MC15C1 Randomized Scrambler Therapy vs TENS for the Treatment of Chemotherapy-Induced Peripheral Neuropathy
Phase: NA
Conditions: Pain, Peripheral Neuropathy, Tingling
Sponsor: Mayo Clinic



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Table of Contents 
MC15C1 Randomized Scrambler Therapy vs TENS for the Treatment of Chemotherapy-Induced Peripheral 
Neuropathy .................................................................................................................................................................... 1 
Protocol Resources ........................................................................................................................................................ 2 
Table of Contents........................................................................................................................................................... 3 
Schema .......................................................................................................................................................................... 5 
1.0 
Background .................................................................................................................................................. 6 
2.0 
Goals .......................................................................................................................................................... 18 
3.0 
Patient Eligibility ....................................................................................................................................... 19 
4.0 
Test Schedule ............................................................................................................................................. 21 
5.0 
Stratification Factors .................................................................................................................................. 22 
6.0  
Registration/Randomization Procedures ................................................................................................ 2423 
7.0 
Protocol Treatment ................................................................................................................................. 2625 
8.0 
Dosage Modification Based on Adverse Events .................................................................................... 2928 
9.0 
Ancillary Treatment/Supportive Care .................................................................................................... 2928 
10.0 
Adverse Event (AE) Reporting and Monitoring .................................................................................... 3029 
11.0 
Measurement of Effect? ......................................................................................................................... 3231 
12.0 
Descriptive Factors................................................................................................................................. 3231 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ....................................................................... 3231 
14.0 
Body Fluid Biospecimens ...................................................................................................................... 3332 
15.0 
Drug Information – Not applicable ........................................................................................................ 3433 
16.0 
Statistical Considerations and Methodology .......................................................................................... 3433 
17.0 
Pathology Considerations/Tissue Biospecimens - Not applicable ......................................................... 3836 
18.0 
Records and Data Collection Procedures ............................................................................................... 3937 
19.0 
Budget .................................................................................................................................................... 4038 
20.0 
References .............................................................................................................................................. 4139 
Appendix I 
Patient instruction sheet for tapering gabapentin and pregabalin ................................................ 4442 
Appendix IIA 
Peripheral Neuropathy Questionnaire for Upper Extremity Neuropathy .................................... 4543 
Appendix IIB 
Peripheral Neuropathy Questionnaire for Lower Extremity Neuropathy.................................... 4644 
Appendix III  
Declaration of most problematic site and symptom .................................................................... 4745 
Appendix IVA 
Peripheral Neuropathy Questionnaire for Upper Extremity Neuropathy .................................... 4846 
Appendix IVB 
Peripheral Neuropathy Questionnaire for Lower Extremity Neuropathy.................................... 4947 
Appendix VA 
Patient Questionnaire: Before Each Treatment for Upper Extremity Neuropathy ...................... 5048 
Appendix VB 
Patient Questionnaire: Before Each Treatment for Lower Extremity Neuropathy ..................... 5250 
Appendix VIA 
Patient Questionnaire: Immediately Post Therapy for Upper Extremity Neuropathy ................. 5452 
Appendix VIB 
 Patient Questionnaire: Immediately Post Treatment for Lower Extremity Neuropathy ............ 5553 
Appendix VII 
EORTC QLQ CIPN-20 Instrument ............................................................................................. 5654 
Appendix VIII 
Patient Analgesic Use Questionnaire .......................................................................................... 5856 
Appendix IXA 
Global Impression of Change and Patient Preference Questionnaire – Upper Extremity ........... 5957 

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Appendix IXB 
Global Impression of Change and Patient Preference Questionnaire – Lower Extremity .......... 6058 
Appendix XA 
Daily Scrambler Treatment Log and Adverse Event Assessment ............................................... 6159 
Appendix XB 
Daily TENS Treatment Log and Adverse Event Assessment ..................................................... 6260 
Appendix XI 
Individual Patient Dermatome Map ............................................................................................ 6361 
Appendix XIIA 
Patient Weekly Follow-up Questionnaire for Upper Extremity Neuropathy ............................ 6563 
Appendix XIIB 
Patient Weekly Follow-up Questionnaire for Lower Extremity Neuropathy ............................ 6765 
Appendix XIII 
Principals of Positioning and Titrating Scrambler Treatment ..................................................... 6967 
Appendix XIVA 
Patient instruction form for using TENS on the upper extremities .......................................... 7169 
Appendix XIVB 
Patient instruction form for using TENS on the lower extremities .......................................... 7270 
Appendix XV 
Functional MRI (fMRI) .............................................................................................................. 7371 
 

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1.0 
Background 
1.1 
Chronic Pain 
Chronic pain is estimated to affect 100 million people in the U.S. alone, resulting in up to 
$635 billion in medical expenses and lost productivity each year (Simon 2012). It 
predisposes to psychiatric comorbidity, and its massive impact is highlighted by the fact 
that it is the most common cause of long-term disability in the U.S. (Stewart, Ricci et al. 
2003). 
In simplest terms, pain can be defined as a bodily sensation experienced during genuine, 
or perceived, tissue injury (Merskey and Bogduk 1994). In the acute setting, this 
sensation can serve a protective role by alerting an individual to avoid potentially harmful 
stimuli and protect a body part during healing. When pain fails to communicate 
biologically useful or accurate information, it is maladaptive and thereby becomes 
pathologic—pain becomes a disease in its own right. It is generally agreed that pain 
becomes “chronic” when it persists beyond the expected period of tissue injury and 
healing. The specific duration of symptoms required to qualify for a diagnosis of chronic 
pain is debatable, but usually this is considered to be three to six months (Merskey and 
Harold 1986). 
The perception of noxious stimuli originates from nociceptors of the peripheral nervous 
system. Nociceptors recognize noxious stimuli in the form of thermal, mechanical, or 
chemical inputs. This stimulation leads to activation of primary sensory nerve fibers that 
transmit this information to the central nervous system, via a complex network of 
interneurons housed predominantly in the dorsal root ganglia, posterior horn of the spinal 
cord, brain stem, and thalamus. Ultimately, signals reach the forebrain for interpretation 
of the sensory experience. There are multiple mechanisms that underlie the dysregulation 
of this system in chronic pain. In the setting of injury, for example, inflammatory changes 
in the biochemical milieu surrounding peripheral nerves can result in hypersensitization 
of nociceptors, such that pain signals are communicated in the absence of appropriate 
stimuli (Woolf and Doubell 1994). Neurons surrounding damaged tissue have even 
shown the ability to develop spontaneous discharges that communicate pain information 
in the absence of external input (Zimmermann 2001). Similarly, spinal cord neurons in 
the central nervous system exposed to repetitive pain stimuli may undergo changes that 
result in transmission of action potentials with a reduced threshold of synaptic input (Ji, 
Kohno et al. 2003). 
Currently, several treatment modalities exist for the management of chronic pain, 
including physical therapy, pharmacologic therapy, behavioral medicine, 
neuromodulation, minimally-invasive interventions, and surgery. Unfortunately, the 
heterogeneous nature of chronic pain syndromes and the lack of a functional 
understanding of chronic pain contribute to the absence of a clearly identifiable, 
appropriate management strategy for many patients. Nonetheless, pharmacologic 
measures are commonly prescribed as a component of chronic pain management. With 
many medications available, such as non-steroidal anti-inflammatory agents, anti-
convulsants, anti-depressants, and opioids, it is exceedingly common for patients to use 
multiple agents to try to achieve reasonable pain control(Freynhagen and Bennett 2009). 
Recognizing the limitations and hazards of polypharmacy, increasing emphasis has been 
placed on the non-pharmacologic options for management of persistent pain. A strategy 
combining psychological and physical medicine approaches can provide significant 
benefit for many of these patients (Allegrante 1996). Neuromodulatory techniques, 

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particularly since the commercial availability of wearable transcutaneous electrical nerve 
stimulation (TENS) units in the mid-1970s, gained popularity as an adjunct to both 
pharmacological and non-pharmacologic pain managements(Maurer 1974). TENS was 
developed based on the Gate Control Theory(Melzack and Wall 1965), which suggests 
the gate of transmission from nociceptive peripheral C fibers is typically closed, but 
opened in pain states, including pathologic pain. In line with the Gate Control Theory, 
TENS is specifically designed to stimulate myelinized Aβ fibers (tactile fibers) and avoid 
the stimulation of C fibers. It is thought that spinal cord stimulation, similar to TENS, 
also works through the Gate Control Theory mechanism stimulating myelinated fibers 
and has been used for chronic pain that has not responded to less invasive approaches. It 
has proven efficacy in such diverse pain syndromes as refractory angina, failed back 
syndrome, complex regional pain syndromes, and other conditions, with the ability to 
reduce pain intensity by over 50% (Marineo 2003; Sabato, Marineo et al. 2005; Abdi, 
Lakkimsetty et al. 2011; Ghatak, Nandi et al. 2011; Marineo, Iorno et al. 2011; Sparadeo 
F 2012; Campbell, Nimunkar et al. 2013; Coyne, Wan et al. 2013; Park, Sin et al. 2013; 
Deer, Mekhail et al. 2014; Moon, Kurihara et al. 2014; Pachman, Weisbrod et al. 2014; 
Sparadeo and D'Amato 2014). However, it is invasive, expensive, and not universally 
effective. While promising in theory, the scientific data supporting such methods remain 
limited without consistently-shown benefit, underscoring the need for novel therapeutic 
options (Cruccu, Aziz et al. 2007; Nnoaham and Kumbang 2008). 
One thought is that while TENS devices have become more sophisticated and can deliver 
signals of varying frequencies, intensities, and morphologies, their nature is so 
stereotypical and non-physiologic that their effectiveness is limited, with patients 
experiencing rapid tachyphylaxis.  
1.2 
Chemotherapy-induced Peripheral Neuropathy (CIPN) 
CIPN is a major and often dose-limiting side effect of antineoplastic agents including the 
taxanes (paclitaxel and docetaxel), platinums (carboplatin, cisplatin, oxaliplatin), vinca 
alkaloids (vincristine, vinblastine, and vinorelbine), proteosome inhibitors (bortezomib) 
and epithelones (such as ixabepilone). The incidence of chemotherapy-induced 
neurotoxicity ranges from 0 to 70% (commonly 30-40%) of patients receiving 
chemotherapy, related to the timing and cumulative dose. Unlike chronic diabetic nerve 
damage it is not caused by nutritional starvation but rapid damage to microtubules of the 
nerves. Pain is a common symptom, usually described as a burning, stinging dysesthesia. 
However, many patients also complain of numbness and tingling and being unable to do 
activities of daily living because of these symptoms.  
Substantial data demonstrate that CIPN can remain as a prominent problem for months to 
years following the completion of chemotherapy (Hershman, Lacchetti et al. 2014). 
Recent American Society of Clinical Oncology (ASCO) guidelines have reviewed the 
prevention and treatment of CIPN (Hershman, Lacchetti et al. 2014). Despite the review 
of 42 randomized prevention trials, none have been proven to be helpful. With regards to 
treatment, only duloxetine has been reasonably proven to be helpful, but only to a limited 
extent (Hershman, Lacchetti et al. 2014). Thus, better therapy is needed for this 
prominent clinical problem. 
1.3 
Scrambler Therapy Development and Mechanisms 
Giuseppe Marineo, a biophysicist who developed an interest in treating chronic pain, 
developed Scrambler Therapy and conducted basic and applied research related to it. This 
research produced a new chronic pain model and consequently its treatment. Marineo 

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Five reports deal with clinical practice experiences(Sparadeo F 2012; Ko, Lee et al. 2013; Park, Sin et al. 2013; Moon, Kurihara et 
al. 2014; Sparadeo and D'Amato 2014), nine are prospective single-arm clinical trials(Marineo 2003; Sabato, Marineo et al. 2005; 
Smith, Coyne et al. 2010; Abdi, Lakkimsetty et al. 2011; Ghatak, Nandi et al. 2011; Ricci, Pirotti et al. 2011; Coyne, Wan et al. 
2013; Pachman, Weisbrod et al. 2014), one is a randomized open-label controlled trial(Marineo, Iorno et al. 2011), and two are 
randomized, blinded, placebo-controlled trials(Campbell, Nimunkar et al. 2013; Starkweather, Coyne et al. 2015). 
 
