Pain Control Using Neuromodulation in Patients Undergoing Definitive Chemoradiotherapy for Locally Advanced Head and Neck Cancer
Phase: NA
Conditions: Cancer of Head and Neck
Sponsor: University of Michigan

1 
 
UMCC 2014.050                                                                                                                                     Version 0.09.8 
 
 
 
 
 
 
Pain Control Using Neuromodulation in Patients Undergoing 
Definitive Chemoradiotherapy or Radiation Therapy for 
Locally Advanced Head and Neck Cancer 
 
 
MAY-21-2019 
 
 
 
 

2 
 
Table of Contents 
 
1.0 Introduction 
2.0 Hypotheses and Objectives 
3.0 Eligibility/Exclusion Criteria 
4.0 Pretreatment Evaluation 
5.0 Subject Screening, Registration Procedure, and Reimbursement 
6.0 Schema 
7.0 Study Design and Calendar 
8.0 Statistical Considerations 
9.0 Reporting Adverse Events 
10.0 Study Monitoring 
11.0 References 
12.0 Appendices 
 

3 
 
1.0 Introduction 
 
More than 50,000 Americans (and more than 750,000 people worldwide) are diagnosed with head 
and neck cancer (HNCa) every year. HNCa impacts oral intake, speech, physical appearance, and 
emotional well-being.  Despite advancements in treatment technology, which improves patient lifestyle 
and comfort, HNCa patient quality of life (QoL) still suffers. [1-3] 
In nearly all of these patients, there is unintentional weight loss, which is associated with lower 
survival rates and is an independent predictor of mortality in patients with stage III and IV tumors.[4]  The 
cause of the weight loss is multifactorial.  The disease itself often results in significant weight loss and 
poor performance status before treatment begins, as up to 18% of patients require pre-treatment enteral 
feeding tube placement.[5]  Mucositis as a result of concurrent chemoradiotherapy occurs in up to 80% 
of patients and further decreases oral intake, resulting in additional weight loss with nadir at the end of 
treatment.[6-9]  These factors also function in a cycle, as poor nutritional status pre-disposes patients to 
toxicity development and compromises treatment effectiveness.[10]  Numerous strategies have been 
tried to reduce mucositis, the resulting pain and odynophagia, and/or the resulting weight loss, including 
narcotic pain medicines, biologically-targeted agents, and feeding tubes, with limited success. 
Transcranial direct current stimulation (tDCS) offers a unique analgesic modality of central pain 
neuromodulation by altering the activity key sensory and motor cortical structures.[11, 12]  tDCS has been 
demonstrated to be safe and effective in several chronic pain conditions, including fibromyalgia and 
multiple sclerosis[13]. However, tDCS pain neuromodulation has never been used in acute pain settings, 
such the temporary mucositis associated with head and neck cancer radiation and chemoradiotherapy.  
tDCS pain neuromodulation could offer significant mucositis and odynophagia relief, thereby reducing 
weight loss, improving performance status, and reducing the need for narcotics. 
This study will be a randomized controlled trial of tDCS pain neuromodulation to relieve 
odynophagia. The randomization will be performed and documented by the statistician.  Patients will be 
randomized to active tDCS or standard care.  Measured outcomes will be both objective and subjective, 
including patient-reported pain, weight loss, and narcotic pain medication requirement. 
Therapy-related oropharyngeal mucositis and odynophagia 
Oral mucositis , a complication of combined radiation and chemotherapy for nearly all patients 
with HNCa, presents a significant clinical and economic problem.  Severe oral mucositis can halt treatment 
and affect clinical outcome; pain and swallowing dysfunction can lead to weight loss, dehydration and 
hospitalization. Advanced planning techniques, such as IMRT, increase tissue sparing and allow dose 
intensification to improve disease outcomes.  Ironically, though, mucositis/odynophagia rates have 
actually increased as significant portions of mucosa are often within the radiotherapy target [14, 15].  A 
large retrospective study reported rates of Grade 3-4 mucositis of 80% and 34% for altered and 
conventional fractionation, respectively, with 16% of patients requiring hospitalization.[8]  The increasing 
use of concurrent chemotherapy also increases mucositis/odynophagia rates.[9] 
The consequences of mucositis and odynophagia, in addition to the pain itself, are far-reaching.  
Odynophagia, combined with compromised swallowing function also as a result of therapy, often leads to 
decreased oral intake and resulting weight loss.  In a retrospective study of 200 patients receiving head 
and neck radiotherapy with or without chemotherapy, oral mucositis was correlated with increased ³5% 
weight loss from 17% to 60%.[16]  Mucositis and odynophagia also have significant economic and quality 
of life impacts, including the estimate that oral mucositis has an incremental cost of $17,000 per 
patient.[16-19] These numbers demonstrate the tremendous morbidity and mortality related to 
mucositis. 

