A Pilot Randomized Sham-Controlled Trial of MC5-A Calmare Therapy (Scrambler Therapy) in the Treatment of Chronic Chemotherapy-Induced Peripheral Neuropathy (CIPN)
Phase: NA
Conditions: Neuropathy
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

 
 
 
 
 
Title: A Pilot Randomized Sham-Controlled Trial of MC5-A Calmare Therapy 
(Scrambler Therapy) in the Treatment of Chronic Chemotherapy-Induced 
Peripheral Neuropathy (CIPN) 
 
NCT02111174 
 
Principal Investigator: Thomas Smith, M.D. 
 
Document Version: September 07, 2016 
 

 
 
 
 
 
A Pilot Randomized Sham-Controlled Trial of MC5-A Calmare Therapy 
(Scrambler Therapy) in the Treatment of  
Chronic Chemotherapy-Induced Peripheral Neuropathy (CIPN) 
 
 
 
Principal Investigator 
Thomas J. Smith, MD FACP 
 
 
 
600 N. Wolfe Street, Blalock 369 
Baltimore, MD 21287 
Office: 410-955-2091 
Fax: 410-955-2098 
Email: tsmit136@jhmi.edu 
 
Statistician 
 
 
Amanda Blackford 
Division of Oncology Biostatistics & Bioinformatics 
The Sidney Kimmel Comprehensive Cancer Center 
 
Supporters 
 
 
The Avon Foundation 
 
 
Protocol Version: 
 
  September 07, 2016 
 
 
 
 
 
 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 2 
 
A Pilot Randomized Sham-Controlled Trial of MC5-A Calmare Therapy 
(Scrambler Therapy) in the Treatment of Chronic Chemotherapy-Induced 
Peripheral Neuropathy 
 
 
Original Protocol:                 June 25, 2013 (Original) 
 
 
 
 
 
 
Protocol Revision Record: October 14, 2013 (Revised) 
 
 
 
 
November 17, 2013 (Revised) 
December 18, 2013 (Revised) 
December 18, 2013 (Revised) 
February 7, 2014 
February 25, 2014 
 
Amendment #1: 
 
June 4, 2014 
Sections revised:  Title page, Sections 2, 6.1.3, 7.9, 8, and 13.4. 
 
Amendment #2: 
 
September 2, 2014 
Sections revised:  Title page, Sections 1, 6.1.3, 6.1.7-8, 6.2.3, 6.2.12 (re-
ordered), 7.5.4, 8, 13.1 and Appendix A (new). 
 
Amendment #3: 
 
June 4, 2015 
Sections revised:  Title page, Sections 2, 7.4, 7.6.1, 7.6.2, 7.6.3, 7.6.4, 8, 12.2 
 
Amendment #4: 
 
August 6, 2015 
Sections revised:  Title page, Sections 6.1.3, 6.1.4, 7.5.1, 7.6.2 (formatting edit), 
7.9 
 
Amendment #5: 
 
May 31, 2016 
 
 
 
 
 
Sections revised: Title page, Section 9 (Adverse Events) 
 
Amendment #6: 
 
July 15, 2016 
 
 
 
 
 
Sections revised: Title page, Section 6.2.3 Exclusion Criteria, Section 8 Study  
 
 
 
 
 
calendar  
 
Amendment #7: 
 
September 7, 2016 
 
 
 
 
Sections revised: Title page, Section 7.5.1.1 (Methods and Intervention)

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 3 
 
 
Table of Contents 
 
1. 
SUMMARY ........................................................................................................................................................ 5 
2. 
SCHEMA ............................................................................................................................................................ 6 
3. 
OBJECTIVES .................................................................................................................................................... 7 
3.1 
PRIMARY .......................................................................................................................................................... 7 
3.2 
SECONDARY ..................................................................................................................................................... 7 
4. 
HYPOTHESES................................................................................................................................................... 7 
4.1 
PRIMARY .......................................................................................................................................................... 7 
4.2 
SECONDARY ..................................................................................................................................................... 7 
5. 
BACKGROUND AND RATIONALE .............................................................................................................. 8 
5.1 
NEUROPATHY DUE TO CHEMOTHERAPY AGENTS (CIPN) .................................................................................. 8 
5.2 
DIRECT NERVE STIMULATION IN CHRONIC PAIN RELIEF ................................................................................. 8 
5.3 
SCRAMBLER THERAPY ..................................................................................................................................... 9 
6. 
PATIENT POPULATION .............................................................................................................................. 13 
6.1 
INCLUSION CRITERIA ..................................................................................................................................... 13 
6.2 
EXCLUSION CRITERIA .................................................................................................................................... 14 
6.3 
INCLUSION OF WOMEN AND MINORITIES ....................................................................................................... 14 
7. 
STUDY DESIGN AND TREATMENT PLAN .............................................................................................. 15 
7.1 
SUMMARY ...................................................................................................................................................... 15 
7.2 
RECRUITMENT ................................................................................................................................................ 15 
7.3 
DETERMINATION OF ELIGIBILITY ................................................................................................................... 15 
7.4 
RANDOMIZATION AND BLINDING ................................................................................................................... 15 
7.5 
METHODS AND INTERVENTION ...................................................................................................................... 16 
7.6 
PATIENT-REPORTED OUTCOMES .................................................................................................................... 18 
7.7 
CONCOMITANT AND SUPPORTIVE THERAPY ................................................................................................... 19 
7.8 
DISCONTINUATION AND WITHDRAWAL OF SUBJECTS .................................................................................... 19 
7.9 
ADDITIONAL INFORMATION ........................................................................................................................... 20 
8. 
STUDY CALENDAR ...................................................................................................................................... 21 
9. 
ADVERSE EVENTS ........................................................................................................................................ 22 
9.1 
GENERAL ....................................................................................................................................................... 22 
9.2 
REPORTING PROCEDURES .............................................................................................................................. 22 
10. 
MEASUREMENT OF EFFECT..................................................................................................................... 23 
11. 
DATA AND SAFETY MONITORING .......................................................................................................... 23 
11.1 
DATA MANAGEMENT ................................................................................................................................ 23 
11.2 
MONITORING ............................................................................................................................................. 23 
12. 
ADMINISTRATIVE PROCEDURES ........................................................................................................... 24 
12.1 
PROTOCOL AMENDMENTS ......................................................................................................................... 24 
12.2 
INFORMED CONSENT ................................................................................................................................. 24 
12.3 
ETHICS AND GOOD CLINICAL PRACTICE ................................................................................................... 24 
12.4 
REGULATORY AUTHORITIES...................................................................................................................... 24 
 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 4 
 
 
 
13. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 25 
13.1 
OVERALL................................................................................................................................................... 25 
13.2 
SAMPLE SIZE AND ACCRUAL ..................................................................................................................... 25 
13.3 
ANALYSIS PLAN ........................................................................................................................................ 26 
13.4 
REPORTING AND EXCLUSIONS ................................................................................................................... 27 
APPENDICES ............................................................................................................................................................ 27 
APPENDIX A: ECOG PERFORMANCE STATUS SCALE ........................................................................................... 28 
APPENDIX B:  MODIFIED BRIEF PAIN INVENTORY ................................................................................................ 29 
APPENDIX C:  EUROPEAN ORGANIZATION FOR RESEARCH AND TREATMENT OF CANCER QUALITY OF LIFE 
CANCER CHEMOTHERAPY INDUCED PERIPHERAL NEUROPATHY-20 INSTRUMENT (CIPN-20) ................................ 31 
APPENDIX D:  CONCOMITANT PAIN MEDICATIONS/PARTICIPANT DIARY ............................................................. 32 
REFERENCES .......................................................................................................................................................... 33 
 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 5 
1. Summary 
Scrambler Therapy is a personalized neuro-cutaneous method of pain relief that has been 
effective in reducing chronic neuropathic pain in multiple uncontrolled trials. Treatment is given 
with common EKG skin electrodes placed above and below the pain, and the Scrambler Therapy 
machine directs electrical signals across the field to simulate non-pain information. The 
treatment is non-invasive and takes 30 minutes a day for 10 days. To date, the pain relief has 
been straightforward and dramatic. 
 