Table 1 
 
Reports, by first author 
Year 
Pt # 
Condition 
Results 
Trial type 
Comments 
1 
Marineo (Marineo 2003) 
2003 
11 
Drug-resistant visceral pain 
Substantial pain reduction 
Prospective trial  
2 
Sabato (Sabato, Marineo 
et al. 2005) 
2005 
226 
multiple chronic pain 
syndromes 
80% of patients with greater than 
a 50% pain reduction 
Prospective trial  
3 
Smith (Smith, Coyne et al. 
2010) 
2010 
18 
Chemotherapy-induced 
neuropathy 
Over 50% reduction in pain 
Prospective trial (16 evaluable) 
4 
Abdi (Abdi, Lakkimsetty et 
al. 2011) 
2011 
10 
Back pain 
28% reduction in pain. 
Prospective trial Abstract only 
5 
Marineo (Marineo, Iorno 
et al. 2011) 
2011 
52 
post-herpetic neuralgia, spinal 
canal stenosis, and post-
surgical neuropathic pain 
Pain reduced more in Scrambler 
arm, than the control arm at 1 
month and 3 months ((P<0.0001) 
Randomized, 
controlled 
Open label trial 
6 
Ricci (Ricci, Pirotti et al. 
2011) 
2012 
82 
Various cancer and non-
cancer pains 
Mean pain scores dropped from 
6.2/10 prior to treatment to 1.6 
just after completing 10 treatment 
days to 2.9, 2 weeks after 
finishing treatment. 
Prospective trial 73 evaluable 
pts. 
7 
Ghatak (Ghatak, Nandi et 
al. 2011) 
2011 
8 
Chronic low back pain 
Pain score drop from 8.12 to 
6.93; Drop in ODI from 49.88 to 
18.44 
Prospective trial Open label 
8 
Sparadeo (Sparadeo F 
2012) 
2012 
173 
Chronic pain >6 months 
Marked pain reduction 
Clinical practice 
experience 
91 provided 3-6 
months f/u 
9 
Coyne (Coyne, Wan et al. 
2013) 
2013 
39 
Cancer pain syndromes, 
including Chemotherapy-
induced neuropathy 
Significant pain reduction with 10 
treatment days that largely lasted 
for 3 months 
Prospective trial  
10 
Smith (Coyne, Wan et al. 
2013) 
2013 
10 
Post-herpetic neuralgia 
95% pain reduction, that largely 
lasted for 3 months 
Prospective trial 
data 
Some pts were 
the same as in a 
previous trial 18 
11 
Ko (Campbell, Nimunkar 
et al. 2013) 
2013 
3 
Post-herpetic neuralgia 
Marked pain reduction 
Clinical practice 
experience 
 

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Reports, by first author 
Year 
Pt # 
Condition 
Results 
Trial type 
Comments 
12 
Park (Park, Sin et al. 
2013) 
2013 
3 
Cancer bone metastases 
Marked pain reduction 
Clinical practice 
experience 
 
13 
Campbell (Campbell, 
Nimunkar et al. 2013) 
2013 
14 
Chemotherapy-induced 
neuropathy 
No differences between active 
and placebo arms 
Prospective, 
double-blind, 
placebo-
controlled trial 
Abstract only 
14 
Pachman (Pachman, 
Weisbrod et al. 2014) 
2014 
37 
Chemotherapy-induced 
neuropathy 
Average pain decreased by 53% 
at end of treatment and benefit 
largely remained for 10 weeks 
after completion. 
Prospective trial 
Decrease in 
tingling and 
numbness, too. 
15 
Sparadeo (Sparadeo and 
D'Amato 2014) 
2014 
91 
Variety of pain syndromes 
Substantial pain reduction 
Clinical practice 
experience 
Consecutive 
patients; Some 
pts were the 
same as in a 
previous trial30 
16 
Moon (Moon, Kurihara et 
al. 2014) 
2014 
147 
Variety of pain syndromes 
 
Clinical practice 
experience 
 
17 
Starkweather 
(Starkweather, Coyne et 
al. 2015) 
2015 
30 
Low back pain 
Significant improvements in 
active vs control group for: 1) 
worse pain and pain interference 
states; 2) pain sensitivity 
measures, and 3) differential 
mRNA expression of 17 pain 
genes 
Prospective, 
double-blind, 
placebo-
controlled trial 
 

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Turning to the clinical practice experiences, as opposed to the prospective trials, two case 
series, published in 2013, each included three patients with cancer pain or post-herpetic 
pain (Campbell, Nimunkar et al. 2013; Park, Sin et al. 2013). Both of these reports came 
from different authors in Korea and both reported positive benefits in the patients who 
were treated.  
Sparadeo et al. reported their clinical practice experience regarding 91 of their initial 173 
patients, representing all of those for whom they had collected data. These patients had a 
variety of pain syndromes, including complex regional pain syndrome (CRPS), spine 
pain, neuralgias (such as post-herpetic or post-chemotherapy), and multi-focal pain 
problems(Sparadeo F 2012). As part of their practice, with these 91 patients, they 
collected visual pain scores before and after each treatment for all of them and Brief Pain 
Inventory (BPI) questionnaires prior to treatment initiation in a subset of them, at three 
and six month follow-ups. The mean pain score prior to the first treatment was 7.2/10 and 
it was 3.0/10 on the 10th day, prior to that day’s treatment. Relatively similar results were 
seen for the different pain syndromes. BPI scores at three to six months of follow-up 
were reported to be improved by more than 50%. 
In a second manuscript, Sparadeo and D’Amato (Sparadeo and D'Amato 2014) analyzed 
the pre- and post-treatment data of 95 individuals (some of whom had been reported in 
the previous publication) entering their Scrambler therapy program for treatment of 
chronic neuropathic pain, divided into two groups: Complex Regional Pain Syndrome 
and Chronic Spine-Based Pain. All patients were weaned from opioids and 
anticonvulsants being used for pain control. The data analysis revealed that 70% of the 
entire sample was still reporting significant improvement three to six months following 
treatment. The two studied groups had similar levels of pain and degrees of lifestyle 
impact. Additionally, the 3-6 month successes were similar in the two treatment groups.  
1.5 
Does Scrambler Therapy Actually Work? 
Arguments against Scrambler therapy certainly exist, with critics attributing much of the 
benefit to a placebo effect. Some of the positive endorsements in social media and on the 
internet are only anecdotal. Additionally, the developer of Scrambler therapy participated 
in the initial clinical trials, and this could be perceived as a potential conflict of interest 
even though it is scientifically desirable and logical to expect that the same person who 
invented this therapy, would be one to report the results. Additionally, there are no large, 
placebo-controlled, double-blinded clinical trials to estimate the effectiveness of 
Scrambler therapy. 
On the other hand, while some reports (Marineo 2003; Sabato, Marineo et al. 2005; 
Marineo, Iorno et al. 2011; Coyne, Wan et al. 2013) involved the inventor of the 
Scrambler device, these positive findings have been independently replicated by diverse 
groups (Smith, Coyne et al. 2010; Abdi, Lakkimsetty et al. 2011; Ghatak, Nandi et al. 
2011; Ricci, Pirotti et al. 2011; Sparadeo F 2012; Campbell, Nimunkar et al. 2013; 
Coyne, Wan et al. 2013; Park, Sin et al. 2013; Moon, Kurihara et al. 2014; Pachman, 
Weisbrod et al. 2014; Sparadeo and D'Amato 2014; Starkweather, Coyne et al. 2015) in 
nearly all of the reported studies, involving over 700 patients in total. In some cases, the 
benefit achieved has been substantial, with some patients achieving complete pain 
resolution and substantially reduced dependence on pharmacologic therapy. There has 
been only one report of a negative experience [(Campbell, Nimunkar et al. 2013)]. This 
was from one small, placebo-controlled trial in patients with chemotherapy-induced 
peripheral neuropathy. This was published only as an abstract, did not show much of a 
reduction in either study arm (arguing against a placebo effect), and it is worth noting that 

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the group did not have much experience using Scrambler therapy prior to conducting this 
trial. This raises concerns regarding the validity of this trial as data have demonstrated an 
extended learning curve with the provision of Scrambler therapy, particularly for 
chemotherapy-induced neuropathy (Pachman, Weisbrod et al. 2014).  
1.6 
Additional Research is Needed 
Additional work is needed to better understand the mechanism of Scrambler therapy and 
to conduct larger randomized clinical trials investigating the efficacy of Scrambler 
therapy in a number of chronic pain states. Randomized, sham-controlled double-blinded 
trials, involving patients with a variety of chronic pain syndromes, would strengthen the 
conclusions from initial studies. The data compiled, to date, support the feasibility and 
value of such an undertaking. However, there is significant controversy amongst those 
who treat patients with Scrambler therapy as to whether a blinded placebo control is 
realistic. Part of the process of correct treatment is placing the electrodes properly and 
getting feedback from the patient that the pain has been markedly improved. If that is not 
achieved, the leads should be reapplied in a different area and the process repeated until 
there is success in replacing the patient’s perception of pain with the characteristic 
pleasant sensation from the Scrambler’s electric stimuli, and markedly improving the 
initial pain. It is, thus, argued by some that the nature of the treatment technique makes 
placebo control impractical, just as in certain surgical procedures (e.g. laparoscopic 
versus open colectomy(2004). Thus, it could be argued that trials should be randomized 
and compared to other potential treatments, rather than a placebo. An example of such a 
trial was discussed above where Scrambler therapy was compared to guideline-based 
drug therapy (Marineo, Iorno et al. 2011). 
The possibility of variability in treatment outcomes being attributed to differences in how 
and where electrodes are applied suggest that the next phase of research more objectively 
evaluate fidelity to intervention in terms of electrode placement over repeated sessions.  
We suspect that there is a group learning phenomenon in how electrodes are placed 
serially, such that teams delivering the intervention may get better at delivering the 
intervention over time.  In order for larger scale trials with more heterogeneous teams to 
eventually implement a trial of scrambler therapy, we need to gather more information 
about fidelity to the intervention through direct observation with video technology.   
1.7  
Rationale for using TENS as a control 
TENS (Transcutaneous electrical nerve stimulation) therapy, first developed in 1974, has 
been utilized for treatment of neuropathic pain from a variety of causes. 
TENS is commonly done using a small unit, operated by a battery, with 2-4 leads that can 
be applied to the skin via sticky attachment pads. They are usually available for patients 
to use at home, following some relatively simple instructions. 
A few small studies have explored TENS units for treatment of diabetic neuropathy. 
Whereas these small studies have not demonstrated convincing evidence of benefit on 
their own, a meta-analysis suggests that TENS may provide some benefit for diabetic 
neuropathy.(Jin, Xu et al. 2010; Pieber, Herceg et al. 2010) Nonetheless, it is generally 
agreed that larger, placebo-controlled clinical trials are necessary to delineate whether 
TENS is helpful for diabetic neuropathy. 
To our knowledge, there are no good studies available looking at TENS therapy for 
treatment of chemotherapy-induced peripheral neuropathy. 

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There are potential pros and cons for evaluating TENS as a sham control. The advantages 
are that it has similarities to the Scrambler machine. For example, wires are placed on the 
skin in a similar manner and an electrostimulation sensation is felt by patients in a similar 
manner. The major disadvantage of using TENS as a control is that it, potentially, may 
actually help chemotherapy-induced peripheral neuropathy. 
1.8 
mRNA Information 
Starkweather et al described mRNA gene expression changes in patients who received 
real versus sham Scrambler therapy. Starkweather et al treated 15 patients with real ST 
and 15 with sham ST for persistent low back pain, and observed in the ST group a 
significant downregulation in the serum mRNAs for 17 pain genes such BDKRB1 and 
NGF at the 3 week mark, many of which code for proteins and receptors that mediate 
inflammation and nociceptive signaling. (Table 1.71) (Starkweather, Coyne et al. 2015). 
We will also obtain a white blood count (WBC) collected as CBC with differential, as 
this count will help to illustrate that there were reasonable numbers of WBCs to obtain 
the RNA for testing. 
Table 1.71. Differential Gene Expression in the Calmare Group at 3 Weeks Post-
Treatment 
Gene 
Fold Regulationa 
p value 
BDKRB1 
-2.468 
0.0069 
CACNA1B 
-1.518 
0.0091 
CHRNA4 
-1.924 
0.0053 
GDNF -2.141 
-2.141 
0.0036 
GRM1 -1.715 
-1.715 
0.0033 
NGF 
-2.599 
0.0040 
NTRK1 
-1.980 
0.0035 
OPRD1 
-1.812 
0.0049 
PENK 
-1.850 
0.0042 
PLA2G1B 
-1.816 
0.0020 
aDifference from sham treatment group. 
1.9a 
fMRI Discussion 
1.9a1 
Functional neuroimaging 
Functional neuroimaging, specifically functional MRI (fMRI), produces 
characteristic patterns during pain activity (Peyron, Laurent et al. 2000). Though 
the CNS circuit of transduction of pain is relatively well-defined (involving relay 
of a signal from dorsal root ganglia to dorsal horn, thalamus, and ultimately 
cortex), it has been postulated that evaluating brain conditions, in terms of 
functional connectivity, will be of high yield, given the alterations that occur 
during pain states (Borsook, Becerra et al. 2011). An elegant example of this has 
been shown with the use of fMRI in complex regional pain syndrome (CRPS), 
which provided evidence of change in CNS circuitry, as it relates to pain 
processing (Lebel, Becerra et al. 2008). fMRI has also been used in a similar 
manner to evaluate CNS processing in migraineurs, both during and between 
attacks, with presently defined brainstem, sub-cortical, and cortical 
changes(Sprenger and Borsook 2012). More recently, fMRI has been used at 
Mayo in a study led by Dr. Fred Cutrer (Mayo Department of Neurology) to 
define alterations in functional differences in patients with chronic daily migraine 
headache versus patients who have reverted from chronic to episodic migraine. 

