study according to the protocol and the entire research staff designated to this 

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study has the education and the training required to perform the proposed procedures, and 
the procedures are allowed under the scope of practice.   
 
Center Readiness 
All local regulatory requirements need to be fulfilled and each study center must have 
written documentation of center/investigator readiness provided by Scripps Translational 
Science prior to enrolling any subjects in the study. 
 
 
 
 
 
24.  References  
 
1. Smith TJ, Saiki CB. Cancer Pain Management. Mayo Clin Proc. 2015 
Oct;90(10):1428-39. 
doi: 
10.1016/j.mayocp.2015.08.009. 
Review.PMID: 
26434968 
2. Goudas LC, Bloch R, Gialeli-Goudas M, Lau J, Carr DB. The epidemiology of 
cancer pain. Cancer Invest. 2005;23(2):182-190.   
3.  Van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, Schouten HC, 
van Kleef M, Patijn J. Prevalence of pain in pa- tients with cancer: a systematic 
review of the past 40 years. Ann Oncol. 2007;18(9):1437-1449. 
 
4. Lewis MA, Zhao F, Jones D, et al. Neuropathic symptoms and their risk factors in 
medical oncology outsubjects with colo- rectal vs. breast, lung, or prostate cancer: 
results from a pro- spective multicenter study. J Pain Symptom Manage. 2015; 
 49(6):1016-1024.   
5.  Pachman DR, Barton DL, Swetz KM, Loprinzi CL. Troublesome symptoms in 
cancer survivors: fatigue, insomnia, neuropathy, and pain. J Clin Oncol. 
2012;30(30):3687-3696. 
 
6. Finnerup NB, Attal N, Haroutounian S, et al. Pharmaco- therapy for neuropathic 
pain in adults: a systematic review and meta-analysis. Lancet Neurol. 
2015;14(2):162-173.  
 
7. Shai N. Gozani, M.D., Ph.D Science Behind QuellTM Wearable Pain Relief 
Technology for Treatment of Chronic Pain. NeuroMetrix Inc, 2015 
 
8. National Cancer Institute. SEER research data 1973-  2012dASCII text data: 
Surveillance, Epidemiology, and End Results (SEER) Program research data 
(1973-2012). www. seer.cancer.gov. Published April 15, 2015. Accessed February 
10th 2016.   
9. American Cancer Society. Cancer Facts & Figures 2015. Atlanta, GA: American 
Cancer 
Society.http://www.cancer.org/acs/groups/content/@editorial/documents/docume
nt/acspc-044552.pdf. Accessed February 10th 2016  
 

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10. Schmidt BL, Hamamoto DT, Simone DA, Wilcox GL. Mechanism of cancer pain. 
Mol Interv. 2010;10(3):164-178.   
11. Ellis A, Bennett DL. Neuroinflammation and the generation of neuropathic pain. 
Br J Anaesth. 2013;111(1):26-37.   
12. Jensen MP. A neuropsychological model of pain: research and clinical 
implications. J Pain. 2010;11(1):2-12.   
13.  DeSantana JM, Walsh DM, Vance C, Rakel BA, Sluka KA. Effectiveness of 
transcutaneous electrical nerve stimulation for treatment of hyperalgesia and pain. 
Curr Rheumatol Rep. Dec 2008;10(6):492-499. 
 
14. Katz J, Rosenbloom BN. The golden anniversary of Melzack and Wall's gate 
control theory of pain: Celebrating 50 years of pain research and management. Katz 
J, Rosenbloom BN. Pain Res Manag. 2015 Nov-Dec;20(6):285-6.  
 
15. Ainsworth L, Budelier K, Clinesmith M, et al. Transcutaneous electrical nerve 
stimulation (TENS) reduces chronic hyperalgesia induced by muscle inflammation. 
Pain. Jan 2006;120(1-2):182-187.  
 
16. Somers DL, Clemente FR. Contralateral high or a combination of high- and low-
frequency transcutaneous electrical nerve stimulation reduces mechanical allodynia 
and alters dorsal horn neurotransmitter content in neuropathic rats. J Pain. Feb 
2009;10(2):221-229. 
 