Chemotherapy induced peripheral neuropathy (CIPN) is a major and often dose-limiting side 
effect of antineoplastic agents. 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.  Pain is the most common symptom, usually described as a burning, 
stinging dysesthesia. There is no standard effective therapy for CIPN pain. 
 
We propose a straightforward randomized controlled trial of actual Scrambler Therapy versus 
sham therapy (electrodes placed on the back, which does not cause pain relief but was perceived 
as active treatment in our pilot trials).  
 
The primary endpoint is patient reported change in pain from day 0 to day 28, on a numeric scale 
of 0-10 (question #3 of the Modified Brief Pain Inventory, Appendix B). Secondary endpoints 
will include changes in the complete Brief Pain Inventory, the CIPN EORTC Q-20 scale, and 
changes in pain drug use. With 30 patients and a one-sided type I error rate of 10%, we have 
87% power to detect a 50% reduction in pain observed in single arm trials and a 10% reduction 
in pain with sham treatment, in patients with a starting pain score of ≥4. 
 
Subjects enter the study and get scrambler therapy or placebo for 10 sessions, usually as 
weekdays, for 2 weeks. Then, they are followed without any protocol treatment until Day 28 
when the primary endpoint is assessed. After the primary assessment is done the groups are “un-
blinded” and informed of their study treatment, real or sham. Those in the sham group with 
scores ≥4 will be offered the standard 10 scrambler sessions. All patients are followed for a total 
of 3 months. 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 6 
2. Schema 
 
 
 
 
 
 
 
 
 
 
Scrambler Therapy, 
N = 15 
10 days treatment 
Sham Therapy, 
N = 15 
10 days treatment 
Primary Assessment at 1 month, unblind. 
Treat with Scrambler therapy if pain ≥4 
and not relieved to the satisfaction of the 
patient. This treatment will start only 
after the 1 month assessment. 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 7 
3. Objectives 
3.1 
Primary 
3.1.1 To determine the change in pain from day 0 to day 28 with scrambler therapy in patients 
with chemotherapy induced peripheral neuropathy and pain (CIPN).  This endpoint also 
serves to get preliminary information for planning future, larger, phase III studies. 
 
The primary measurement tool for pain will be the Brief Pain Inventory (BPI) (modified 
specifically for CIPN by the originator, Dr. Charles Cleeland, and used with permission) 
which gives information on Pain Now, Worst, Least and Average Pain, and Interference 
with Normal Activity. 
3.2 
Secondary 
3.2.1 The secondary endpoints will include changes in the complete Brief Pain Inventory, the 
CIPN EORTC Q-20 scale, and changes in pain drug use. 
3.2.2 The primary measurement tools used to determine if MC-5A Calmare therapy will 
improve endpoints include the following: neuropathy (European Organization for 
Research and Treatment of Cancer Quality of Life Cancer Chemotherapy Induced 
Peripheral Neuropathy-20 Instrument (CIPN-20)); opiate use (morphine oral equivalent 
daily dose, MOED) and other drug (anti-depressant, anti-convulsant) use. We will also 
study the duration of the effect. 
 
4. Hypotheses 
4.1 
Primary 
 Scrambler Therapy will improve pain related to chemotherapy-induced neuropathy 
significantly more than sham therapy at day 28.  
4.2 
Secondary 
 Scrambler Therapy will result in significant improvements in the total CIPN modified 
Brief Pain Inventory score and the motor and sensory subscales of the CIPN 20 compared 
to sham therapy. 
 Pain medication and morphine oral equivalent dose (MOED) daily amounts will decrease 
by at least 20% more from the start of treatment Day 1 (pre) to Day 30 days (post), in the 
group receiving scrambler therapy versus those who received sham therapy.   

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 8 
5. Background and Rationale 
5.1 
Neuropathy due to chemotherapy agents (CIPN) 
CIPN is a major and often dose-limiting side effect of antineoplastic agents1 including the 
taxanes (paclitaxel and docetaxel), platinums (carboplatin, cis-platinum, and oxaliplatin), vinca 
alkaloids (vincristine, vinblastine, and vinorelbine), proteosome inhibitors (bortezimib2), 
immunomodulating drugs such as lenalomid3, and epithelones such as ixabepilone4. 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.5 Unlike chronic 
diabetic nerve damage, it is not caused by nutritional starvation but rapid damage to 
microtubules of the nerves.6 Pain is the most common symptom, usually described as a burning, 
stinging dysesthesia. However, many patients also complain of numbness and being unable to do 
activities of daily living because they cannot feel their fingertips or toes. This numbness is often 
progressive over the day such that sensation is lost by the end of the day. 
 
There is no standard effective therapy for CIPN pain. Tricyclic antidepressants (TCAs) do not 
work for CIPN and have significant adverse effects. Amitriptyline7 and Nortryptiline8 were no 
better than placebo in randomized trials. Lamotrigine had no effect on CIPN in a randomized 
placebo controlled trial.9 Gabapentin does not work for CIPN when compared to placebo.10 
Magnesium and calcium infusion does not prevent oxaliplatin-induced neuropathy11. Vitamin E 
may be helpful but may also protect the cancer; use is not suggested until larger randomized 
trials are completed. Acetyl-L-carnitine has been reported to reduce established CIPN in one 
small series12 but the investigators caution against its use until safety and efficacy can be 
confirmed in larger randomized trials.13 Venlafaxine14 reduced the incidence or prevented 
oxaliplatin-CIPN from 76% to 35% but has only been tested in oxaliplatin, a drug not used in 
breast cancer treatment, and has not been tested as a treatment drug. Topical baclofen-
amitriptyline-ketamine (BAK) gel reduced CIPN-sensory symptoms compared to placebo15, but 
incompletely and not in the feet – where the symptom is most common. Duloxetine (Cymbalta) 
is the only drug shown in a randomized trial to reduce CIPN pain scores16, but only from 6 to 5 
over 6 weeks, caused side effects, and only worked for oxaliplatin neuropathy -- not for taxane-
induced CIPN which is far more common in women with breast cancer. 
 
Acupuncture reduced CIPN pain scores in small, non-randomized series of 517 and 1818 cancer 
patients. In one larger trial, acupuncture relieved CIPN from paclitaxel and oxaliplatin more 
effectively than drug treatment with Vitamin B12 injections, 67% vs. 40%19. In one small trial, 
nerve conduction studies showed improvement after acupuncture: 5 of 6 patients improved 
clinically, correlated with improvements in mean nerve conduction velocity (NCV) (m/s) and 
mean amplitude (μV) (p=0.03)20 suggesting that CIPN-damaged nerves can indeed repair.    
However, none of these trials had any standard control or sham/placebo group. 
5.2 
Direct Nerve Stimulation in Chronic Pain Relief 
There is much clinical experience that CIPN and other chronic pain syndromes can be helped by 
direct nerve stimulation21. The hypothesized mechanisms by which direct nerve stimulation 
reduces pain include reducing impulses from the damaged nerve, raising the “gate” threshold for 
pain at the spinal cord, reducing “wind up” (central sensitization of the spinal cord and brain that 
amplifies the abnormal feelings), and reducing psychological maladaptation to pain22. Spinal 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 9 
cord stimulation has been successful in small, non-randomized series23 24 for chronic pain from 
reflex sympathetic dystrophy25 and post-herpetic neuropathy26 but has not been assessed in 
CIPN. Peripheral nerve stimulation27 28 is growing in use but there are no controlled trials to 
date. Not all therapies work, however, as the published data show that trans-cutaneous electrical 
nerve stimulation (TENS) is not useful in cancer pain29, and TENS has not been evaluated in 
CIPN.30  
5.3 
Scrambler Therapy 
5.3.1 Rationale for nerve-based treatments like Scrambler Therapy 
Scrambler Therapy is a novel treatment whose efficacy for CIPN is supported by clinical 
experience and pilot trials, but for which rigorously designed, sham-controlled trials do not exist.  
The goal of the device is to provide “non-pain” information to the cutaneous nerves to block the 
effect of pain information 
 
The device is a cutaneous electrical stimulator that uses C fiber stimulation to transmit patterns 
of waveforms simulating 16 different action potentials to reset the brain to perceive non-pain 
from areas previously interpreted as painful. Proprietary software designs the patient-specific 
cutaneous electro-stimulation to reduce the abnormal pain intensity. The device consists of a 
multiprocessor apparatus able to simulate 5 artificial neurons by the application of surface 
electrodes on skin pain areas. The 
device synthesizes 16 different types 
of nerve action potentials similar to 
the endogenous kinds, strings them 
into sequences, and directly 
stimulates the peripheral nerves.  
 