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The preliminary findings from these studies have been encouraging. 
1.9a2 
fMRI use in this study 
Drawing on its use in neuro-imaging of other pain states, we see opportunity to 
characterize changes in CNS processing of patients with chronic pain conditions 
receiving ST. This approach would not only enable reporting of objective data, 
but also potentially elucidate the mechanism of ST, which currently remains 
hypothetical. Of note, unpublished data presented in Korea showed dramatic 
improvement of the fMRI in patients treated with Scrambler Therapy, lasting at 
least 3 months. (Kong Sung Taik. Scientific Validation on Scrambler Therapy - 
Case Result of Resting-State fMRI. International Symposium: New Paradigm in 
Pain Management, September 27, 2014, Seoul) 
The fMRI sequences will be analyzed and interpreted with assistance of 
investigator David Borsook MD PhD, a neurologist and Chair in Pain Systems 
Neuroscience at Boston Children’s Hospital, and his colleague, Lino Becerra 
PhD. Both of these individuals are experts in the use of functional imaging in 
pain conditions. 
Brain system adaptations in responders (greater than 50% pain or tingling 
reduction) vs. non-responders data will be provided from this work. 
1.9b 
Sensation Changes 
Our clinical experience with patients receiving Scrambler therapy has supported that 
patients develop improved normal sensation in areas treated with Scrambler therpy. This 
includes improved feeling and proprioception. Thus, we plan to look at quatitative 
sensory testing (QST) in a subset of patients on this trial. Dr Peter Dyck and colleagues at 
Mayo have world-renowned expertise in this area. We will, in an exploratory manner, 
obtain  touch pressure and heat pain testing on both the dorsal foot and the lateral leg in 
10 patients per study arm, before Scrambler/TENS therapy and on the last couple days of 
ScramblerTENS  therapy. 
1.9c 
Audiovisual recording rationale 
As Scrambler therapy is operator dependent and there is a learning curve with providing 
it, obtaining audiovisual recording of the treatment sessions should be helpful. This 
recording may allow us to ask for outside input for individual treatments that are being 
performed. It may also allow us to provide examples of successful treatment of individual 
patients. Of course, patient confidentiality issues need to be kept in mind. 
We are proposing to include video recording of intervention delivery into the routine 
delivery of the intervention. Using established direction/observation protocols developed 
with local clinical communication research experts, we will consent patients to be video 
recorded.  
Dr Jon Tilburt, a co-investigator on this protocol, has extensive expertise with regard to 
patient communication topics, which have included audiovisual recording sessions of 
patient encounters. After the trial is completed this recordings may be used to conduct a 
structured “fidelity to treatment” analysis in which two independent raters score the 
recorded intervention delivery for fidelity to protocol a priori criteria based on scientific 
expert criteria. If we do this, raters will be blind to the final clinical outcomes of 
participants, although they would hear patients’ thoughts while they were getting the 
treatments. 
 
 
 

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2.0 
Goals 
2.1 
Goal 1 Efficacy 
Evaluate the efficacy of Scrambler therapy compared to TENS therapy for pain and/or 
tingling related to CIPN. 
Hypothesis 1: Scrambler therapy will improve pain related to chemotherapy induced 
neuropathy more than TENS therapy.  
2.2 
Goal 2 Tolerability 
Evaluate the tolerability of Scrambler therapy and compare it to TENS therapy, in this 
population. 
Hypothesis 2: Scrambler therapy will be well tolerated and there will be no substantial 
differences in side effects between the Scrambler and TENS treatment groups.  
2.3 
Goal 3 Efficacy 
Evaluate whether Scrambler therapy, compared to TENS therapy, can decrease the use of 
pain medication for CIPN. 
Hypothesis 3: Pain medication and morphine oral equivalent dose (MOED) daily 
amounts will decrease more in the group receiving Scrambler therapy, compared to those 
who received TENS therapy.  
2.4 
Goal 4 mRNA 
Explore whether mRNA gene expression before and after scrambler therapy shows 
similar findings to what Starkweather et al observed. 
Hypothesis 4: Scrambler therapy will be associated with mRNA gene expression 
modifications as was previously reported by Starkweather et al. 
2.5 
Goal 5 fMRI 
Utilizing high-field MRI, to define alterations in functional differences (using resting 
state BOLD measures to measure differences in functional connectivity) in treated with 
the Scrambler device in the setting of chemotherapy induced peripheral neuropathy pain. 
In the same subjects, we will utilize high-field MRI to measure morphometric changes in 
specific cortical (cingulate, S1 and hippocampus) and subcortical regions (basal ganglia). 
Hypothesis 5: Scrambler therapy will be associated with fMRI changes  
2.6  
Goal 6 Quantitative Sensory Testing 
Explore whether Scrambler therapy will alter sensation. 
Hypothesis 6: Scrambler therapy will be associated with improved sensation, as detected 
by quantitative sensory testing. 
 
 
 

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3.0 
Patient Eligibility 
3.1 
Inclusion criteria  
3.11 
Age ≥18 years. 
3.12 
Pain or symptoms of CIPN of 3 months duration, for which the patient wants 
intervention.  
NOTE: Neurotoxic chemotherapy must have been completed ≥3 months prior to 
registration and there must be no further planned neurotoxic chemotherapy for 
>5 months after registration. 
3.13 
Patients have to relate that tingling or pain was at least a four out of ten problem 
≤7 days prior to registration, on a 0-10 scale where zero was no problem and ten 
was the worst possible problem.  
NOTE: The patient is expected to have tingling or pain of at least 4/10 at the time 
of the first treatment (Appendix II: A or B).  
3.14 
ECOG Performance Status (PS) = 0, 1, or 2. 
 
ECOG Performance Status* 
 
ECOG Performance Status 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry 
out any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.  Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5 649-655, 1982. 
3.15 
Life expectancy 6 months. 
3.16 
Ability to complete questionnaire(s) by themselves or with assistance. 
3.17 
Ability to provide informed written consent. 
3.18 
Case review by the study chair, or designate, as a case where treatment should be 
tried. 
3.2 
Exclusion Criteria 
3.21 
Any of the following because this study involves an investigational device whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
 
Pregnant women 
 
Nursing women 
 
Women of childbearing potential who are unwilling to employ adequate 
contraception 
3.22 
Existing operational implantable drug delivery systems, e.g. Medtronic 

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Protocol version: 27May2016 
Synchromed. 
 
3.23 
Existing implantable medical electronic devices, life-supporting medical devices, 
and medical monitoring devices. 
Note: Metal implants for orthopedic repair, e.g. pins, clips, plates, cages, joint 
replacements are allowed, as are central venous access devices. 
 
3.24 
History of myocardial infarction or ischemic heart disease within the past six 
months. 
 
3.25 
History of epilepsy, brain damage, use of anticonvulsants for seizure prevention, 
concurrently using ketamine, symptomatic brain metastases. 
 
3.26 
Skin conditions such as open sores that would prevent proper application of the 
electrodes. 
 
3.27 
Other medical or other condition(s) that in the opinion of the investigators might 
compromise the objectives of the study. 
 
3.28 
Currently receiving gabapentin or pregabalin and not willing to be weaned off of 
these medications prior to Scrambler therapy initiation.  
Note: It is OK to continue these medications in patients who are receiving TENS. 
(See Appendix I). 
 
3.29a 
History of peripheral neuropathy prior to receiving neurotoxic chemotherapy. 
 
3.29b Prior treatment with Scrambler therapy. 
 
 

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4.0 
Test Schedule  
Use for first treatment period; repeat for second treatment period 
 
Active Monitoring Phase 
Tests and procedures 
≤30 days  
prior to 
registration 
Day 1, 
Prior to 
therapy 
Daily for 14 
consecutive days 
beginning on Day 1 
of active therapy 
Last day of 
assigned 
therapy 
(±1 day) 
Weekly 
for 
8 weeks 
History and exam, PS1, Eligibility 
questions2 (Appendix II: A or B) 
X 
 
 
 
 
Pregnancy test3 
 
X 
 
 
 
Declaration of most problematic site 
(upper versus lower extremities) and 
most problematic symptom (tingling 
versus pain): Appendix III 
X 
 
 
 
 
Pain/tingling questionnaire regarding the 
prior week (Appendix IV: A or B) 
 
X4 
 
 
 
Patient Questionnaire: Before each 
treatment (Appendix V: A or B) 
 
X5 
X5 
 
 
Patient Questionnaire: After each 
treatment (Appendix VI: A or B) 
 
 
X5 
 
 
EORTC CIPN 20 (Appendix VII) 
 
X 
 
X6 
X 
Patient Questionnaire: Analgesic Use 
(Appendix VIII) 
 
X 
X 
 
X 
Patient Questionnaire After each therapy  
and during weekly follow-up: Global 
Impression of Change and Patient 
Preference (Appendix IX: A or B) 
 
 
X7 
 
X7 
Daily Treatment Log and Adverse 
Assessment (Appendix X) 
 
 
X 
 
 
Individual Patient Dermatome Map-
Electrode Placement (Appendix XI) 
Scrambler only 
 
 
X 
 
 
Audiovisual recordingsR 
 
 
X8 
 
 
Weekly follow-up patient questionnaire 
(Appendix XII:A or B) 
 
 
 
 
X9 
Written patient summary (if the patient is 
willing to provide)R 
 
 
 
 
X10 
Research Blood draw for CBC/diff and 
mRNA11,R 
 
X 
 
X 
 
fMRI12,R 
 
X 
 
X 
 
Quantitative Sensory Testing13,R 
 
X 
 
X 
 

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Protocol version: 27May2016 
 
Active Monitoring Phase 
Tests and procedures 
≤30 days  
prior to 
registration 
Day 1, 
Prior to 
therapy 
Daily for 14 
consecutive days 
beginning on Day 1 
of active therapy 
Last day of 
assigned 
therapy 
(±1 day) 
Weekly 
for 
8 weeks 
Study Coordinator/Nurse phone call to 
discuss therapy and any concerns, 
record any adverse events that are 
reported and to remind the patient to 
complete questionnaires and mail them 
 
 
X14 
 
X 
 
Footnotes: 
1. PS must be done 7 days prior to registration. 
2. Appendix II A or B, as labeled depending on neuropathy area type. (This evaluation is used for 
eligibility.) 
3. For women of childbearing potential only. Must be done prior to first Scrambler therapy (or the 
first day of the second treatment period, if Scrambler therapy is crossover).  
NOTE: This testing is not needed for TENS therapy. 
4. Appendix IV A or B, as labeled depending on neuropathy area to be treated  
5. Beginning on Day 1 of active treatment and continuing for 14 consecutive days, complete 
Appendix V daily pre/post therapy. If no therapy is received on a day during this 
timeframe, complete once daily. To be filled out only for primarily treated area. For post-
therapy questionnaires VIA and VIB.  
6. Prior to the last therapy. 
7. Appendix IX A or B, as labeled depending on pain or neuropathy area to be treated.  
8. If patient provides written consent for AV recording. Recording may be done on any day. 
9. Appendix XII A or B, as labeled depending on pain or neuropathy area to be treated. 
10. To be completed any time after completion of active treatment. 
11. Optional use in selected patients: Blood draws are completed at Baseline (prior to treatment) and 
on the last planned day or two of treatment (e.g., Day 9 or 10, if 10 treatments are given but 
sooner if earlier treatment completion is planned) (±2 days). Ideally, do prior to treatment. See 
Section 14.0. 
12. fMRI: Optional use in selected patients, do at baseline and on approximately the last day of the 
initial treatment (±1 day). 
13. Quantitative sensory testing: Optional use in selected patients, do at baseline and then the last day 
of the initial treatment (±3 days) on 10 patients from each cohort. Do prior to treatment. 
14. For TENS patients only: Study Coordinator or Nurse to call on Treatment Day 2 and once on 
Treatment Day 8-10 to assess toxicities and remind the patient to complete daily questionnaires 
and mail them back. 
R  Research funded 
 
5.0 
Stratification Factors  
5.1 
Gender: Male vs female. 
5.2 
Causative drug: Paclitaxel-regimen vs oxaliplatin-regimen vs other/combination. 
5.3  
Primary problematic area: Upper vs lower extremity. 
5.4 
Primary problematic symptom: Pain vs tingling. 

