A Pilot Trial of Scrambler Therapy for Pain Associated With Pancreas Cancer

Pancreas cancer causes pain in 70% of newly diagnosed patients rising to over 80% in advanced
cancer patients, and is the most common serious symptom. Pancreas cancer pain is strongly
correlated with worsened survival, and relief of pain is correlated with better survival.
Pancreas cancer pain is neuropathic in origin and sensation, arising from direct invasion of
local tissues. Pancreas cancer pain is relieved by local nerve blocks in about 75% of cases,
but the relief is often incomplete, temporary, and the procedure is invasive with some risks.
As the cancer grows to involve more nerves, or the nerves regrow, the pain typically comes
back. For the 46,420 newly diagnosed pancreas cancer patients and the 39,500 patients who die
of it each year, pain is the one constant symptom.

Scrambler Therapy is a novel treatment increasingly supported by clinical experience and
multiple trials. The goal of the device is to provide "non-pain" information through the
cutaneous nerves to block the effect of pain information. The device is a cutaneous
electrical stimulator that creates waveforms simulating 16 different action potentials, then
transmits the action potentials via C fibers. The goal is to reset the brain to perceive
"non-pain" from areas previously interpreted as painful, similar to spinal cord stimulation.
The multiprocessor apparatus directly stimulates the peripheral nerves by the application of
surface electrodes on the skin, similar to EKG electrodes, putting the electrodes above and
below the site of pain.

Preliminary data on Scrambler therapy in pancreas cancer Scrambler Therapy appears to work on
pain based on results from multiple trials. In fact, the first trial was done on patients
with abdominal pain from abdominal cancers. In this first trial, 11 cancer patients (3
pancreas, 4 colon, 4 gastric) suffering from drug resistant visceral pain were studied during
the patients' first ten treatment sessions. The pain score before the treatment is shown next
to the pain score after treatment, for each daily treatment. The electrodes were placed to
surround the pain, following the dermatomes, as shown in Figure 2. The active (yellow)
electrodes are always paired across the pain with the passive (black) electrode. Pain was
quickly and markedly reduced and maintained until death. As then inventor wrote, "During the
applications, all the patients reported a very rapid (in the order of a few seconds)
disappearance of the perception of pain. All patients responded fully to the protocol and
none reported undesirable side effects. Compliance was excellent." Nine of 11 stopped pain
drugs within the first 5 applications. "During the reference period, nine out of eleven
patients (81.8%) are seen to have stopped requesting painkillers between the second and the
fifth treatment session. The remaining two patients (18.2%) considerably reduced the dosage
and undertook mild therapy."

To be blunt, no one really believed these results. The magnitude of pain relief was large,
with a simple machine using non-invasive therapy. To this day, the trial has not been
replicated. But over the next decade, more and more evidence about Scrambler Therapy emerged
from different investigators that led the investigators to believe that there was a signal
worth exploring for relief in pancreas cancer. In the second trial, 226 patients with
neuropathic pain including failed back surgery, brachial plexus neuropathy, and others were
treated. Over 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. The investigators
have recently compiled the published reports of Scrambler Therapy for a review.

4. Study Procedures

Study Design and Treatment Plan The investigators propose a straightforward single arm trial
of actual Scrambler Therapy to see if pain can be relieved. This study also serves to get
preliminary information for planning future, larger, phase III studies that could compare to
celiac plexus block, spinal cord stimulation, or sham treatment. The investigators anticipate
completing the study in less than 12 months, with 18 completed subjects having up to 10
treatment sessions each.

Recruitment

1. Patients will be recruited through the Kimmel Cancer Center's outpatient oncology clinics,
and the inpatient oncology and palliative care consult services. The palliative care service
now sees over 1000 new consultations annually, with about half with cancer, and pancreas
cancer pain is one of the most common reasons for consultation.

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. Script: "Tell me when something
is felt."

2. Then, over a few seconds, the intensity is increased to what is maximally tolerated.
"Tell me when tolerance has been reached." In practice, this has been universally
understood.

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 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.

4. 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.

Days 2-10:

1. Treatment will be administered using the same principles (each day evaluated
independently and not necessarily reproducing the electrode arrangements and 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.

Dose and Application

1. Electrodes are applied on the skin surrounding 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

Statistical Considerations Overall This is a single-arm, pilot study to evaluate the effect
of Scrambler Therapy for patients with pancreas cancer who have an average daily pain rating
of ≥4 out of 10 based on the Modified Brief Pain Index, question #3.