The scientific rationale for the 
observed pain relief is shown in 
Figure 1. The relationship between 
clinical pain relief and the 
hypothesized active principle 
requires further validation and 
independent studies, but we have 
some hypotheses. First, it is not just 
C fibre excitation; electrical C fibre 
excitation without information 
should also produce pain, whereas 
Calmare therapy produces pain 
relief. Second, Calmare therapy is not just producing widespread paraesthesia. The patient feels 
the effect of stimulation only in the painful area under the electrode contact-area. Immediately 
after the treatment, no parasthesia or anesthesia is noted. Furthermore, the intensity of 
stimulation current is very low, and peaks never exceed 5.5 mA, which is likely too low to 
produce analgesia. Fourth, the sensation perceived by the patient (electrical current, pressure, 
flow, or other “bee sting” sensations under the electrodes) suggests that non-pain stimuli are 
being felt, not just analgesia numbing sensation. Another aspect of the hypothesized pain relief is 
Figure 1: Mechanisms of pain and Calmare Treatment 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 10 
that analgesia occurs within minutes or hours and slowly accumulates over several days, 
suggesting nerve remodulation or remodelling. 
 
The exact mechanism by which similar types of nerve stimulation reduce pain is complex and 
not completely understood. Regardless of the mechanism, the therapy appears to work or at least 
warrant further testing. 
5.3.2 Preliminary data on Scrambler therapy 
The Scrambler Therapy device appears to work on pain 
based on results from multiple trials. In the first trial, 11 
cancer patients (3 pancreas, 4 colon, 4 gastric) suffering 
from drug resistant visceral pain were studied during their 
first ten treatment sessions.31 Pain was quickly and 
markedly reduced and maintained until death. Nine of 11 
stopped pain drugs within the first 5 applications. In the 
second trial, 226 patients with neuropathic pain including 
failed back surgery, brachial plexus neuropathy, and others 
were treated.32 80% of patients responded with > 50% pain 
relief, 10% responded with pain relief from 25% to 
49%, and only 10% had no response (P<0.0001). 
 
Based on these results the FDA approved Scrambler 
therapy for cancer pain treatment February 25, 2009. 
In clinical practice, over 4000 patients have been 
treated worldwide with no reported side effects except 
occasional transient worsening of pain. In addition, at 
least one patient had some temporary bruising under 
the sites of the electrodes. 
 
In the first US trial, Smith et al33 studied 16 typical 
patients (median age 56, usual chemotherapy drugs) 
with refractory CIPN and pain scores over 6. Each 
patient was treated for 10 sessions of 60 minutes each, 
Monday through Friday. The electrodes were applied in 
the areas of the pain, as shown in Figure 2. The results 
are shown in Figure 3. The average pain reduction was 
59%, similar to direct spinal cord stimulation. The effect 
on some patients was dramatic, with 4 people having no 
pain and several resumed normal activity. The effect was 
persistent, lasting weeks to months in most patients, with 
successful retreatment if needed.  
 
Mayo Clinic investigators have now replicated these 
results in a pilot trial, with a 47% reduction in CIPN 
pain.34 The 10 day time period is too short for any 
Figure 2:MC5-A Scrambler Therapy 
for CIPN, application of electrodes for 
each 30 minute session 
Figure 3: Scrambler Therapy and CIPN 
Results, Smith et al. 
0
1
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4
5
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7
1
2
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4
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CIPN Pain Score 0-10
CIPN Mean
Figure 4: Scrambler Therapy and 
CIPN pain, Mayo Clinic 
Figure 5: Scrambler Therapy and 
Neuropathic Pain, Ricci et al. 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 11 
Figure 7: Reduction in Chronic Pain with 
Scrambler Therapy 
Figure 8: Pilot trial of Scrambler therapy for 
low back pain 
natural reduction in CIPN, making this unlikely to be natural resolution. (Figure 4) 
 
Ricci et al treated 47 cancer pain patients (many types of pain, not just CIPN) with Scrambler 
therapy. Pain intensity decreased by 74% from 4.7 (SD 2.9) at baseline to 2.5 (SD 2.3) at the end 
of the second week of treatment and 2.6 (SD 2.6) at one month. (Figure 5) Nearly all patients 
found it satisfactory or very satisfactory and would continue using it.35  
 
In a pilot randomized trial36, 52 patients with chronic 
neuropathic pain (spinal cord stenosis, failed back 
syndrome, post-herpetic neuropathy) were randomized 
to Scrambler therapy or treatment by the same expert 
group following standard pharmacology guidelines37. 
The patients had post-surgical failed back, post herpetic, 
or spinal stenosis neuropathy. These results are shown 
in Figure 6. The mean pain intensity score at outset 
was 8.1. At one month, the Scrambler therapy group 
had a 91% decrease in pain to 0.7 points, and the 
standard therapy group had a 28% reduced pain score, 
which was maintained for 3 months. Pain drug 
consumption decreased by 72% in the Scrambler 
therapy group, including opiates, anti-depressants, and 
anti-convulsants. Allodynia, or pain on normal 
touching of the skin, was reduced in the Scrambler 
therapy patients from 77% to 15% at 3 months. All 
differences were both clinically and statistically 
significant.  
 
Other small series show a >50 % reduction in 
refractory post –herpetic pain38 and cancer pain39. 
 
In a large series of complicated pain patients, 
including spinal pain, neuralgia, chronic regional pain 
syndrome, and multisite pain, D’Amato and colleagues 
reported a significant reduction in pain scores across 
all diagnostic groups40. (Figure 7) 
 
In a recent trial, Pachman et al treated 13 patients with 
refractory low back pain at the Mayo Clinic. Mean average daily pain scores decreased by 54% 
from baseline to day 10 of treatment.  Median weekly pain scores decreased by 70% after 10 
weeks of follow up, as shown in Figure 8. Patients also reported improvements in quality of life 
that persisted through 10 weeks of follow up. The data suggest that scrambler therapy effectively 
treats chronic low back pain, supporting the conduct of a placebo-controlled, randomized trial. 
(Pachman D, et al. submitted for publication)  
 
Figure 6: Scrambler Therapy (top) 
compared to best medical management 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 12 
In the most recent trial, Smith and colleagues treated 33 patients with CIPN and found a 
significant reduction in pain persisting to 90 days (Figure 9) and dramatic improvement in how 
the pain interfered with normal life (Figure 10). 41 
 
 
 
In this trial of 39 patients, Smith et al also saw significant improvements in both the motor and 
sensory subscales of the CIPN-20. (All p values < 0.001) Again, this was a single arm trial with 
no sham or placebo group. 
 
 
 
 
While these results in CIPN are promising, there are NO sham or placebo controlled trials. The 
results to date could potentially be due to placebo effect, as seen in one small trial of high 
frequency spinal cord stimulation42, but typical placebo CIPN effects are only about 10% pain 
relief over 3 months 8-15. In the recent successful trial of duloxetine for CIPN16, the CIPN 
placebo group had reduced pain scores of only 0.1-0.2 points (on a 10-point scale) over 6 weeks, 
whereas the Scrambler Therapy 2-4 point drop happened within 10 days. Another alternative 
explanation is that the CIPN resolves over time, but the 10 day time period of treatment is likely 
to be too short for CIPN to resolve. We need sham or placebo-controlled trials to ensure that the 
treatment actually works, and if it works, the duration of effect. 
 