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6.0  
Registration/Randomization Procedures  
6.1 
Registration Procedures 
6.11 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page 
and enter the registration/randomization application. The 
registration/randomization application is available 24 hours a day, 7 days a week. 
Back up and/or system support contact information is available on the Web site. 
If unable to access the Web site, call the MCCC Registration Office at (
 between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday through 
Friday). 
The instructions for the registration/randomization application are available on 
the MCCC web page
 and detail the 
process for completing and confirming patient registration. Prior to initiation of 
protocol treatment, this process must be completed in its entirety and a MCCC 
subject ID number must be available as noted in the instructions. It is the 
responsibility of the individual registering the patient to confirm the process has 
been successfully completed prior to release of the study agent. Patient 
registration via the registration/randomization application can be confirmed in 
any of the following ways: 
 
Contact the MCCC Registration Office 
. If the patient was 
fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.12 
Correlative Research 
An optional correlative research component is part of this study, there will be an 
option to select if the patient is to be registered onto this component (see Sections 
7.0 and 14.0). 
 
Patient has/has not given permission to give his/her blood sample for 
research testing 
 
Patient has/has not given permission to have functional MRI testing (fMRI) 
for research testing 
 
Patient has/has not given permission to have Quantitative Sensory Testing 
(QSART) for research testing 
 
Patient has/has not given permission to have audiovisual recording for 
research testing 
At the time of registration, the following will be recorded: 
 
Patient has/has not given permission to store and use his/her sample(s) for 
future research of cancer at Mayo. 
 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn, prevent, or treat other health problems. 
 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
6.2 
IRB approval 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients. 

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Protocol version: 27May2016 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
. If the necessary documentation is not submitted in advance of attempting 
patient registration, the registration will not be accepted and the patient may not be 
enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
6.3 
Verification 
Prior to accepting the registration, registration application will verify the following: 
 
Patient eligibility 
 
Existence of a signed consent form 
 
Existence of a signed authorization for use and disclosure of protected health 
information 
6.4 
Treatment location requirements 
Treatment on this protocol must commence at Mayo Clinic Rochester under the 
supervision of a medical oncologist, pain specialist, or associated allied health personnel. 
6.5 
Start of treatment 
Treatment cannot begin prior to registration and must begin 50 days after registration. 
6.6 
Booklets 
Patient questionnaire booklet is available on site; copies are not acceptable for these 
submissions. 
6.7 
Randomization Procedures 
6.71 
The factors defined in Section 5.0, together with the registering membership, will 
be used as stratification factors. 
6.72  
After the patient has been registered into the study, the values of the stratification 
factors will be recorded, and the patient will be assigned to one of the following 
treatment groups using the Pocock and Simon dynamic allocation procedure 
which balances the marginal distributions of the stratification factors between the 
treatment groups. 
 
Scrambler Therapy 
 
TENS Therapy 
6.8 
Optional continuation - Treatment Crossover 
6.81 
Patient may enter crossover treatment once original 2 weeks of treatment and 8 
weeks of observation are complete. 
6.82 
Complete Optional Crossover Continuation form. 
 
 

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Protocol version: 27May2016 
7.0 
Protocol Treatment 
7.1 
Treatment Schedule for Scrambler arm 
7.11 
Day 1- Initial treatment  
7.111  The locations of symptoms will be assessed. 
7.112  Pretreatment questionnaires completed 
7.113 Placement of electrodes and treatment 
A decision will be made by the treating person as to where electrodes 
should be placed, keeping in mind that the general principal regarding 
Scrambler Therapy is that the cutaneous EKG electrode patches, or 
channels, are applied above and below the area of pain/tingling if 
possible. The placement of the electrode pair of each channel follow the 
"geometry" of the pain, which in CIPN normally extends in vertical 
arrangement. See appendix XIII for principles of this treatment. 
More specifically, the treatment is carried out using surface electrodes, 
two for each channel (maximum 5) of the device, depending on need. 
Choosing where to apply the electrodes is important. As basic technique, 
the electrodes should never be applied directly on the painful area, but, 
ideally, should be 2-3 fingerbreadths proximal, distal, or lateral to the 
pain. 
Treatment should be started and over about 10-30 seconds, the intensity 
should be increased to the maximal level that is tolerated. In doing so, 
the operator will ask the patient to let it be known when they feel any 
stimulation, then when they note any stinging feeling and then when any 
stinging is too uncomfortable. The goal is to have the patient at the 
highest tolerable setting while helping the baseline tinging and/or pain 
and to be below any substantial discomfort under the electrodes.  
The patient should then be asked whether he/she has any residual 
pain/tingling in the area of focus. The goal is to reduce all pain to zero. If 
there is residual pain, then the operator can choose to increase intensity if 
possible, relocate the electrodes of the initial channel, or, if there is 
substantial improvement with the initial channel and pain is outside the 
area of the initial channel, another channel can be used to treat the 
residual pain/tingling area, again striving for a complete resolution of the 
discomfort. 
If a patient develops pain or a burning sensation with any of the 
electrodes, then the treatment should be interrupted and the electrode 
should be moved farther away from the pain source. For the electrodes 
that were moved, the intensity should start again as described above. 
7.12 
Subsequent days of Scrambler Therapy 
7.121 Treatment will be administered using the above outlined principles of the 
recommended scrambler for 30 minutes of application time, on up to 10 
consecutive weekdays as long as the patient has numbness/pain/tingling 
rating of more than 0 at the time they come in for treatment. This is 

MC15C1 
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Protocol version: 27May2016 
because without pain, there is no guidance to the provider about 
electrode placement. Subsequent treatments can rapidly be titrated up to 
the highest intensity tolerated during the previous treatment. Up to three 
days may be skipped to  allow for weekends and holidays, if needed. 
Treatment must start on a Monday, Tuesday, or Wednesday; with the 
goal being 3 consecutive days of treatment before break (e.g. treatment 
cannot start Wednesday before Thanksgiving holiday weekend). The 
total of 10 treatments must be scheduled to be able to be completed 
within 16 calendar days). 
7.122 The electrode placement may be modified on subsequent days, 
depending on how a patient responds to treatment. 
7.2 
Treatment Schedule for TENS arm 
7.21 
TENS Treatment Procedure 
7.211 The patient will be given a new TENS machine that they will be able to 
keep. This unit will include a set of directions for use of this machine.  
7.212 The study nurse will explain how to use the TENS machine, including a 
hands on learning session. 
7.213 Written instructions will also be provided to the patient (Appendix XIV) 
7.214 The patient will be instructed to use the TENS machine for 30 minutes 
per day, for 14 days, to address the area deemed most problematic (upper 
or lower extremities) of CIPN. 
7.215 If the patient has questions during their 2 week treatment, they can call 
the study nurse. 
7.216 The patient may also use the TENS on other areas of involvement (e.g. if 
their lower extremities are the main focus of the study, they may also 
treat their upper extremities). 
7.3 
Optional Substudies 
7.31 
Functional MRI (fMRI) 
We plan to do fMRI on a subset of 12 patients, before Scrambler therapy and on 
the last planned day or two of treatment (±1 day). 
We will use the same approach have been used in the past for imaging 
experiments (Lebel, Becerra et al. 2008; Upadhyay, Knudsen et al. 2008; 
Upadhyay, Maleki et al. 2010).  Subjects will be scanned on a HDxt 3.0T - 60cm 
TRM,Spectro (GE). During the MR session, subjects will be placed in the 
magnet for the experimental procedure and attached to various physiological 
monitoring apparatuses. During the experimental procedure, a series of standard 
anatomical images will be acquired. Once the anatomical images are completed, 
subjects will also undergo RSN (10 min), and DTI (10 min) imaging. The total 
estimated time the subject will be inside the magnet is 60 minutes. The imaging 
details are described below. 
Anatomical Scans: We will use an established approach for imaging experiments. 
Subjects will be scanned on a 3.0T - 60cm TRM, Spectro (GE).). We will acquire 
anatomical images using a magnetization prepared rapid gradient echo 
(MPRAGE) sequence (128 1.33mm-thick slices with an in-plane resolution of 1 
mm (256x256)). 

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Protocol version: 27May2016 
Resting State Scans (RSN): We will first obtain magnitude and phase images to 
unwarp functional scans; slice location, number, and thickness will be the same 
as those used in functional scans consisting of 41 slices with isotropic voxels 
(3mm) and 64x64 in-plane resolution.  Then for RSN, we will generate images 
with a Gradient Echo EPI sequence (TR/TE = 2.5/30ms); 120 volumes will be 
collected per functional scan. 
Diffusion Tensor Imaging (DTI): We will collect all DTI data using a single, 
shot-twice refocused echo planar pulse sequence at a 1.75 x 1.75 x 2.5 mm3 
resolution. We will collect 8 single, non-diffusion weighted (b = 0 sec/mm2) 
volumes and 72, diffusion-weighted volumes with different gradient orientation 
at b = 1000 sec/mm2 (TR = 7900 msec, TE = 92 msec, 5/8 partial Fourier, 3-fold 
SENSE acceleration). Fifty axial slices are sufficient to cover the entire cerebral 
cortex. 
7.32 
mRNA blood testing 
mRNA blood testing will be done on a subset of 12 patients. Blood draws for 
CBC with differential and mRNA are completed at Baseline (prior to treatment) 
and on the last day or two of treatment (e.g., Day 9 or 10, if 10 treatments are 
given but sooner if earlier treatment completion is planned; ideally collected 
prior to treatment) (±2 days). 
For details on collection and processing see Section 14.0. 
7.33 
Audiovisual recording 
For patients receiving Scrambler therapy who agree to participate in the audio-
visual recording portion of this current trial, the established procedures are 
outlined below: 
o 
An audio-video recording device will be placed in the treatment room prior 
to starting Scrambler Therapy. The device runs during the treatment and then 
is turned off. 
o 
A study assistant will upload video files to a secure server the day of each 
recording.  
o 
Files will be named “StudyID_Date” (MC15C1_3-2-2016) and placed in an 
“Original Recordings” folder.  
o 
Files will be converted to Audacity and WAV formats.  
o 
Recordings will be removed from the recorders following overnight backup 
on the specified research server. 
o 
Audio-video recording files will be deidentified (e.g. removal of names) 
using Audacity editing software.  
o 
After recordings have been de-identified, they will be converted to .WAV 
file type and stored for future review. 
7.34 
Quantitative Sensory Testing (QST) 
We will do QST before Scrambler/TENS therapy and on the last day (±3 days)of 
Scrambler/TENS therapy. We will only do this testing on patients that have 
lower extremity neuropathy as their major symptom (as opposed to upper 

MC15C1 
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Protocol version: 27May2016 
extremity neuropathy). We will obtain touch pressure and heat pain testing on 
both the dorsal foot and the lateral leg in 10 patients per study arm. 
This testing will be ordered as a clinical test and paid for by research dollars. 
Note: 
 is our contact person for ordering this test and the IRB 
number should be noted when ordering it. 
 
7.4 
Optional Crossover Continuation 
7.41 
Patients electing to crossover to the opposite treatment arm will be expected to 
complete an additional 2 weeks of treatment and 8 weeks of observation. 
7.42 
Substudies will not be offered for patients on crossover/continuation except by 
permission of PI. 
 
8.0 
Dosage Modification Based on Adverse Events 
If a patient develops any substantial toxicity from the treatment (not expected), then treatment 
with either TENS or Scrambler therapty should be stopped. 
9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care 
Patients should, otherwise receive appropriate supportive care for their pain as clinically 
indicated. 
9.2 
Gabapentinoid use 
Patients should not receive gabapentinoids (e.g. Neurontin®, Lyrica®) during treatment 
with Scrambler therapy. If patients are on gabapentinoids at the time of registration and 
are randomized to Scrambler therapy, they must be weaned off prior to receiving 
Scrambler therapy. 
9.3 
Other pain treatment 
Other pain treatments are allowed if the pain is not satisfactorily controlled. All pain 
treatments and pain-related medications will be recorded. 
9.4 
Investigational agents 
Concurrent use of investigational agents is not permitted unless preapproved by PI. 
 