Sample Size and Accrual The investigators are anticipating that the starting pain score on
average will be ≥4 based on Virginia Commonwealth (VCU), Hopkins, Italian, and Mayo Clinic
data. The investigators are conservatively anticipating that a relative reduction in average
pain score by Day 28 will be 33%, a level which is considered minimal clinically important,
based on the VCU, Italian, Mayo Clinic, and Walter Reed data. It is anticipated that
approximately 90% of the patients will agree to be re-evaluated at Day 28 and have paired
ratings available for evaluation. Thus, the study will enroll 20 patients expecting 18 to be
evaluable for the primary endpoint. Based on prior studies, the investigators assume that the
average pain value at baseline is at least 4 on a 0-10 scale with a standard deviation (SD)
of the original pain value expected to fall in the range of 1-1.5 in this patient population.

As such, a conservative estimate of the standard deviation of the change across patients from
Day 0 to Day 28 would be approximately up to 2. Using a one-sample paired t test with a
sample size of 18 patients, this design will provide at least 80% power to detect a minimum
of 33% reduction in average pain score at Day 28 compared to Day 0 with a two-sided type I
error of 5%. The table below shows statistical power under different scenarios of a range of
baseline pain scores and intra-patient correlation for a 33% relative reduction at Day 28. In
the situation when variation of the starting pain score is larger than expected (e.g.,
SD=2.0), the sample size remains sufficient for this endpoint if the patients have moderate
to severe pain to start with (i.e., 5 or above).

Analysis of Primary Endpoint

1. Baseline and change at Day 28 in average daily pain score will be treated as continuous
variables and summarized with descriptive statistics. Each will be explored to determine
if transformations (e.g. log or square-root) are necessary to achieve normality.

2. Exploratory plots will be created and means will be estimated along with 95% confidence
intervals.

3. The investigators will use the paired t-test and Wilcoxon sign rank test as appropriate
to determine whether or not the data shows evidence of change from baseline.

4. The primary analysis will include all patients who have received at least one session of
treatment; the investigators' experience is that >90% will complete treatment.

5. A sensitivity analysis may be performed with patients who have completed 10 sessions of
treatment, but the investigators anticipate that this highly motivated group will have
>90% completion rates.

Analysis of Secondary Endpoints

1. All of the secondary endpoints will be summarized by item and by type of questionnaire,
respectively, using descriptive statistics. A summary score of Brief Pain Inventory
(BPI) will also be calculated by adding the total number of points across items.

2. The normality of distributions will be assessed and transformations be made as
appropriate. Mean changes will be estimated with 95% confidence intervals. Changes from
baseline will be evaluated using paired t tests or Wilcoxon signed rank tests.

3. A repeated measure of analysis of variance (ANOVA) will be used to test if there are any
changes over time on pain scores.

4. Adjustment for multiple comparisons will not be made due to the pilot nature of study
seeking to generate hypotheses to be tested in future larger randomized trials.

Inclusion Criteria:

- Men and women 18 years of age or older with cancer

- English speakers

- Documented pancreas cancer by cytology or histology

- Pain in the abdomen with an average daily pain rating of > 46 out of 10, using the BPI

- A life expectancy > 5 days, so that some treatments can be given)

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1, 2, 3, or 4

- The patient must be able to understand the study regimen, its requirements, risks, and
discomforts, and is able and willing to sign an informed consent form.

Exclusion Criteria:

- 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.]

- Use of an investigational agent for pain control concurrently or within the past 30
days

- Receipt of radiation to the abdomen for any reason during the planned 10-day treatment
time

- History of an allergic reaction or previous intolerance to transcutaneous electronic
nerve stimulation

- Patients with implantable drug delivery systems, e.g. Medtronic Synchromed;

- 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).

- A history of myocardial infarction or ischemic heart disease within the past six
months

- Patients with history of epilepsy, brain damage, or symptomatic brain metastases

- Skin conditions such as open sores that would prevent proper application of the
electrodes; or other condition(s) that in the opinion of the investigators might
compromise the objectives of the study.

- Patients currently receiving anti-convulsants (such as gabapentinoids, e.g.
gabapentin (Neurontin) or pregabalin (Lyrica) will be tapered off these
medications over 7 days because of new data that suggests patients do not do as
well when on gabapentin or pregabalin. The study team will provide instructions
on how to do this.