While several hundred thousand CIPN patients stand to benefit, the bigger group of beneficiaries 
is the 116 million Americans with chronic pain43. Evaluating if Scrambler Therapy works in one 
well-defined pain group will stimulate the needed research with other pain patients. 
 
 
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Figure 9: Impact of Scrambler 
Therapy on neuropathic pain 
Figure 10:  “How much does pain 
interfere with walking?” 
Figure 11: Reduction in  
sensory symptoms 
sensory
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Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 13 
6. Patient Population 
6.1 
Inclusion Criteria 
6.1.1 Men and women, 18 years of age or older with cancer. 
6.1.2 English speakers. 
6.1.3 CIPN neuropathy: Received neurotoxic chemotherapy in any setting as cancer treatment; 
including taxanes-such as paclitaxel or docetaxel;  platinum-based compounds such as 
carboplatin or cis-platinum or oxaliplatin; or, vinca alkaloids such as vincristine, 
vinblastine, or vinorelbine, or proteosome inhibitors such as bortezimib. 
 
NOTE:  Patients should no longer be receiving the therapy that caused the CIPN, or have 
recently started a new treatment that may worsen CIPN.  Patients on a treatment that may 
cause CIPN for a period of time where CIPN does not appear to be worsening may be 
allowed at discretion at the Principal Investigator. 
6.1.4 Pain or symptoms of peripheral neuropathy of >3 month's duration attributed to 
chemotherapy-induced peripheral neuropathy. 
6.1.5 An average daily pain rating of > 4 out of 10, using the following question from the BPI: 
Please rate your pain by circling the one number that best describes your leg and/or feet 
pain/discomfort (it is understood that the neuropathy discomfort from chemotherapy is 
not always called a ‘pain’ by all patients, but, for this study, that ‘discomfort’ should be 
considered to be a ‘pain’) from the chemotherapy related neuropathy on average over 
the past week.  (Scale 0-10; 0= No pain, 10= Pain as bad as you can imagine) 
6.1.6 Life expectancy >3 months 
6.1.7 ECOG Performance Status 0, 1, 2, or 3 (see Appendix A).   
6.1.8 Patient understands the study regimen, its requirements, risks, and discomforts, and is 
able and willing to sign an informed consent form. 
 
 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 14 
6.2 
Exclusion Criteria 
6.2.1 Any of the following: pregnant women, nursing women, women of childbearing potential 
or their sexual partners who are unwilling to employ adequate contraception (condoms, 
diaphragm, birth control pills, injections, intrauterine device [IUD], surgical sterilization, 
subcutaneous implants, abstinence, etc.). 
6.2.2 Use of an investigational agent for pain control concurrently or within the past 30 days. 
6.2.3 History of or previous intolerance to transcutaneous electronic nerve stimulation.  
6.2.4 Patients with implantable drug delivery systems, e.g. Medtronic Synchromed. 
6.2.5 Patients with heart stents or metal implants such as pacemakers, automatic defibrillators, 
cochlear implants, aneurysm clips, vena cava clips and skull plates. (Metal implants for 
orthopedic repair, e.g. pins, clips, plates, cages, joint replacements are allowed). 
6.2.6 Patients with a history of myocardial infarction or ischemic heart disease within the past 
six months. 
6.2.7 Patients with history of epilepsy, brain damage, or symptomatic brain metastases. 
6.2.8 Prior celiac plexus block, or other neurolytic pain control treatment. 
6.2.9 Other identified causes of painful parasthesias existing prior to chemotherapy (e.g., 
radiation or malignant plexopathy, lumbar or cervical radiculopathy, pre-existing 
peripheral neuropathy of another etiology: e.g., carpal tunnel syndrome, B12 deficiency, 
AIDS, monoclonal gammopathy, diabetes, heavy metal poisoning amyloidosis, syphilis, 
hyperthyroidism or hypothyroidism, inherited neuropathy, etc.) that might be responsible 
for the patient’s current neuropathic symptoms. 
6.2.10 Skin conditions such as open sores that would prevent proper application of the 
electrodes. 
6.2.11 Currently receiving anti-convulsants (such as gabapentinoids, e.g. gabapentin (Neurontin) 
or pregabalin (Lyrica). Because of data that support that patients do not do as well when 
on gabapentin or pregabalin, all patients on these medications will be weaned off them 
prior to study initiation.  The study team will provide instructions on how to do this. 
6.2.12 Other medical or other condition(s) that in the opinion of the investigators might 
compromise the objectives of the study 
6.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 15 
7. Study Design and Treatment Plan 
7.1 
Summary 
We propose a straightforward randomized controlled trial of actual Scrambler Therapy versus 
sham therapy (electrodes placed on the back, which does not cause pain relief but is perceived as 
active treatment in a pilot trial).  This study also serves to get preliminary information for 
planning future, larger, phase III studies. 
7.2 
Recruitment 
Patients will be recruited through the Kimmel Cancer Center’s outpatient oncology clinics.  
Participants may also be referred from other centers to consider participation; however, direct 
recruitment strategies are not planned. 
7.3 
Determination of Eligibility 
Eligibility for participation will be reviewed and confirmed by a member of the study staff.  
Upon successful eligibility, the patient will be eligible for registration into the study, at which 
time a study-specific subject ID/number will be assigned.   
 
For patients who reach the study team without the referral of their treating oncologist, a member 
of the patient’s care team will be consulted to confirm that s/he believes that the participant is 
appropriate for protocol participation. 
 
Study intervention cannot begin until the patient is successfully registered and after 
randomization has taken place (per below).   
7.4 
Randomization and Blinding 
Upon eligibility confirmation, participants will be randomized to the Scrambler Therapy or sham 
treatment group.  A list will be tabulated by a study statistician and provided to a member of the 
study team not directly involved in recruitment or provided in a way that the next assignment is 
not known (i.e., prepared, sealed envelopes to be opened at the time of randomization). The 
randomization assignments will be made as close as possible the planned day 1 of intervention 
and made available to the study team member who will administer the Scrambler intervention.   
 
Whenever possible, for any outcome other than a patient-reported outcome, such as diary entries, 
the data will be recorded or reviewed by the study coordinator, not the treatment person.  If 
possible, the study coordinator will meet with participants prior to or after the treatment session 
such that the coordinator interacting with the participant is not aware of the treatment 
assignment. 
 
All participants will be asked whether they thought that they received Scrambler Therapy or 
sham therapy. This will be evaluated at the end of the first treatment and after the last treatment. 
 
All patients will be un-blinded after the Day 28 data collection is complete. Participants 
randomized to the sham group who still have an average daily pain rating of ≥4 after the day 28 
data collection is complete (for the primary endpoint) will be offered 10 Scrambler Therapy 
sessions. This group will not be separately analyzed or considered part of the primary endpoint; 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 16 
however, their pain scores recorded after the primary endpoint is assessed will be summarized 
with the rest of the sham group using an intent-to-treat approach.  We will keep to the original 2 
and 3 month time periods for assessment, and not add a two week delay, in order to finish at 3 
months total. These originally sham-randomized participants with an average daily pain rating of 
<4 after the day 28 data collection is complete may be offered 10 Scrambler Therapy sessions at 
the discretion of the Principal Investigator. 
7.5 
Methods and Intervention 
7.5.1 Scrambler Therapy 
The locations of symptoms will be assessed on both the upper and lower extremities. Treatment 
will be given to both arms and legs based on the number of electrodes available and the desire to 
have a short, defined period of treatment. 
7.5.1.1 Treatment Days 
 
Day 1/Treatment Initiation: 
1. Treatment should be initiated by turning on the stimulus for the first electrode pair. The 
intensity of the stimulus is increased until the patient can first feel some sensation 
associated with one or both of the electrodes.  
2. Then, over a few seconds, the intensity is increased to what is maximally tolerated.  
3. Once the intensity is at its maximum setting, the research therapist will evaluate the level 
of pain.  If the pain level is not decreased, the machine will be reset to zero, the 
electrodes will be repositioned and the machine will be restarted in the manner described 
above.  If the pain is not completely resolved with one set of electrodes, a second set will 
be applied in a similar fashion. Once satisfactory electrode placement and stimulus 
intensity is determined, therapy is maintained for a total of 30 minutes. The exact 
assessment and electrode location process is outlined in The Calmare Manual. 
4. The same process will be followed for the opposite foot. 
5. 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 evaluated. Considerations 
include subjective patient intolerance, stimulation of a cutaneous nerve branch, or 
exacerbation of hyperesthesia or allodynia associated with the neuropathic process. These 
problems can be addressed by moving one or both of the electrodes farther away from the 
area of pain.  For the electrodes that were moved, the intensity should again be increased 
and maintained at maximum for 30 minutes as described above.  
6. Once placement of the electrodes have been finalized, photographs may be taken of the 
sites of the electrodes including lower arms, hands, lower legs, feet, and lower back to 
document the placement of the electrodes on each day. These photographs will be 
documented in the patients’ electronic medical record and will not include any 
identifying features.   
 