 
 

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10.0 
Adverse Event (AE) Reporting and Monitoring 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov). 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial. 
First, identify and grade the severity of the event using a copy of the CTCAE 
v4.0. Next, determine whether the event is expected or unexpected (refer to 
Sections 10.12 and if the adverse event is related to the medical treatment or 
procedure (see Section 10.13). With this information, determine whether an 
adverse event should be reported as an expedited report (see Section 10.2) or as 
part of the routinely reported clinical data. Important: All AEs reported via 
expedited mechanisms must also be reported via the routine data reporting 
mechanisms defined by the protocol (see Sections 10.3). 
Expedited and routine reports are to be completed within the timeframes and via 
the mechanisms specified in Sections 10.2 and 10.3. All expedited AE reports 
must also be sent to the local Institutional Review Board (IRB) according to local 
IRB’s policies and procedures. 
10.12 Expected vs. Unexpected 
 
The determination of whether an AE is expected is based on adverse event 
information provided in Section 10.3 of the protocol. 
 
Unexpected AEs are those not listed in the adverse event information 
provided in Section 10.3 of the protocol. 
10.13 Assessment of Attribution 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
Definite - The adverse event is clearly related to the investigational agent(s). 
Probable - The adverse event is likely related to the investigational agent(s). 
Possible - The adverse event may be related to the investigational agent(s). 
Unlikely - The adverse event is doubtfully related to the investigational agent(s). 
Unrelated - The adverse event is clearly NOT related to the investigational 
agent(s) 
10.2 
Expedited Adverse Event Reporting Requirements  
 
Grade 4 or 5 Unexpected with 
Attribution of Possible, 
Probable, or Definite 
Increased 
Incidence of an 
Expected AE1 
FDA Form 3500 (MedWatch) 
within 10 working days2 
X 
X 
1. An increased incidence of an expected adverse event (AE) is based on the patients 
treated for this study at their site. A list of known/expected AEs is reported in the 
package insert or the literature, including AEs resulting from a drug overdose. 
2. Submit form to the FDA, MedWatch, 5600 Fishers Lane, Rockville, MD 20852-
9787, by fax at 1-800-332-0178 or online at 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm.  

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Protocol version: 27May2016 
11.0 
Measurement of Effect? 
11.1 
Primary means of assessment 
Patient reported outcome data, as illustrated in the appendices will be the primary means 
of assessment. 
11.2 
Adverse Event Assessment 
Adverse events will be evaluated by using CTCAE criteria based on patient reporting and 
nurse observation and/or assessment. 
11.3 
mRNA 
mRNA results will be correlated with outcomes. See Section 14.0. 
11.4 
Functional MRIs (fMRI)  
fMRI results will be correlated with outcomes. See Appendix XV. 
 
12.0 
Descriptive Factors  
12.1 
Age (years): <70 vs. ≥70 
12.2 
Duration of pain or neuropathy symptoms in months at baseline: 3 to 6 vs. >6. 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
13.1 
Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  
 
If the patient never received treatment, on-study material must be submitted.  
13.2 
Major violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
Cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. All data up until the point of confirmation of a major violation must be 
submitted.  
13.3 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  
 

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Protocol version: 27May2016 
14.0 
Body Fluid Biospecimens 
In a subset of patients, blood will be obtained to look at mRNA gene expression in patients before and after Scrambler and TENS therapy  
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol* 
Correlative Study (Section 
for more information) 
Mandatory or 
Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per tube  
(# of tubes to be 
collected) 
Baseline 
Prior to 
Tx 
Last Day 
of Tx  
±2 days 
Process at 
site?  
(Yes or 
No) 
Temperature 
Conditions for 
Storage 
/Shipping 
mRNA gene expression  
(Section 14.2) 
Optional 
Whole Blood 
EDTA 
(lavender) 
6 mL 
(1) 
X 
X 
No 
Ambient 
CBC with differential for 
correlation with mRNA 
Optional 
Whole Blood 
EDTA 
(lavender) 
3 mL 
(1) 
X 
X 
Yes** 
Ambient 
*NOTE: Collection is only at Mayo Clinic in Rochester, MN 
**Process through clinical lab so results are in medical record 
14.2  
Collection and Processing  
14.21 mRNA gene expression 
The samples will be obtained prior to the first Scrambler therapy and on the last day (±2 days) of Scrambler therapy. 
14.3 
Shipping and Handling 
14.31 Kits will not be used.  
14.32 After collection, blood will be taken directly to Dr Andreas Beutler’s laboratory on Guggenheim 13 for processing. 
14.4 
Background and Methodology 
14.41 mRNA Gene Expression 
We, through Dr Andreas Beutler’s lab, will obtain RNA expression levels that will be directly comparable to the 
originally reported assay, i.e., relative changes such as before and after treatment. This result will be expressed as a “fold 
change”, such as saying “after scrambler the expression levels of gene X was increased 2-fold and Y was diminished to 
0.7-fold.” That calculation will be made relative to a reference gene that is assumed to be stable. 
We will do RNA quantification genome-wide. The panel will then represented by genes of interest and a dozen reference 
genes, out of ca. 11,000-15,000 genes for which reliable expression levels will be available. 
Via this process, we will look at all of the interesting-appearing genes from the Starkweather et al manuscript. This 
method will allow us to, hopefully, confirm that the gene changes were in line with that previously reported. 
 

MC15C1 
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Protocol version: 27May2016 
15.0 
Drug Information – Not applicable  
16.0 
Statistical Considerations and Methodology  
16.1 
Primary Endpoint 
The primary endpoint of this study is the proportion of patients who achieve at least 50% 
reduction in pain or tingling scores from baseline after two weeks of therapy. 
16.2 
Study Design 
This is a prospective randomized study to explore the efficacy of Scrambler therapy 
compared to TENS therapy for the treatment of chemotherapy induced peripheral 
neuropathy. Patients will be randomized at a 1:1 ratio to receive either scrambler therapy 
or TENS therapy for two weeks and will be observed for eight weeks following 
treatment. The primary outcome is the reduction in pain or tingling scores after 2 weeks 
of scrambler therapy or TENS therapy.   
 
At the end of the eight-week observational period, patients are allowed to cross over to 
receive the other therapy for two weeks and will, again, be followed for an additional 
eight weeks. Outcomes of this second period of treatment are for exploratory purposes 
only. There will be no fMRI, quantitative sensory testing, or mRNA gene expression 
done in this second period. 
16.3 
Analysis Plan 
16.31 Primary endpoint 
Evaluate the efficacy of Scrambler therapy compared to TENS therapy for pain 
and/or tingling related to CIPN. 
The main efficacy endpoint is defined as achieving 50% reduction in pain or 
tingling from baseline.  At enrollment, patients will be asked to select either pain 
or tingling as their primary symptom of concern.  Allowing the patients to select 
their main symptom (pain or tingling) is reasonable since the scores and the 
patterns of reduction were similar for pain and tingling after Scrambler therapy as 
shown by Pachman et al.(Pachman, Weisbrod et al. 2014)  
Descriptive statistics (mean, sd, median, range) of pain and tingling scores and 
changes pre- and post-treatment scores will be summarized and the percentage of 
pain and tingling reduction from baseline will be calculated for each timepoint, 
separately by treatment  arm. Longitudinal plots of scores by arm will be 
provided. The frequency and percentages of patients who achieved more than 
50% reduction in pain and/or tingling scores after 2 weeks of therapy (scores 
from the last treatment day compared to the pre-treatment data, using the 
question related to average symptom [pain or tingling, whichever the patient 
chose when entering the study] over the previous 24 hours) and after 8 weeks of 
observation (scores from Week 8 form) from baseline (scores from Day 1 pre-
treatment form) will be summarized by treatment arm and will be compared 
between arms using a Chi-square test (or Fisher-exact test as appropriate). 
 
16.32 Secondary efficacy endpoints 
Perceived treatment efficacy from the Subjective Global Impression of Change 
instrument (Appendix IXA and B) will be summarized (median and range for 
impression of change and frequency for preference) by arm and compared 

MC15C1 
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Protocol version: 27May2016 
(Wicoxon rank-sum test for impression of change and Chi-square test for 
preference) between treatment arms. 
EORTC CIPN20 scores and changes in scores will be summarized (mean, sd, 
median, range) at each time point by arm and will be compared between arms 
using two-sample t-tests. 
16.33 Goal: Evaluate the tolerability of Scrambler therapy and compare it to TENS 
therapy, in this population. 
Frequency and type of toxicities occurred during therapy will be summarized by 
treatment arm and compared between arms using Fisher-exact test. 
16.34 Goal: Evaluate whether Scrambler therapy, compared to TENS therapy, can 
decrease the use of pain medication for CIPN. 
Type and frequency of analgesic used will be summarized by treatment arms and 
will be compared using Fisher-exact test. 
16.35 Goal: Explore whether mRNA gene expression changes are similar to that 
previously reported by Starkweather et al. 
In a descriptive manner, the gene expression will be compared to what was 
previously reported. 
16.36 Goal: Explore whether Scrambler therapy will change fMRI. 
Changes in fMRI following Scrambler therapy will be described in the subset of 
patients selected for this component of the study. 
16.37  Descriptive statistics will be used for the data from Quantitative Sensory Testing. 
16.4 
Accrual and Duration of Study 
We plan to accrue 50 patients on this trial. Given our previous experience with requests 
for Scrambler Therapy, we estimate an accrual rate of 3 patients per month so that we 
expect to complete accrual within 1.5 years.  With a maximum total time of treatment and 
observation of 5 months, the expected total duration of the study is 2 years.  
16.5 
Sample size 
The sample size of 50 patients (25 per arm) in this prospective randomized study is 
mostly determined by feasibility. This study is not designed as a confirmatory study, 
hence, not powered as such. The primary purpose of this study is to estimate the effect of 
scrambler therapy for the treatment of CIPN which will inform hypothesis formulation 
for future studies. If the data from this study suggest a clinically non-ignorable effect of 
scrambler therapy compared to TENS therapy, we will plan for a larger study to confirm 
its benefit. However, if the data from this trial show a very large difference in changed 
pain scores between the two arms, such that the primary endpoint is positive with a p-
value of less than 0.05, we will interpret this outcome as evidence that Scrambler therapy 
is better than TENS therapy, or vice-versa, depending on which arm is doing better. 
More than 45% of patients in Pachman et al.’s study experienced treatment effect (50% 
or more reduction in symptom scores) after 2 weeks of scrambler therapy(Pachman, 
Weisbrod et al. 2014). This estimate includes patients who were enrolled early in the trial 
who did not respond to the treatment as well as the later cohort, potentially due to the 
study team’s inexperience in the beginning of the trial. With the current level of 
experience, we expect a much higher percentage of reduction in patients’ symptom scores 
after scrambler therapy in this trial.  The likelihood of detecting an improvement of 30% 
or more after scrambler therapy compared to TENS is high with a sample size of 25 

MC15C1 
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Protocol version: 27May2016 
patients per arm. Table 16.51 shows the minimum detectable improvement with at least 
80% power at a one-sided.05 significance level for various plausible scenarios with 25 
patients per arm.  
Table 16.51. Minimum Detectable Improvement with 80% power at a one-sided 0.05 
significance level 
Proportion of patients achieving 50% or more 
reduction in symptom scores from baseline 
Minimum 
Detectable 
improvement 
Power (%) 
TENS 
Scramber 
.05 
.32 
.27 
80 
.10 
.40 
.30 
80 
.20 
.54 
.34 
81 
.30 
.65 
.35 
81 
.40 
.75 
.35 
82 
 
16.6 
Missing Data 
Missing data are expected to be low in this prospective study, however, every attempt 
will be made to follow-up with patients to complete questionnaires. Patients will not be 
replaced if the data of primary endpoint are missing, instead, we will record and 
summarize the pattern of missing data. Exploratory analysis using simple imputation 
and/or multiple imputation maybe performed as appropriate. We plan to use last values 
carried forward for the initial 14 day daily data. 
16.7 
Data and Safety Monitoring 
The study chair(s) and the study statistician will review the study at least twice a year to 
identify accrual, adverse event, and any endpoint problems that might be developing. The 
Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring Board (DSMB) is 
responsible for reviewing accrual and safety data for this trial at least twice a year, based 
on reports provided by the MCCC Statistical Office. 
16.8 
Adverse Event Stopping Rules 
16.81 The stopping rules specified below are based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study re-opening to accrual or (2) at any time during 
the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation. The 
study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
16.82 Adverse events will be monitored separately by arm. Accrual will be temporarily 
suspended to this study if at any time we observe events considered at least 
possibly related to study treatment (i.e. an adverse event with attribute specified 
as “possible”, “probable”, or “definite”) that satisfy either of the following: 
• if 3 or more patients in the first 10 treated patients experience a grade 3 or 
higher adverse event. 
• if after the first 10 patients have been treated, 30 % of all patients experience a 
grade 3 or higher adverse event. 