17. Chan CW, Tsang H. Inhibition of the human flexion reflex by low intensity, high 
frequency transcutaneous electrical nerve stimulation (TENS) has a gradual onset 
and offset. Pain. Feb 1987;28(2):239-253.  
18.  Dean J, Bowsher D, Johnson MI. The effects of unilateral transcutaneous electrical 
nerve stimulation of the median nerve on bilateral somatosensory thresholds. Clin 
Physiol Funct Imaging. Sep 2006;26(5):314-318. 
 
19. Dailey DL, Rakel BA, Vance CG, et al. Transcutaneous electrical nerve stimulation 
reduces pain, fatigue and hyperalgesia while restoring central inhibition in primary 
fibromyalgia. Pain. Nov 2013;154(11):2554-2562.  
 
20.  Sluka KA, Deacon M, Stibal A, Strissel S, Terpstra A. Spinal blockade of opioid 
receptors prevents the analgesia produced by TENS in arthritic rats. J Pharmacol 
Exp Ther. May 1999;289(2):840- 846. 
 
21. Leonard G, Goffaux P, Marchand S. Deciphering the role of endogenous opioids in 
high-frequency TENS using low and high doses of naloxone. Pain. Oct 
2010;151(1):215-219.   
22.  Smith TJ, Coyne PJ, Parker GL, Dodson P, Ramakrishnan V. Pilot trial of a 
patient-specific cutaneous electrostimulation device (MC5-A Calmare") for 
chemotherapy-induced peripheral neuropathy. J Pain Symptom Manage. 
2010;40(6): 883-891. 
 

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23. Pachman DR, Weisbrod BL, Seisler DK, et al. Pilot evaluation of Scrambler 
therapy for the treatment of chemotherapy- induced peripheral neuropathy. Support 
Care Cancer. 2015; 23(4):943-951.  
24. Johnson MI. Transcutaneous Electrical Nerve Stimulation (TENS) and TENS-like 
devices: do they provide pain relief? Pain Reviews. 2001;8:121-158.   
25. Johnson MI, Bjordal JM. Transcutaneous electrical nerve stimulation for the 
management of painful conditions: focus on neuropathic pain. Expert Rev 
Neurother. May 2011;11(5):735- 753.  
26. Chen CC, Tabasam G, Johnson MI. Does the pulse frequency of transcutaneous 
electrical nerve stimulation (TENS) influence hypoalgesia? A systematic review of 
studies using experimental pain and healthy human participants. Physiotherapy. 
2008;94:11-20.   
27. Law PP, Cheing GL. Optimal stimulation frequency of transcutaneous electrical 
nerve stimulation on people with knee osteoarthritis. J Rehabil Med. Sep 
2004;36(5):220-225.   
28. Moran F, Leonard T, Hawthorne S, et al. Hypoalgesia in response to transcutaneous 
electrical nerve stimulation (TENS) depends on stimulation intensity. J Pain. Aug 
2011;12(8):929-935.  
29. Farrar JT, Young JP, LaMoreaux L, et al. Clinical importance of changes in chronic 
pain intensity measured on an 11-point numerical pain rating scale. Pain. 
2001;94:149–158. 
30. Younger J, McCue R, Mackey S. Pain Outcomes: A Brief Review of Instruments 
and Techniques. Current pain and headache reports. 2009;13(1):39-43. 
 
 
 

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25. Appendix 

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PATIENT’S GLOBAL IMPRESSION OF CHANGE (PGIC) SCALE 
 
 
Date:_______________ 
 
Name:_____________________________________________  DOB:______________ 
 
Chief Complaint (Presenting Problem): ____________________________________ 
______________________________________________________________________ 
 
 
Since beginning treatment at this facility, how would you describe the change (if any) in 
ACTIVITY LIMITATIONS, SYMPTOMS, EMOTIONS and OVERALL QUALITY OF LIFE, 
related to your post-concussive condition? 
 
Choose ONE.   
___No change (or condition has gotten worse) (1)  
___Almost the same, hardly any change at all (2)  
___A little better, but no noticeable change (3)  
___Somewhat better, but the change has not made any real difference (4) 
___Moderately better, and a slight but noticeable change (5) 
___Better and a definite improvement that has made a real and worthwhile difference (6) 
___A great deal better and a considerable improvement that has made all the difference (7) 
 
 
Patient’s 
Signature:____________________________________________________________ 

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