 
Days 2-10: 
1. Treatment will be administered using the same principles (each day evaluated 
independently and not necessarily reproducing the electrode arrangements and 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 17 
stimulation parameters of the previous day) for 30 minutes on consecutive days 
(Monday-Friday for 2 weeks).  
2. Up to two or three days may be skipped to allow for weekends and/or holidays, if needed. 
If the participant presents without any pain, then the treatment will be “held” for that day 
and this information will be recorded.   
3. Treatment does not proceed if the patient does not have pain. 
7.5.1.2 Dose and Application 
 
1. Electrodes are applied on the skin in the pain-affected area. 
2. The electrodes are never applied directly on the pain area, unless there is no pain free 
area. In that case, the electrode will be applied to the most pain free area, as per the 
manufacturer’s and inventors instructions. 
7.5.2 Sham Treatments 
The sham treatment has been extensively tested at the Mayo Clinic with half of the 10 patients 
able to discern that their treatment was a sham. (Loprinzi, Barton, Pachman, Smith, unpublished 
data) 
7.5.2.1 Treatment Days 
 
1. The Sham procedure will be implemented in exactly the same way as the Scrambler 
Therapy procedure, except that the placement of the electrodes will occur on the back, 
not near the spinal column (away from the main region of pain, which in CIPN is 
nearly always maximal in the feet).  
2. The distal electrode (black) will be placed on the back midway from the posterior axillary 
line and the midline on the left side in the T8 dermatome.  
3. The proximal electrode (non-black) will be placed on the back midway from the posterior 
axillary line and the midline on the left side in the T4 dermatome. 
7.5.2.2 Dose and Application 
The electrodes will be applied and sessions will continue similarly as in the Scrambler Therapy 
group, with the exception of the different placement areas noted. 
 
We will attempt to control for bias by having the lead-placer use the same script and follow 
exactly the same procedures, asking the exact same questions (“Do you feel any sensation?” “Let 
me know when you feel the sensation.” “Let me know when you feel the sensation is at your 
limit of tolerance.”) when placing “real” or sham leads. 
7.5.3 Calmare Device 
The device has FDA 510(k) approval, "Scrambler ST 5 TENS Device," (K081255) granted in 
February 2009. 
 
A device has been provided to SKCCC by the manufacturer, Competitive Technologies, Inc.  
The device has passed approval by Johns Hopkins Clinical Engineering. 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 18 
7.5.4 Additional Information 
We will include information in the informed consent form to suggest that participants wear loose 
fitting clothing where electrode placement may be easily placed underneath clothing to avoid the 
need to change into an exam gown at each visit.   
7.6 
Patient-Reported Outcomes 
7.6.1 General 
In addition to the patient-reported outcomes described below and as outlined on the Study 
Calendar, the following information will be collected for all participants:   
 
1. Before and after each Scrambler Therapy/Sham treatment session daily, the “pain now” 
question from the BPI will be asked and documented, as in prior studies:  “Please rate 
your pain/discomfort on a scale of 1 to 10 with the one number that best tells how much 
pain/discomfort from the chemotherapy related neuropathy you have RIGHT NOW.”   
2. Patients will be asked to state whether they believe they are receiving the active or sham 
therapy at the end of the 1st and last treatment.  
3. Patients will be asked after the end of the last treatment:  “Did the treatment help you 
with the pain and or numbness?” Yes/ No. “Would you want to continue the treatment if 
it was available?” Yes/No 
7.6.2 BPI Short Form – Modified for CIPN 
The Brief Pain Inventory (BPI) short form44 is a pain assessment tool used with cancer patients 
to measure both severity of pain (first 5 items) and interference caused by pain (item 6 with 7 
components) on 0-10 scales (0=does not interfere; 10=completely interferes.) It is widely used in 
cancer pain evaluation45 and has been modified specifically for neuropathy46.  
 
The BPI short form will be completed at baseline, end of treatment and at 1 month (28 days), 2 
months (8 weeks), and 3 months (12 weeks) after the Scrambler/Sham therapy. Those 
participating in sham therapy group and choosing Scrambler therapy after 28 days, will complete 
the BPI at the end of Scrambler therapy, and at 1 and 2 months after the Scrambler therapy. 
Before and after Scrambler/Sham therapy daily, the “pain now” question from the BPI (question 
#4) will be asked and documented, as in prior studies. 
7.6.3 European Organization for Research and Treatment of Cancer Quality of Life Cancer 
Chemotherapy Induced Peripheral Neuropathy-20 Instrument (CIPN-20) 
The EORTC QLQ-CIPN2047 is a 20-item CIPN-specific questionnaire which includes three 
scales assessing sensory (9 items: #31-36, 39, 40, 48), motor (8 items: #37, 38, 41-45, 49), and 
autonomic (3 items: #46, 47, 50) symptoms and functioning with each item measured on a 1-4 
scale (1 – not at all; 4 – very much).  The EORTC QLQ-CIPN20 has been tested in cancer 
patients receiving a variety of chemotherapies and has been shown to have internal consistency 
reliability based on Cronbach’s alpha coefficients of 0.82, 0.73, and 0.76 for the three scales, 
respectively, with excellent validity and reliability48. The CIPN-20 will be completed at baseline, 
end of treatment and at 1 month (28 days), 2 months (8 weeks), and 3 months (12 weeks) after 
the Scrambler/Sham therapy. Those participating in sham therapy group and choosing Scrambler 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 19 
therapy after 28 days, will complete the CIPN-20 at the end of Scrambler therapy, and at 1 and 2 
months after the Scrambler therapy. 
 
NOTE:  Please see questionnaires in Appendices A and B. 
7.6.4 Concomitant Medications 
Participants will also keep a diary where they will record each dose of pain medication 
(prescription and over the counter) they take in real time throughout each 24 hour period during 
Scrambler/sham intervention. This diary will be brought to the sessions and the study coordinator 
(NOT the study team member administering the intervention) will review the diary for 
completeness and clarity.  Participants will also be asked to complete a diary of pain medications 
for a 7-day period around the time of the monthly follow-up timepoints as outlined above for the 
patient-reported outcomes.   
 
The following table will be used to convert all opiates to morphine oral dose equivalents 
(MOEDs), when applicable: 
 
Morphine oral dose equivalents49 
Drug intake for prior 24 hours 
Oral 
Equivalent 
Parental 
equivalent 
Doses and 
Total mgs 
taken 
Conversion 
Factor 
Total 
MOED 
(mg) 
Morphine immediate release 
30 mg 
10 mg 
 
 
 
Morphine sustained release 
30 
10 
 
 
 
Codeine  
200 mg 
100 mg 
 
 
 
Oxycodone  immediate release 
20 mg 
Not available 
 
 
 
Oxycodone extended release 
20 mg 
Not available 
 
 
 
Hydrocodone immediate release 
30 mg 
Not available 
 
 
 
Hydromorphone  
7.5 mg 
1.5 mg 
 
 
 
Methadone 
10 mg 
5 mg 
 
 
 
Fentanyl transdermal 
1 mcg/hour equivalent to 2 mg 
oral morphine/hour 
 
 
 
TOTAL 
 
7.7 
Concomitant and Supportive Therapy 
The concomitant medications and therapies deemed necessary for the supportive care and safety 
of the subject are allowed, provided their use is documented in the medical records.  
 