MC15C1 
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Protocol version: 27May2016 
• if any grade 5 adverse events are observed that are related to study treatment. 
 
16.83 If accrual is temporarily suspended, the study will be reviewed to determin 
whether accrual should continue or be permanently closed.  
 
16.84 We note that we will review Grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
 
 

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Protocol version: 27May2016 
16.9 
Gender and minority accrual considerations 
This study is open to patients from all races. Historical data indicate that no more than 
10% of patients will be ethnic minorities. Subset analysis along ethnic subpopulations 
will hence have a lack of power to draw substantive conclusions but will provide some 
data for future meta-analytic procedures and hypotheses generation. 
 
Ethnic Category 
Sex/Gender (%) 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
1 
0 
1 
Not Hispanic or Latino 
30 
19 
0 
49 
Ethnic Category: Total of all subjects 
30 
20 
0 
50 
Racial Category 
 
American Indian or Alaskan Native 
1 
0 
0 
1 
Asian 
1 
1 
0 
2 
Black or African American 
1 
2 
0 
3 
Native Hawaiian or other Pacific Islander 
0 
1 
0 
1 
White 
27 
16 
0 
43 
Racial Category: Total of all subjects* 
30 
20 
0 
50 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or  
Central American, or other Spanish culture or origin, regardless of race. The  
term “Spanish origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the 
original peoples of North, Central, or South America, and who maintains tribal 
affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as 
Pacific Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the  
Middle East, or North Africa. 
 
17.0 
Pathology Considerations/Tissue Biospecimens - Not applicable  
 
 
 

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18.0 
Records and Data Collection Procedures 
18.1 
Submission Timetables 
18.11 Initial Material(s) 
Case Report Form (CRF) 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study 
2 weeks after registration 
Research Submission 
(see Sections 4.0 and 14.0) 
End of (ALL) Active Treatment/Cancel 
Notification 
Submit 2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
Patient Questionnaire 
2 weeks after registration - Patient questionnaire booklet 
must be used; copies are not acceptable for this submission 
Booklet Compliance  
2 weeks after registration - This form must be completed 
only if the booklet(s) contains absolutely NO patient 
provided assessment information 
 
18.12 Test Schedule Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
Observation 
At end of 
treatment 
Adverse Event  
X 
X 
 
Research Submission  
(see Sections 4.0 and 14.0) 
X 
X 
 
End of Initial Treatment 
 
 
X 
Optional Crossover Continuation 
 
X 
 
Patient Questionnaire 1 
X 
X 
X 
Booklet Compliance 2 
X 
X 
X 
End of (ALL) Active 
Treatment/Cancel Notification  
 
 
X 
ADR/AER (see Section 10.0) 
At each 
occurrence  
 
 
1. Patient questionnaire booklet must be used; copies are not acceptable for this submission. 
2. This form must be completed only if the booklet contains absolutely NO patient provided assessment 
information. 
 
 
 

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Protocol version: 27May2016 
20.0 
References 
 
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Borsook, D., L. Becerra, et al. (2011). "Biomarkers for chronic pain and analgesia. Part 2: how, where, 
and what to look for using functional imaging." Discovery medicine 11(58): 209-219. 
Campbell, T., A. J. Nimunkar, et al. (2013). "A randomized, double-blind study of “Scrambler” therapy 
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Coyne, P. J., W. Wan, et al. (2013). "A Trial of Scrambler Therapy in the Treatment of Cancer Pain 
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palliative care pharmacotherapy. 
Cruccu, G., T. Z. Aziz, et al. (2007). "EFNS guidelines on neurostimulation therapy for neuropathic 
pain." European journal of neurology : the official journal of the European Federation of 
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Dale, A. M., B. Fischl, et al. (1999). "Cortical surface-based analysis. I. Segmentation and surface 
reconstruction." NeuroImage 9(2): 179-194. 
DaSilva, A. F., L. Becerra, et al. (2008). "Colocalized structural and functional changes in the cortex of 
patients with trigeminal neuropathic pain." PloS one 3(10): e3396. 
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Neuromodulation Appropriateness Consensus Committee." Neuromodulation : journal of the 
International Neuromodulation Society 17(6): 515-550; discussion 550. 
Fox, M. D., A. Z. Snyder, et al. (2005). "The human brain is intrinsically organized into dynamic, 
anticorrelated functional networks." Proceedings of the National Academy of Sciences of the 
United States of America 102(27): 9673-9678. 
Freynhagen, R. and M. I. Bennett (2009). "Diagnosis and management of neuropathic pain." BMJ 339: 
b3002. 
Ghatak, R. K., S. N. Nandi, et al. (2011). "Prospective study of application of biological communication 
(cybernatics) in management of chronic low back pain--a preliminary report." Nepal Medical 
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Hershman, D. L., C. Lacchetti, et al. (2014). "Prevention and management of chemotherapy-induced 
peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology 
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Ji, R. R., T. Kohno, et al. (2003). "Central sensitization and LTP: do pain and memory share similar 
mechanisms?" Trends in neurosciences 26(12): 696-705. 
Jin, D. M., Y. Xu, et al. (2010). "Effect of transcutaneous electrical nerve stimulation on symptomatic 
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Ko, Y. K., H. Y. Lee, et al. (2013). "Clinical experiences on the effect of scrambler therapy for patients 
with postherpetic neuralgia." The Korean journal of pain 26(1): 98-101. 

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Lebel, A., L. Becerra, et al. (2008). "fMRI reveals distinct CNS processing during symptomatic and 
recovered complex regional pain syndrome in children." Brain : a journal of neurology 131(Pt 7): 
1854-1879. 
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Starkweather, A. R., P. Coyne, et al. (2015). "Decreased low back pain intensity and differential gene 
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3): 23-37. 
 
 
 
 

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Appendix I 
Patient instruction sheet for tapering gabapentin and pregabalin 
 
Tapering of gabapentin or pregabalin will preferably occur over two weeks. Lower doses may be tapered 
over one week to accommodate patient availability with approval of Dr. Loprinzi. During first week of 
taper, drug will be reduced approximately 25% for 3-4 days, then an additional 25% so that the drug has 
been reduced by approximately 50% by the end of the first taper week. Drug will continue to be reduced 
during the second week every few days until the final dose is taken the evening prior to treatment. Patient 
provider or Dr Loprinzi will need to be contacted if different doses of pills are needed. Patients will be 
instructed on potential symptoms of withdrawal and be asked to contact study staff if symptoms are 
experienced, as the taper may need to be adjusted. The decision of which dose to begin tapering (morning, 
noon, evening) will be decided between patient and study staff. 
 
Patient Form 
 
Gabapentin/Pregabalin 
(circle one) 
mg 
mg 
mg 
mg 
Day/Date 
 
 
 
 
1=
/
/
 
pills 
pills 
pills 
pills 
2=__/__/__ 
__pills 
__pills 
__pills 
__pills 
3=
/
/
 
pills 
pills 
pills 
pills 
4=
/
/
 
pills 
pills 
pills 
pills 
5=__/__/__ 
__pills 
__pills 
__pills 
__pills 
6=
/
/
 
pills 
pills 
pills 
pills 
7=
/
/
 
pills 
pills 
pills 
pills 
8=__/__/__ 
__pills 
__pills 
__pills 
__pills 
9=
/
/
 
pills 
pills 
pills 
pills 
10=
/
/
 
pills 
pills 
pills 
pills 
11=
/
/
 
pills 
pills 
pills 
pills 
12=__/__/__ 
__pills 
__pills 
__pills 
__pills 
13=
/
/
 
pills 
pills 
pills 
pills 
14=
/
/
 
pills 
pills 
pills 
pills 
Day 1 of Treatment 
0 pills 
0 pills 
0 pills 
0 pills 
 
Potential symptoms of gabapentin withdrawal may include nausea, insomnia, restlessness, agitation, 
anxiety, disorientation, confusion, light sensitivity, sweating, headaches, palpitations, chest pain, and flu-
like symptoms. 
 

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Appendix IIA Peripheral Neuropathy Questionnaire for Upper Extremity Neuropathy 
(Used for Eligibility) 
 
 
 
 
 
 
 
How much of a problem has pain in your fingers or hands been in the past week? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No pain in 
fingers and/or 
hands 
 
 
 
 
 
 
 
 
 
Pain in fingers 
and/or hands as 
bad as you can 
imagine 
 
How much of a problem has tingling in your fingers or hands been in the past week? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No tingling in 
fingers and/or 
hands 
 
 
 
 
 
 
 
 
 
Tingling in fingers 
and/or hands as 
bad as you can 
imagine 
 
 
 
 
 
 
 
Initials______________ 
Study #_____________ 
Date_____________ 
Day____________ 

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Appendix IIB Peripheral Neuropathy Questionnaire for Lower Extremity Neuropathy 
(Used for Eligibility) 
 
 
 
 
 
 
 
How much of a problem has pain in your toes or feet been in the past week?  
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No pain in 
toes and/or 
feet 
 
 
 
 
 
 
 
 
 
Pain in toes and/or 
feet as bad as you 
can imagine 
 
How much of a problem has tingling in your toes or feet been in the past week?  
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No tingling in 
toes and/or 
feet 
 
 
 
 
 
 
 
 
 
Tingling in toes 
and/or feet as bad 
as you can 
imagine 
 
 
 
Initials_______________ 
Study #______________ 
Date_________ 
Day__________ 

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Appendix III  Declaration of most problematic site and symptom 
 
Most problematic symptom: 
 
___ Pain  
 
___Tingling 
 
Most problematic site: 
 
___Upper extremities 
 
___ Lower extremities  
 
 
Initials_______________ 
Study #______________ 
Date_________ 
Day__________ 

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Appendix IVA Peripheral Neuropathy Questionnaire for Upper Extremity Neuropathy 
 
 
 
Everyone has aches and pain at some time. We are interested in your 
experience of numbness, tingling and pain that you have developed related 
to chemotherapy. 
 
 
 
How much of a problem has pain in your fingers or hands been in the past week? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No pain in 
fingers and/or 
hands 
 
 
 
 
 
 
 
 
 
Pain in fingers 
and/or hands as 
bad as you can 
imagine 
 
How much of a problem has tingling in your fingers or hands been in the past week? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No tingling in 
fingers and/or 
hands 
 
 
 
 
 
 
 
 
 
Tingling in fingers 
and/or hands as 
bad as you can 
imagine 
 
How much of a problem has numbness in your fingers or hands been in the past week? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No numbness 
in fingers 
and/or hands 
 
 
 
 
 
 
 
 
 
Numbness in 
fingers and/or 
hands as bad as 
you can imagine 
 
 
 
 
Initials______________ 
Study #_____________ 
Date_________ 
Day__________ 

MC15C1 
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Protocol version: 27May2016 
Appendix IVB Peripheral Neuropathy Questionnaire for Lower Extremity Neuropathy 
 
 
Everyone has aches and pain at some time. We are interested in your 
experience of numbness, tingling and pain that you have developed related 
to chemotherapy. 
 
 
 
 
 
How much of a problem has pain in your toes or feet been in the past week?  
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No pain in 
toes and/or 
feet 
 
 
 
 
 
 
 
 
 
Pain in toes and/or 
feet as bad as you 
can imagine 
 
How much of a problem has tingling in your toes or feet been in the past week?  
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No tingling in 
toes and/or 
feet 
 
 
 
 
 
 
 
 
 
Tingling in toes 
and/or feet as bad 
as you can 
imagine 
 
How much of a problem has numbness in your toes or feet been in the past week?  
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No numbness 
in toes and/or 
feet 
 
 
 
 
 
 
 
 
 
Numbness in toes 
and/or feet as bad 
as you can 
imagine 
 
 
 
 
Initials_______________ 
Study #______________ 
Date_________ 
Day
 

MC15C1 
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Protocol version: 27May2016 
Appendix VA Patient Questionnaire: Before Each Treatment for Upper Extremity Neuropathy 
Everyone has aches and pains at some time. We are interested in your 
experience of numbness, tingling and pain that you have developed 
related to chemotherapy. 
Please address these questions related to this. Please comment only on 
symptoms in the primarily treated area. 
 