The use of other concurrent investigational drugs or devices for management of pain is not 
allowed unless approved by the Principal Investigator. 
7.8 
Discontinuation and Withdrawal of Subjects 
All patients who initiate protocol intervention will be included in the overall evaluation of 
response (intent-to-treat analysis). All reasons for discontinuation of therapy should be 
documented clearly in the record.  
 
Unless the subject refuses, follow-up will continue for the planned 12 weeks duration after the 
study intervention.   

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 20 
7.8.1 Discontinuation of Intervention 
The reasons for discontinuation or protocol treatment include: 
 
 
Non-compliance with the study protocol; including, but not limited to not attending the 
majority of scheduled visits.  
 
Unacceptable major toxicity.  
 
Intercurrent illness or condition that would, in the judgment of the treating investigator, 
affect assessment of clinical status to a significant degree or require discontinuation of 
study intervention. 
 
At subject’s own request. Note: The reason for discontinuation from the study must be 
documented. The patients will be included in the overall evaluation of response (intent-
to-treat analysis) if any protocol intervention was administered prior to withdrawal. 
 
Study is closed or cancelled for any reason. 
7.8.2 Withdrawal from Study 
The reasons for withdrawal from the study include: 
 
 
Subject withdraws consent for follow-up. 
 
Subject is lost to follow-up. 
 
Study is terminated for any reason. 
7.9 
Additional Information 
There will be co-investigators who require training on the MC5-A Calmare equipment in order to 
administer the scrambler and sham therapy.  In order to best complete this training, it is not 
realistic to expect that these patients will stay blinded to the treatment assignment of the 
“scrambler” vs. “sham” treatment due to the communication between the staff performing the 
training.   
 
The patients to be approached to take part in training will have a diagnosis also of peripheral 
neuropathy, as this will be the population in the randomized study.  We will use the same, IRB-
approved informed consent and the study team will explain to these patients that their 
participation will not be randomized, that they will receive scrambler therapy; however, that all 
other aspects of the study (including questionnaires, pain and medication diary collection) will 
continue as per the primary trial.  This discussion will be documented in the medical and 
research records.   
 
We expect to need 2-3 participants for training activities; however, in case of study staff changes 
during the study or any need for additional training, we will increase our recruitment goal by a 
total of 5 participants.   
 
In case of any non-evaluable patients, we will increase our recruitment goal by a total of 5 
participants. The total recruitment goal with all potential additional participants will be 40. 
 
 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 21 
8. Study Calendar 
 
Tests and procedures 
Baseline 
Daily 
during 
intervention 
Follow-up 8,9 
Prior to 
registration 
Day 1 prior 
to first 
session 
Palliative care consult 1 
X 
 
 
 
Physical assessment 2 
 
X 
X 
 
Brief Pain Inventory “pain now”, 
before and after treatment 
 
 
X 
 
Brief Pain Inventory Short 
Form-CIPN (Appendix B) 
 
X 
 
X 
EORTC QLQ CIPN-20 scale 
(Appendix C) 
 
X 
 
 
X 
Concomitant Medication Review  
(Appendix D) 3 
 
X 
X 
X 
Randomization 4 
 
X 
 
 
Intervention:  Scrambler  
Therapy/ Sham Treatment 5,6 
 
 
X 
X 
Patient preference 7 
 
X 
 
X 
 
1. A palliative care consult will be required of all potential patients.  This is needed to confirm medical history, 
current symptoms, and eligibility/appropriateness for the clinical trial.  A member of the Palliative Care team at 
Johns Hopkins, who is also a study team member, will conduct this visit.   
2. Prior to each Scrambler Therapy/Sham Treatment session a physical assessment will be done by a member of the 
study team to document any new/changes in physical symptoms related to CIPN; a full physical exam is not 
planned. This is to ensure good performance status, absence of sores, etc. 
3. All pain medications will be recorded daily during intervention and for a 7 day period around follow-up 
questionnaires; opioids will be converted as described for data analyses. 
4. Eligible subjects are randomized to receive Scrambler Therapy or Sham Treatment.  Up to 5 additional 
participants will be included in a non-randomized fashion for training sessions with study staff; these participants 
will not count towards the overall accrual goal.  NOTE:  To distinguish training participants from those involved 
in the randomized clinical trial, these subjects will be assigned unique/different study numbers.   
5. A phone call will be made 3-7 days after the last treatment session (Scrambler Therapy or Sham Treatment) to 
ask about any untoward symptoms that may have happened upon withdrawal of MCA-5. 
6. Participants randomized to the sham group will be offered the option to receive the Scrambler Therapy, if, at Day 
28 their pain is still ≥4, and not relieved to their satisfaction. These patients will be “un-blinded” and offered 10 
sessions of Scrambler therapy.   
7. After the first and last session of Scrambler Therapy/Sham Treatment, participants will be asked whether they 
think they received the Scrambler Therapy or the Sham Treatment.  After the final session, participants will also 
be asked the following questions: “Did the treatment help you with the pain and or numbness?” (Yes/No), and 
“Would you want to continue the treatment if available?” (Yes/No) 
8. Follow-up may occur by phone/mail, if required.  
9. Patients who receive Scrambler Therapy after Sham Treatment will have follow-up assessments at the same 
timepoints as if originally assigned to receive Scrambler Therapy; these participants will be on study for about 4 
months to complete all assessments. 
 
Note: The schedule should be followed as closely as is realistically possible; however, the schedule may be modified 
due to problems such as scheduling delays or conflicts (e.g., clinic closure, poor weather conditions, vacations, etc.) 
with the guidance of the Principal Investigator/designee, as appropriate, and will not be reportable as a deviation 
unless the endpoints of the study are affected. 

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Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 22 
9. Adverse Events 
In the published or in-press trials to date no side effects have been reported.  Since the electrodes 
are applied to areas that do not hurt, and if pain is observed then the electrodes are removed, 
there has not been pain from the device.  Hypersensitivity to the gel on the skin electrode is 
possible.  Patients may feel an electrical stimulation similar to TENS therapy. 
 
In over 4000 patients treated, and our own experience, we have not observed any significant side 
effects. We have had a handful of patients who reported slightly worse pain the night of the first 
treatment, usually with subsequent relief, but have not observed any pattern for this. 
 
To date, 14 patients have received treatment on this study at Johns Hopkins University. There 
was one incident where the Scrambler Therapy machine malfunctioned resulting in the patient 
feeling a short, temporary jolt, which resulted in no permanent damage to the patient. There is a 
small risk that patients may receive a small electrical charge from the machine, which will be a 
surprise to the patient but is not hurtful or harmful. 
9.1 
General 
In the case that adverse events related to the study intervention are reported, these will be 
recorded per the descriptions and grading scales found in the revised National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 for adverse event 
reporting that can be found at http://ctep.cancer.gov/reporting/ctc.html. 
 
Information about all intervention-related adverse events, including those volunteered by the 
subject, discovered by investigator/study personnel questioning, or detected through physical 
examination, or other means, will be collected, followed, and reported appropriately.   
 
The adverse events related to any ongoing treatment for the patient’s underlying cancer or other 
medical conditions will not be collected. 
9.2 
Reporting Procedures 
All intervention-related adverse events will be captured on the appropriate study-specific report 
forms (CRFs) or in a designated database.  
 
The same applies to any adverse event classified as a “serious adverse event;” these will also 
only be reported if intervention-/study-related.   
 
Any unexpected intervention-related adverse events and serious adverse events will be reported 
to the IRB per current institutional standards. If an adverse event requires modification of the 
informed consent, these modifications will be provided to the IRB with the report of the adverse 
event. If an adverse event requires modification to the study protocol, these modifications will be 
provided to the IRB as soon as is possible. 
 
 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 23 
10. Measurement of Effect 
The primary outcome is described Section 13.1 below.  
 
For any outcome other than a patient-reported outcome, such as diary entries, the data will be 
recorded or reviewed by the study coordinator, not the treatment person. 
 
Our statistical consultation service is headed by Dr. Gary Rosner, Professor of Oncology and 
Director of the Quantitative Sciences Program and Biostatistics/ Bioinformatics Division. He 
will appoint a masters-level statistician to continue work with us as data become available. 
 
11. Data and Safety Monitoring 
11.1 Data Management 
All information will be collected on study-specific case report forms by the study staff or in a 
designated database.  
 
All study data will be reviewed for completeness and accuracy by the Principal Investigator. The 
study data may also be periodically reviewed by the Sidney Kimmel Comprehensive Cancer 
Center Clinical Research Office. 
11.2 Monitoring  
This is a Level 1 study under the SKCCC Data Safety Monitoring Plan (06/25/2010). The 
Clinical Research Office QA Group will perform an audit at the end of the first year and then 
periodically depending on the rate of accrual and prior audit results. 
 
The SKCCC CRO will perform data and safety monitoring, oversight of adverse events and 
other protocol events for this research. 
 
All trial monitoring and reporting will be reviewed annually by the SKCCC Safety and 
Monitoring Committee.  
 
 

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Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 24 
12. Administrative Procedures 
12.1 Protocol Amendments 
Any changes to the protocol will be made in the form of an amendment and must be approved by 
the IRB before implementation. The Principal Investigator (or her designee) is responsible for 
the coordination and development of all protocol amendments, and will disseminate this 
information to the participating centers. 
12.2 Informed Consent 
The Principal Investigator (or his designee) will explain to each subject the nature of the study, 
its purpose, procedures involved, expected duration, potential risks and benefits. Each subject 
will be informed that participation in the study is voluntary and that she may withdraw from the 
study at any time, and that withdrawal of consent will not affect her subsequent medical 
treatment. This informed consent will be given by means of a standard written statement and will 
be submitted for IRB approval prior to use. No patient will enter the study before her informed 
consent has been obtained. In accordance with the Health Insurance Portability and 
Accountability Act (HIPAA), the written informed consent document (or a separate document to 
be given in conjunction with the consent document) will include a subject authorization to 
release medical information to the study sponsor and supporting agencies and/or allow these 
bodies, a regulatory authority, or Institutional Review Board access to subjects’ medical 
information that includes all hospital records relevant to the study, including subjects’ medical 
history. 
12.3 Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and Good Clinical Practice, as 
described in: 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations). 
3. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 
1964, amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
 
The investigator agrees to adhere to the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice. 
12.4 Regulatory Authorities 
12.4.1 Institutional Review Board 
Information regarding study conduct and progress will be reported to the Institutional Review 
Board (IRB) per the current institutional standards of each participating center. 
 
 

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Version:  Amendment #7, September 02, 2016Page 25 
13. Statistical Considerations 
13.1 Overall 
The primary endpoint is change in patient-reported pain from day 0 to day 28 as measured by the 
Modified Brief Pain Index, question #3 (Appendix B).  This endpoint also serves to get 
preliminary information for planning future, larger, phase III studies. 
 
Secondary endpoints will include the total Brief Pain Inventory score, the sensory and motor 
subscales of the CIPN 20, and the Morphine Oral Equivalents Dose at day 28 compared to sham 
therapy. We will also report the daily (days 1-10) changes in “pain now” before and after each 
treatment, to be comparable to all the other reported studies. 
13.2 Sample Size and Accrual 
We are anticipating that the starting pain score will be 4-6 based on VCU, Italian, and Mayo 
Clinic data. We are anticipating that the reduction in CIPN pain score will be over 50% based on 
the VCU, Italian, and Mayo Clinic data. We anticipate a possible 10% reduction in pain scores 
over 30 days based on the randomized trial data for placebo compared to gabapentin and other 
drugs.   
 
The primary objective of this study is to determine if patients randomized to the Scrambler 
therapy have a larger reduction in pain scores than those randomized to the placebo, or sham, 
treatment. Power calculations were performed using a simulation approach.  Pain scores were 
simulated using a bivariate normal distribution with a mean (SD) of 4 (2) at baseline for both 
groups, with means ranging from 2.8 to 3.6 (30% to 10% decrease) for the control group post-
treatment and mean of 2 (50% decrease) for the Scrambler group post-treatment.  Post-treatment 
scores for both treatment arms were assumed to have a SD = 1.5.  Based on previous data, a 
value of 0.3 was assumed for the within-patient correlation between pre- and post-treatment 
scores. 
 
Any patient with 1) a simulated pain score at baseline less than 4, or 2) a simulated pain score 
less than 0 post-treatment, or 3) a simulated pain score greater than 10 at either time point, was 
replaced until all criteria were met, to reflect the actual scores we will see.  Simulated scores 
were then rounded to the nearest integer to also reflect the nature of the scale.  The change in 
pain score was calculated for each patient, and differences were compared between groups with a 
two-sample t test.  Power was defined as the proportion of simulations that yielded a one-sided p 
value for the t test < 0.10.  1000 simulations for each scenario were performed.  The table below 
shows sample sizes and resulting power for the differences between treatment arms. 
 
Total N 
Power 
Percent Decrease 
in Treatment Arm 
Percent Decrease in 
Control Arm 
30 
60 
90 
87.3% 
86.6% 
77.6% 
50% 
50% 
50% 
10% 
20% 
30% 
 
To detect the proposed effect size, 30 patients total, 15 on Scrambler therapy and 15 on the sham 
arm, will yield 87.3% power with a 1-sided type I error rate of 10%. 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 26 
 
We will record the same pain data on the group that receives sham treatment if they elect to 
receive actual Scrambler treatment at the end of their 28-day treatment period. However, this is 
not a “crossover” design trial wherein each patient serves as his/her own control.  Data collection 
for the primary endpoint will occur before patients in the sham arm are given the option to 
receive Scrambler treatment.  This data will not be formally analyzed but instead used to help 
plan future studies. 
13.3 Analysis Plan 
13.3.1 Primary Endpoint 
Pain scores will be summarized for each treatment arm at each time point with summary 
statistics.  The mean change in scores in each treatment arm will be described with one sample 
paired t tests.  The primary endpoint will be evaluated by testing for differences in change in pain 
scores between the two treatment arms with a one-sided t test.  We will conclude a significant 
difference between treatment arms if the p value < 0.10.  This difference will be reported with a 
90% confidence interval. 
 
Because this is a small study that is looking for an unbiased signal of activity, and the first 
randomized sham-controlled study for Scrambler therapy, we did not want to set the bar too high 
for concluding a positive effect of the treatment.  This is not the definitive phase 3 studies for 
this treatment but more like an early randomized phase 2 study.  Instead, this study will 
contribute information that will be useful in planning larger studies of the potential benefit of 
Scrambler therapy.  The estimates used in the power calculation were based on data collected 
from a large series of patients, and even if we see the same differences in our study, we are less 
likely to conclude a positive treatment effect with a significance level < 0.05 due to the smaller 
sample size.  We chose a type I error threshold of 10% to account for this, so that a p-value of 
0.07 or 0.08 for the primary endpoint, for example, would not yield a negative study but instead 
suggest that larger studies are worthy of pursuit. 
13.3.2 Secondary Endpoints 
Secondary endpoints include change in all of the pain scores (worst, least, average, right now, 
relief) recorded by the BPI, changes in the CIPN-20 sensory and motor subscales, and change in 
medication use and doses; all were measured at entry, 1, 2, and 3 months. All of these 
measurements will be summarized by treatment group using descriptive statistics and confidence 
intervals and tested for differences between treatment arms using t tests, Wilcoxon rank sum 
tests or Fisher’s exact tests as appropriate.  Changes in scores over time will be analysed using 
appropriate regression models estimated with GEE or random effects to control for correlation 
between measurements from the same patient.  All p values will be calculated for descriptive 
purposes only and we do not plan to control for multiple comparisons.  
 