Directions: Please answer the following questions: 
 
1. How much numbness do you have in your fingers or hands right now (circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
2. How much numbness have you had in your fingers or hands at its worst over the past 24 hours 
(circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
3. How much numbness have you had in your fingers or hands on average over the past 24 hours 
(circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
4. How much tingling do you have in your fingers or hands right now (circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
5. How much tingling have you had in your fingers or hands at its worst over the past 24 hours 
(circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
6. How much tingling have you had in your fingers or hands on average over the past 24 hours 
(circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
7. How much pain do you have in your fingers or hands right now (circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
Initials_______________ 
Study #______________ 
Date_________ 
Day__________ 

MC15C1 
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Protocol version: 27May2016 
8. How much pain, that you consider to be from your chemotherapy, have you had in your fingers 
or hands at its worse over the past 24 hours (circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
9. How much pain have you had in your fingers or hands on average over the past 24 hours 
(circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
10. Which is the most problematic symptom, related to the fingers or hands neuropathy, that 
you have had over the past day? 
 
___Numbness 
 
___Tingling 
 
___Burning/shooting pain 
 
___Other, please indicate________________________________________________________ 
______________________________________________________________________________
_________________________________________________________________ 
 

MC15C1 
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Protocol version: 27May2016 
Appendix VB Patient Questionnaire: Before Each Treatment for Lower Extremity Neuropathy 
 
Everyone has aches and pains at some time. We are interested in your 
experience of numbness, tingling and pain that you have developed 
related to chemotherapy.  
 
Please address these questions related to this. Please comment only on 
symptoms in the primarily treated area. 
 
Directions: Please answer the following questions: 
 
 
1. How much numbness do you have in your toes or feet right now (circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
2. How much numbness have you had in your toes or feet at its worst over the past 24 hours 
(circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
3. How much numbness have you had in your toes or feet on average over the past 24 hours 
(circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
4. How much tingling do you have in your toes or feet right now (circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
5. How much tingling have you had in your toes or feet at its worst over the past 24 hours (circle 
one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
6. How much tingling have you had in your toes or feet on average over the past 24 hours (circle 
one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
 
 
Initials_______________ 
Study #______________ 
Date______________ 
Day______________ 

MC15C1 
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Protocol version: 27May2016 
 
7. How much pain do you have in your toes or feet right now (circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
 
 
8. How much pain, that you consider to be from your chemotherapy, have you had in your toes or 
feet at its worst over the past 24 hours (circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
 
 
9. How much pain, have you had in your toes or feet on average over the past 24 hours (circle one 
number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
 
10. Which is the most problematic symptom that you have now (over the past day)? 
 
___Numbness 
 
___Tingling 
 
___Burning/shooting pain 
 
___Other, please indicate________________________________________________________ 
______________________________________________________________________________
________________________________________________________ 
  

MC15C1 
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Protocol version: 27May2016 
Appendix VIA Patient Questionnaire: Immediately Post Therapy for Upper Extremity Neuropathy 
 
 
 
Everyone has aches and pain at some time.  We are interested in your 
experience of numbness, tingling and pain that you have developed 
related to chemotherapy. 
 
 
 
 
Please complete questionnaire immediately after each daily treatment session. Please comment only on 
symptoms in the primarily treated area. 
 
 
 
Directions: Please answer the following questions: 
 
1. How much numbness do you have in your fingers or hands right now (circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
2. How much tingling do you have in your fingers or hands right now (circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
3. How much pain do you have in your fingers or hands right now (circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
Initials_______________ 
Study #______________ 
Date_____________ 
Day______________ 

MC15C1 
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Protocol version: 27May2016 
Appendix VIB  Patient Questionnaire: Immediately Post Treatment for Lower Extremity 
Neuropathy 
 
 
Everyone has aches and pain at some time.  We are interested in your 
experience of numbness, tingling and pain that you have developed 
related to chemotherapy. 
 
 
 
 
 
Please complete questionnaire immediately after each daily treatment session. Please comment only on 
symptoms in the primarily treated area. 
 
Directions: Please answer the following questions: 
 
 
1. How much numbness do you have in your toes or feet right now (circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
2. How much tingling do you have in your toes or feet right now (circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
 
3. How much pain do you have in your toes or feet right now (circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
 
 
 
 
 
 
Initials_______________ 
Study #______________ 
Date_________ 
Day
 

MC15C1 
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Protocol version: 27May2016 
Appendix VII EORTC QLQ CIPN-20 Instrument 
EORTC QLQ – CIPN20 
Patients sometimes report that they have the following symptoms or problems. Please indicate 
the extent to which you have experienced these symptoms or problems during the past week. 
Please answer by circling the number that best applies to you. 
 
During the past week: 
 
 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
 
 
 
 
 
 
31 Did you have tingling fingers or hands? 
1 
2 
3 
4 
32 Did you have tingling toes or feet? 
1 
2 
3 
4 
33 Did you have numbness in your fingers or hands? 
1 
2 
3 
4 
34 Did you have numbness in your toes or feet? 
1 
2 
3 
4 
35 Did you have shooting or burning pain in your fingers or hands? 
1 
2 
3 
4 
36 Did you have shooting or burning pain in your toes or feet? 
1 
2 
3 
4 
37 Did you have cramps in your hands? 
1 
2 
3 
4 
38 Did you have cramps in your feet? 
1 
2 
3 
4 
39 Did you have problems standing or walking because 
of difficulty feeling the ground under your feet? 
1 
2 
3 
4 
40 Did you have difficulty distinguishing  
between hot and cold water? 
1 
2 
3 
4 
41 Did you have a problem holding a pen, which 
made writing more difficult? 
1 
2 
3 
4 
42 Did you have difficulty manipulating small objects with 
your fingers (for example, fastening small buttons)? 
1 
2 
3 
4 
43 Did you have difficulty opening a jar or 
bottle because of weakness in your hands? 
1 
2 
3 
4 
44 Did you have difficulty walking because your 
feet dropped downwards? 
1 
2 
3 
4 
 
Please go on to the next page 
 

MC15C1 
57  
  
Protocol version: 27May2016 
 
During the past week: 
 
 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
45 Did you have difficulty climbing stairs or getting up 
out of a chair because of weakness in your legs? 
1 
2 
3 
4 
46 Were you dizzy when standing up from 
a sitting or lying position? 
1 
2 
3 
4 
47 Did you have blurred vision? 
1 
2 
3 
4 
48 Did you have difficulty hearing? 
1 
2 
3 
4 
 
 
 
 
 
 
Please answer the following question only if you drive a car 
 
 
 
 
49 Did you have difficulty using the pedals? 
1 
2 
3 
4 
 
 
 
 
 
 
Please answer the following question only if you are a man 
1 
2 
3 
4 
50 Did you have difficulty getting or maintaining an erection? 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
©QLQ-CIPN20 Copyright 2003 EORTC Study Group on Quality of Life. All rights reserved 
 

MC15C1 
58  
  
Protocol version: 27May2016 
Appendix VIII Patient Analgesic Use Questionnaire 
 
 
 
 
 
 
 
 
Please list all pain medications (drug, dose, and quantity) used in the past 24 hours.  
 
 
Drug 
Unit Dose 
Quantity over past 24 hours 
Example Acetaminophen or Tylenol 
500 mg 
4 pills 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initials_______________ 
Study #______________ 
Date_________ 
Day__________ 

MC15C1 
59  
  
Protocol version: 27May2016 
Appendix IXA Global Impression of Change and Patient Preference Questionnaire – Upper 
Extremity 
 
 
SUBJECT GLOBAL IMPRESSION OF CHANGE – NEUROPATHY 
(Upper Extremity)  
 
_________________________________________________________________ 
 
 
 
1. Since beginning the study treatment, my fingers or hands neuropathy symptoms are: 
-3 
-2 
-1 
0 
+1 
+2 
+3 
very much 
worse 
moderately 
worse 
a little 
worse 
about the 
same 
a little 
better 
moderately 
better 
very much 
better 
 
 
 
 
 
 
 
 
2. Since beginning the study treatment, my finger or hand pain is: 
-3 
-2 
-1 
0 
+1 
+2 
+3 
very much 
worse 
moderately 
worse 
a little 
worse 
about the 
same 
a little 
better 
moderately 
better 
very much 
better 
 
 
 
 
 
 
 
 
3. Since beginning the study treatment, my overall quality of life is: 
-3 
-2 
-1 
0 
+1 
+2 
+3 
very much 
worse 
moderately 
worse 
a little 
worse 
about the 
same 
a little 
better 
moderately 
better 
very much 
better 
 
 
 
 
 
 
 
 
Would you recommend this therapy to other patients with problems similar to yours? 
 
 
___ No 
 
___ Yes 
 
___ Unsure 
 
 
Comments: 
 
_____________________________________________________________________________________
_____________________________________________________________________________________ 
_____________________________________________________________________________________
_____________________________________________________________________________________ 
 
 
 
 
Initials_______________ 
Study #______________ 
Date_________ 
Day__________ 

MC15C1 
60  
  
Protocol version: 27May2016 
Appendix IXB Global Impression of Change and Patient Preference Questionnaire – Lower 
Extremity 
SUBJECT GLOBAL IMPRESSION OF CHANGE – NEUROPATHY (Lower Extremity) 
_______________________________________________________________________ 
 
 
1. Since beginning the study treatment, my toes or feet neuropathy symptoms are: 
-3 
-2 
-1 
0 
+1 
+2 
+3 
very much 
worse 
moderately 
worse 
a little 
worse 
about the 
same 
a little 
better 
moderately 
better 
very much 
better 
 
 
 
 
 
 
 
2. Since beginning the study treatment, my toe or foot pain is: 
-3 
-2 
-1 
0 
+1 
+2 
+3 
very much 
worse 
moderately 
worse 
a little 
worse 
about the 
same 
a little 
better 
moderately 
better 
very much 
better 
 
 
 
 
 
 
 
3. Since beginning the study treatment, my overall quality of life is: 
-3 
-2 
-1 
0 
+1 
+2 
+3 
very much 
worse 
moderately 
worse 
a little 
worse 
about the 
same 
a little 
better 
moderately 
better 
very much 
better 
 
 
 
 
 
 
 
  
Would you recommend this therapy to other patients with problems similar to yours? 
 
 
___ No 
 
___ Yes 
 
___ Unsure 
 
Comments: 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
 
 
 
 
Initials_______________ 
Study #______________ 
Date_________ 
Day__________ 

MC15C1 
61  
  
Protocol version: 27May2016 
Appendix XA Daily Scrambler Treatment Log and Adverse Event Assessment 
 
 
Patient Name: ____________________________________________ 
 
Date: ______________ 
 
 
 
Pain Area #1 ________________________________ 
 
VAS Score:  
Pre: __________ 
During: __________ 
Post: __________ 
 
Cable 1 
Max Setting: _______ 
Total Treatment Time: _____ (mins) 
Cable 2 
Max Setting: _______ 
Total Treatment Time: _____ (mins) 
Cable 3 
Max Setting: _______ 
Total Treatment Time: _____ (mins) 
Cable 4 
Max Setting: _______ 
Total Treatment Time: _____ (mins) 
Cable 5 
Max Setting: _______ 
Total Treatment Time: _____ (mins) 
 
 
Pain Area #2 ________________________________ 
 
VAS Score:  
Pre: __________ 
During: __________ 
Post: __________ 
 
Cable 1 
Max Setting: _______ 
Total Treatment Time: _____ (mins) 
Cable 2 
Max Setting: _______ 
Total Treatment Time: _____ (mins) 
Cable 3 
Max Setting: _______ 
Total Treatment Time: _____ (mins) 
Cable 4 
Max Setting: _______ 
Total Treatment Time: _____ (mins) 
Cable 5 
Max Setting: _______ 
Total Treatment Time: _____ (mins) 
 
Adverse Effects Assessment: Please note any toxicities/adverse effects of treatment 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________ 
 
 
Notes/Comments: 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________ 
 
Initials_______________ 
Study #______________ 
Date_________ 
Day
 

MC15C1 
62  
  
Protocol version: 27May2016 
Appendix XB Daily TENS Treatment Log and Adverse Event Assessment 
 
 
 
 
Patient Name: ____________________________________________ 
 
 
 
 
 
Pain Area #1 ________________________________ 
 
 
Cable 1 
Max Setting: _______ 
Total Treatment Time: _____ (mins) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pain Area #2 ________________________________ 
 
 
 
 
 
Cable 2 
Max Setting: _______ 
Total Treatment Time: _____ (mins) 
 
 
 
 
 
 
 
 
 
 
Adverse Effect Assessment: Please note any adverse effects of treatment 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________ 
 
 
Notes/Comments: 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________ 
Initials_______________ 
Study #______________ 
Date_________ 
Day__________ 

MC15C1 
65  
  
Protocol version: 27May2016 
Appendix XIIA 
Patient Weekly Follow-up Questionnaire for Upper Extremity Neuropathy  
 
Everyone has aches and pains at some time. We are interested in your 
experience of numbness, tingling and pain that you have developed 
related to chemotherapy. Please address these questions related to this.  
 