We will also compare baseline characteristics between treatment arms.  Because treatment 
assignment is randomized, we do not expect to see differences.  However, if we detect imbalance 
in variables such as concomitant medicinal use and supportive treatment, then we will control for 
this in the main analyses. 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 27 
13.3.3 Intention to treat 
Analysis will be done by intention to treat, not “as treated”, with full inclusion of subjects. 
13.4 Reporting and Exclusions 
Subjects who sign a consent form, but do not initiate protocol intervention for any reason (e.g., 
subjects who are screen failures), will be replaced and will not count towards our accrual goal.  
No data from subjects included as part of training will be included in the study analyses. 
 
 
 
 
APPENDICES 
 
A 
ECOG Performance Status Scale 
B 
Modified Brief Pain Inventory (Modified for CIPN) 
C 
European Organization for Research and Treatment of Cancer Quality of Life Cancer 
Chemotherapy Induced Peripheral Neuropathy-20 Instrument (EORTC QLQ-CIPN-20) 
D 
Concomitant Pain Medications/Participant Diary 
 
 
 
 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 28 
APPENDIX A: ECOG Performance Status Scale 
  
Score 
Definition 
0 
Asymptomatic (Normal activity. Fully active, able to carry on all pre-
disease performance without restriction) 
1 
Symptomatic, fully 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 
Symptomatic, in bed less than 50% of day (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 
Symptomatic, in bed more than 50% of day,  
but not bedridden (Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours.) 
4 
Bedridden (Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.) 
 
 
 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 29 
APPENDIX B:  Modified Brief Pain Inventory  
 
NOTE:  A modified format may be presented to participants, on study-specific forms/booklets; 
however, all questions will be phrased/worded as below. 
 
 
1. Please rate your pain by circling the one number that best describes your pain/discomfort 
(it is understood that the neuropathy discomfort from chemotherapy is not always called a 
‘pain’ by all patients, but, for this study, that ‘discomfort’ should be considered to be a 
‘pain’) from the chemotherapy related neuropathy at its WORST in the last 24 hours. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
 
 
 
 
 
 
 
 
 
Pain as bad  
pain 
 
 
 
 
 
 
 
 
as you can imagine 
 
2. Please rate your pain/discomfort from the chemotherapy related neuropathy by circling 
the one number that best describes your pain/discomfort at its LEAST in the last 24 
hours. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
 
 
 
 
 
 
 
 
 
Pain as bad  
pain 
 
 
 
 
 
 
 
 
as you can imagine 
 
3. Please rate your pain/discomfort by circling the one number that best describes your 
pain/discomfort from the chemotherapy related neuropathy on the AVERAGE. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
 
 
 
 
 
 
 
 
 
Pain as bad  
pain 
 
 
 
 
 
 
 
 
as you can imagine 
 
4. Please rate your pain/discomfort by circling the one number that best tells how much 
pain/discomfort from the chemotherapy related neuropathy you have RIGHT NOW. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
 
 
 
 
 
 
 
 
 
Pain as bad  
pain 
 
 
 
 
 
 
 
 
as you can imagine 
 
5. Since starting the treatment, how much RELIEF has the treatment used in this study 
provided?  Please circle the one percentage that most shows how much relief you have 
received. 
0%      10%     20%       30%   40%     50% 60% 
70% 
80% 
90% 
100% 
No 
 
 
 
 
 
 
 
 
 
Complete 
relief  
 
 
 
 
 
 
 
 
relief 
 
 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 30 
6. Circle the one number that describes how during the past 24 hours pain/discomfort from 
your chemotherapy related neuropathy has interfered with your: 
 
A. General Activity 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Does not 
 
 
 
 
 
 
 
 
Completely 
 
interfere  
 
 
 
 
 
 
 
 
interferes 
 
B. Mood 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Does not 
 
 
 
 
 
 
 
 
Completely 
 
interfere  
 
 
 
 
 
 
 
 
interferes 
 
C. Walking Ability 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Does not 
 
 
 
 
 
 
 
 
Completely 
 
interfere  
 
 
 
 
 
 
 
 
interferes 
 
D. Normal work includes both work outside the home and housework 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Does not 
 
 
 
 
 
 
 
 
Completely 
 
interfere  
 
 
 
 
 
 
 
 
interferes 
 
E. Relations with other people 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Does not 
 
 
 
 
 
 
 
 
Completely 
 
interfere  
 
 
 
 
 
 
 
 
interferes 
 
F. Sleep 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Does not 
 
 
 
 
 
 
 
 
Completely 
 
interfere  
 
 
 
 
 
 
 
 
interferes 
 
G. Enjoyment of life 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Does not 
 
 
 
 
 
 
 
 
Completely 
 
interfere  
 
 
 
 
 
 
 
 
interferes 
 
 
 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 31 
APPENDIX C:  European Organization for Research and Treatment of Cancer Quality of 
Life Cancer Chemotherapy Induced Peripheral Neuropathy-20 Instrument (CIPN-20) 
 
NOTE:  A modified format may be presented to participants, on study-specific forms/booklets; 
however, all questions will be phrased/worded as below. 
 
Please circle the words in the box for how much the symptoms bother you: 
 
Sensory subscale 
Scores 
0 
1 
2 
3 
Tingling in the Fingers/Hands  
None at all 
A little bit 
Quite a bit 
Very much 
Tingling in the Toes/Feet 
None at all 
A little bit 
Quite a bit 
Very much 
Numbness in the 
Fingers/Hands 
None at all 
A little bit 
Quite a bit 
Very much 
Numbness in the Toes/Feet 
None at all 
A little bit 
Quite a bit 
Very much 
Shooting/burning in the 
Fingers/Hands 
None at all 
A little bit 
Quite a bit 
Very much 
Shooting/burning in the 
Toes/Feet 
None at all 
A little bit 
Quite a bit 
Very much 
Problems standing/walking 
None at all 
A little bit 
Quite a bit 
Very much 
Difficulty distinguishing 
hot/cold 
None at all 
A little bit 
Quite a bit 
Very much 
Difficulty in  hearing 
None at all 
A little bit 
Quite a bit 
Very much 
Summary Score 
These are summed for each section. 
Motor subscale 
Scores 
0 
1 
2 
3 
Cramps in the fingers/hands 
None at all 
A little bit 
Quite a bit 
Very much 
Cramps in the toes / feet 
None at all 
A little bit 
Quite a bit 
Very much 
Difficulty manipulating small 
objects 
None at all 
A little bit 
Quite a bit 
Very much 
Problems holding a pen 
None at all 
A little bit 
Quite a bit 
Very much 
Difficulty opening a jar 
None at all 
A little bit 
Quite a bit 
Very much 
Difficulty walking 
None at all 
A little bit 
Quite a bit 
Very much 
Difficulty with stairs 
None at all 
A little bit 
Quite a bit 
Very much 
Difficulty using car foot 
pedals 
None at all 
A little bit 
Quite a bit 
Very much 
Scores 
These are summed for each section. 
 
NOTE:  Used with registration and permission, EORTC. 
 
 
 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 32 
APPENDIX D:  Concomitant Pain Medications/Participant Diary 
 
Instructions:  Please note below all pain medications that you take during your participation on 
this study. 
 
Medication 
Name 
Dose 
Record the number of times the medication was taken each day 
Date: 
 
Date: 
 
Date: 
 
Date: 
 
Date: 
 
Date: 
 
Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Completed by: 
 
 
 
 
Date:    
 
 
 
 
Participant’s signature 
 
 
Reviewed by:  
 
 
 
 
Date:    
 
 
 
 
Study team member’s signature 
 
 
 
 

Scrambler Therapy for CIPN 
Principal Investigator:  Thomas J. Smith, M.D. 
 
 
 
 
 
 
 
Version:  Amendment #7, September 02, 2016Page 33 
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