Directions: Please answer the following questions about your 
symptoms. 
 
1.  How much of a problem has numbness in your fingers or hands been in the past week?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
numbness in 
fingers 
and/or hands 
 
 
 
 
 
 
 
 
 
Numbness in 
fingers and/or 
hands as bad as 
you can imagine 
 
2. How much numbness have you had in your fingers or hands at its worst over the past 24 hours 
(circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
3. How much numbness have you had in your fingers or hands on average over the past 24 hours  
(circle one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
4. How much of a problem has tingling in your fingers or hands been in the past week?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No tingling 
in fingers 
and/or hands 
 
 
 
 
 
 
 
 
 
Tingling in 
fingers and/or 
hands as bad as 
you can 
imagine 
 
5. How much tingling have you had in your fingers or hands at its worst over the past 24 hours (circle 
one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
6. How much tingling have you had in your fingers or hands on average over the past 24 hours (circle 
one number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
Initials_____________ 
Study #______________ 
Date_________ 
Day__________ 

MC15C1 
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Protocol version: 27May2016 
7. How much of a problem has pain in your fingers or hands been in the past week?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No pain in 
fingers 
and/or hands 
 
 
 
 
 
 
 
 
 
Pain in fingers 
and/or hands as 
bad as you can 
imagine 
 
8. How much pain, have you had in your fingers or hands at its worst over the past 24 hours (circle one 
number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
9. How much pain, have you had in your fingers or hands on average over the past 24 hours (circle one 
number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
 
10. Which is the most problematic symptom that you have now (over the past day)? 
 
___Numbness 
 
___Tingling 
 
___Burning/shooting pain 
 
___Other, please indicate______________________________________________________________ 
________________________________________________________________________________ 
________________________________________________________________________________ 

MC15C1 
67  
  
Protocol version: 27May2016 
Appendix XIIB 
Patient Weekly Follow-up Questionnaire for Lower Extremity Neuropathy  
 
Everyone has aches and pains at some time. We are interested in your experience of numbness, tingling 
and pain that you have developed related to chemotherapy. Please address these questions related to this.  
 
Directions: Please answer the following questions about your symptoms 
 
1. How much of a problem has numbness in your toes or feet been in the past week?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
numbness in 
toes and/or 
feet 
 
 
 
 
 
 
 
 
 
Numbness in 
toes and/or feet 
as bad as you 
can imagine 
 
2. How much numbness have you had in your toes or feet at its worst over the past 24 hours (circle one 
number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
3. How much numbness have you had in your toes or feet on average over the past 24 hours (circle one 
number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
4. How much of a problem has tingling in your toes or feet been in the past week?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No tingling 
in toes 
and/or feet 
 
 
 
 
 
 
 
 
 
Tingling in toes 
and/or feet as 
bad as you can 
imagine 
 
5. How much tingling have you had in your toes or feet at its worst over the past 24 hours (circle one 
number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
6. How much tingling have you had in your toes or feet on average over the past 24 hours (circle one 
number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
Initials_____________ 
Study #______________ 
Date_________ 
Day
 

MC15C1 
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Protocol version: 27May2016 
7. How much of a problem has pain in your toes or feet been in the past week?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No pain in 
toes and/or 
feet 
 
 
 
 
 
 
 
 
 
Pain in toes 
and/or feet 
as bad as 
you can 
imagine 
 
8. How much pain, have you had in your toes or feet at its worst over the past 24 hours (circle one 
number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
9. How much pain, have you had in your toes or feet on average over the past 24 hours (circle one 
number)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
As bad 
as can be 
 
 
10. Which is the most problematic symptom that you have now (over the past day)? 
 
___Numbness 
 
___Tingling 
 
___Burning/shooting pain 
 
___Other, please indicate_______________________________________________________________ 
_____________________________________________________________________________________
_______________________________ 
 
 
 

MC15C1 
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Protocol version: 27May2016 
Appendix XIII Principals of Positioning and Titrating Scrambler Treatment 
Algorithm 1: Basic Scrambler Treatment Algorithm 
 
 
 
 
 
 
 
1. Assess/Locate Area of Pain 
 
Start with area of most severe pain 
2. Place Electrodes 
 
 
Place electrodes outside area of pain, in 2 D line of pain (horizontal or 
vertical), and on the same side as pain, preferably 2 fingerbreadths outside of 
pain area 
 
The area under electrode should be free of pain and allodynia 
 
The area under the electrode should have good sensation 
 
*If the above criteria are not met, use Algorithm 2 
3. Begin Treatment (turn on channel) 
 
Ask 3 questions: 
 
When do you feel something? 
 
When do you feel a sting? 
 
When do you feel maximum tolerated intensity without 
discomfort? 
 
*May need to turn up past sting to treat effectively 
*During process may turn up as quickly as tolerated to the 
maximum tolerated intensity after the sting 
0 pain 
Continue to treat for 30 
minutes 
*May turn up intensity if 
intensity has decreased 
during treatment and if 
patient tolerates  
Decreased pain, but >0 
 
Try again to increase 
intensity. If patient does 
not tolerate further 
increase then return to 
tolerable intensity and 
add another channel 
(Step 1) to attempt 
zeroing pain 
OR 
If at max on machine and 
pain still>0 add another 
channel (Step 1) to 
attempt zeroing pain 
No change in pain 
 
Zero machine and 
reposition electrodes 
Increased 
Pain/Discomfort 
 
If increase of his/her 
pain, move one 
electrode farther  
(may mean that initial 
electrode placement 
is in area of pain) 
If different/new area of 
pain presents then place 
new set of electrodes using 
same algorithm 
No limit to number of 
electrodes used per area 

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Algorithm 2: Advanced Scrambler Treatment Algorithm 
(If patient does not meet criteria for proper electrode placement) 
 
 
 
 
 
Option 1: Reduce Area of Pain 
 
Place all electrodes above area of pain  
 
 
For feet, place electrodes on leg above area of pain, most likely 
minimum of 2 electrode sets, but may use as many as fit and 
are tolerated, or pain/tingling is zeroed 
 
 
For hands, place electrodes on arm above area of pain, most 
likely minimum of 2 electrode sets, but may use as many as fit 
and are tolerated, or pain/tingling is zeroed 
 
Goal: Replace pain or tingling with new/different tingling sensation in 
the area of pain, in order to reduce area of pain/tingling and allow for 
proper placement of electrodes in next session 
 
Treat for 30 minutes after tingling begins 
 
 
* Patient assessed daily for ability to follow Algorithm 1 
Option 2: Treat in area of pain  
 
When electrode cannot be placed in area of non-pain, an electrode can 
be placed in the area of least pain and then Algorithm 1 can be followed 
 
However, this can cause increased pain and discomfort and therefore 
this technique should be used based on provider experience and patient 
tolerability 

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Appendix XIVA 
Patient instruction form for using TENS on the upper extremities 
1. You will be given a TENS machine, that you will be able to keep. 
2. A nurse will provide hands-on instructions. 
3. Before use, make sure that the TENS unit is charged. 
4. Place a set of pads on the front and back of one wrist; then do the same thing on the other wrist 
with another set of pads. 
5. Turn on the TENS machine. 
6. Increase the intensity of the signal so that a signal is felt and it is comfortable.. 
7. Treat for a total of 30 minutes. 
 

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Appendix XIVB 
Patient instruction form for using TENS on the lower extremities 
1. You will be given a TENS machine, that you will be able to keep. 
2. A nurse will provide hands-on instructions. 
3. Before use, make sure that the TENS unit is charged. 
4. Place a set of pads below the ankle bone, inside and outside on one ankle; then do the same thing 
on the other ankle with another set of pads. 
5. Turn on the TENS machine. 
6. Increase the intensity of the signal so that a signal is felt and it is comfortable. 
7. Treat for a total of 30 minutes. 
 
 
 

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Appendix XV Functional MRI (fMRI) 
Data Analysis  
Functional Data Analysis  
Functional image data sets will be processed and analyzed using FSL (FMRIB’s Software Library, 
www.fmrib.ox.ac.uk/fsl). Processing steps will include spatial filtering, high-pass temporal filtering, 
motion correction, geometric unwarping of EPI images, removal of all non-brain areas in images, and 
mean-based intensity normalization.  Patients whose scans indicate head motion that exceeds 3mm will be 
excluded from the study. 
Seed based connectivity analysis:  
Functional connectivity will be measured using a seed correlation based approach (Fox, Snyder et al. 
2005; Zhang, Snyder et al. 2008). For each subject, all brain time-courses will be orthogonalized to the 
eigen time-courses from WM and CSF extracted using a singular value decomposition (SVD)(Loan 1996)  
Correlation coefficients (CC) will be computed between the eigen time-course from the seed ROI and all 
other voxels in the brain. We will register the resulting statistical parametric maps from first-level 
analysis to the MNI 152 Brain (Montreal Neurological Institute) using FMRIBs Linear Image 
Registration Tool (FLIRT www.fmrib.ox.ac.uk/fsl). These registered CC maps will be transformed using 
a Fisher z-transform and entered into a mixed effects group analysis. The resulting z-statistic maps will be 
subjected to alternative hypothesis testing using Gaussian mixture modeling (GMM) for 
thresholding(Pendse, Borsook et al. 2009) with adaptive estimation of the null hypothesis. 
Resting State Networks (RSN) using Independent Component Analysis (ICA): 
The inherent run to run and inter data set variability of ICA will be captured by running ICA on 
independent data sets multiple times for each group. All ICA runs from each group will be entered into a 
RAICAR analysis(Yang, LaConte et al. 2008)to assess reproducibility of RSNs across runs and groups. 
We will compute p-values for reproducibility of each RSN using a non-parametric method. The matched 
ICA maps for significant RSNs from each subject group will be voxel-wise transformed to Normality 
followed by a mixed effects group analysis. The resulting statistical maps will be thresholded using 
mixture modeling that maximizes the model evidence. 
Correlation Analysis: 
We will carry out multivariate regression analysis across ROIs using (1) the estimated parameters for 
GLM and estimated sources in melodic results versus psychometric measures (e.g., depression scores, 
pain scores, anxiety levels); and (2) a fuzzy cluster analysis (FCA) that examines associations between 
ROIs using the psychometric measures and parameter estimates as features of interest. 
Morphometric Analysis 
Gray Matter Volume and Cortical Thickness: Gray Matter Volume: For cortical thickness, we will 
perform 2 MPRAGE scans in all subjects and average them for increased SNR. We will then construct 
and inflate hemisphere surfaces for the cortex based on the method defined by Dale and Fischl using 
Freesurfer (http://surfer.nmr.mgh.harvard.edu/) tools.(Dale, Fischl et al. 1999; Makris, Kaiser et al. 2006)  
This cortical mapping technique is described in an approach we have published in patients with trigeminal 
neuropathy(DaSilva, Becerra et al. 2008), opioid dependence(Upadhyay, Maleki et al. 2010) and 
migraine(Maleki, Becerra et al. 2011).  
 
Article I. Correlation with Functionally Defined ROI’s:  We will perform the initial functional analysis 
of cortical areas activated during mechanical stimulation as noted above. Group statistical maps 
will be co-registered onto the reconstructed average surface brains of the subjects using 
Freesurfer.  Using this surface-based approach, we can achieve precise cortical mapping and 

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measurements of cortical thickness leading to functionally defined ROIs identified during these 
chemical based experiments.  
 
Correlation of disease frequency with Cortical Thickness: Changes in cortical thickness will be correlated 
with disease frequency and determine areas that seem to change with time. Other parameters, such as age, 
and disease duration will be regressed out. 
 
Diffusion Tensor Imaging Analysis 
Initially, we will correct all DTI datasets for eddy current distortion and head motion using FSL tools 
(Smith 2002). Fractional Anisotropic (FA) diffusion will be characterized on a voxel-wise basis by using 
a least squares fit of the tensor model to the DTI data in order to calculate the eigenvalues, λ1, λ2 and λ3, 
and the eigenvectors e1, e2 and e3 of each DTI dataset and determine from them the fractional anisotropy 
(fa)(Pierpaoli and Basser 1996; Basser and Pierpaoli 1998)  Fractional anisotropy maps will be registered 
to a standard brain using FSL’s DTI tools.  Group differences will be determined from aggregate results 
for each group (Upadhyay, Maleki et al. 2010).  
Correlation analysis: 
We will correlate observed changes in fractional anisotropy (FA) values with changes in RSN and various 
group characteristics and measures such as disease duration and frequency.