4 
 
Odynophagia and weight loss mitigation therapies 
Narcotics and local anesthetics are standard therapies for acute mucositis and odynophagia, 
however, their efficacy is modest and they are associated with significant side effects in this generally 
elderly patient population.[20]  Recently, newer approaches have been tried with biologically-targeted 
mucosa-protective agents and by modifying pain perception. 
Amifostine is a pro-drug that supplies sulfhydryl groups as alternative oxidative targets to DNA, 
thereby reducing the DNA damage induced by radiotherapy.  This raises the possibility that amifostine 
would also be radioprotective for tumor cells.  Despite being adopted as a reasonable radioprotective 
treatment by ASCO in 2008 guidelines,[21] the randomized data supporting this is mixed.  Two studies 
showed a benefit with amifostine,[22, 23] while two studies showed no benefit.[24, 25]   
Recombinant human keratinocyte growth factor (KGF, palifermin) stimulates proliferation and 
repair of the aerodigestive mucosa.  Palifermin was found to significantly reduce oral mucositis due to 
conditioning for stem cell transplant. [26, 27]  Results were unfortunately less in Phase I and II studies of 
its use in head and neck cancer patients receiving radiotherapy, though there was a trend towards 
benefit.[28]  Phase III randomized trials comparing a higher dose of palifermin against placebo showed 
modest reductions in clinician-assessed mucositis rates and duration in both definitive and post-operative 
settings.  Patient-reported outcomes and opioid use were similar between the groups.[29, 30]  
Unfortunately, the benefit of mucosal protection with amifostine or palifermin has been limited. 
Another strategy includes oral rinse with the anti-depressant doxepin which addresses the 
patient’s perception of pain from mucositis, rather than reducing mucositis directly.[31]  Preliminary 
results have been reported for a Phase III randomized cross-over trial comparing doxepin oral rinse against 
placebo in the relief of oral mucositis pain during radiotherapy for head and neck cancer.  The doxepin 
mouth rinse significantly reduced patient-reported pain scores in both the initial and cross-over phases, 
though placebo alone also resulted in pain reduction.  Most compellingly, 64% of the trial participants 
chose to continue use of the doxepin mouth rinse in the optional continuation phase.  The authors also 
noted that the doxepin mouth rinse was associated with increased burning/stinging, unpleasant taste, 
and drowsiness, but was generally well-tolerated.[32]  This study confirms that therapies to address the 
perception of pain, other than opioids, can be a successful strategy. 
Several different approaches have targeted treatment-related weight loss directly, though 
randomized evidence comes from only a few small trials.[33]  Nutritional support without a feeding tube 
had mixed results in several trials.[33].  Early enteral feeding tube placement has been advocated by some, 
and appeared to have some benefit in one trial.[5, 34]  Enteral feeding offers an effective but less than 
ideal intervention of last resort for patients with severe ongoing weight loss. 
tDCS pain neuromodulation 
Therapies that directly modulate brain activity in specific neural networks might be particularly 
suited to relieve chronic pain in individuals with cancer. Ultimately, this underlies the interest in 
neurostimulation approaches, which are being explored at multiple levels of the neuroaxis, including the 
peripheral nerves, spinal cord, deep brain structures, and cortex [35]. Among the methods of central 
neurostimulation, two of them, repetitive transcranial magnetic stimulation (TMS) and transcranial direct 
current stimulation (tDCS), are particularly appealing as they can change brain activity in a non-invasive, 
painless and safe way. TMS is a method of brain stimulation that was developed in 1985 [36]. It is based 
on a time-varying magnetic field that generates an electric current inside the skull where it can be focused 
and restricted to small brain areas by appropriate stimulation coil geometry and size [37]. This current 
applied repetitively, repetitive TMS (rTMS), induces a cortical modulation that lasts beyond the time of 
stimulation [37]. Although tDCS has different mechanisms of action, it induces similar modulatory effects. 
Several animal studies in the 1960s showed that this technique changes brain activity reliably [38, 39]. 
tDCS is based on the application of a weak direct current to the scalp that flows between two relatively 

5 
 
large electrodes, the anode and cathode. The effects depend on polarity of stimulation: cathodal 
stimulation induces a decrease in cortical excitability, while anodal stimulation induces an increase in 
cortical excitability. Studies have shown that the efficacy of tDCS depends critically on parameters such as 
electrode position and current strength [38, 39]. In fact, application of tDCS for 13 min to the motor cortex 
can modulate cortical excitability for several hours [40, 41]. The most common protocol with tDCS is the 
M1-S0 montage for 20min. Moreover, 2mA is the most effective dose of stimulation, compared with 1mA, 
at the clinical and biological levels [42]. Doses are relatively confortable at 2mA, but can become less 
tolerable above that. The effects are also accumulative, been daily sessions for 1-2 weeks more reliable 
to achieve faster analgesia, which can be maintained with more sparse sessions later. Hence, our decision 
to have a more frequent sessions at the beginning of the trial. This approach follows other long-term 
studies with tDCS. 
We have recently reported significant acute reductions in µ-opioid receptor (MOR) availability in 
pain-related regions during a single session of real tDCS in a postherpetic neuralgia patient [43].  The µ-
opioid system is the most important mechanism involved in the regulation of nociceptive signals, and 
specific target of several opioid analgesics currently available for clinical use. The case report utilized 
[11C]carfentanil, a selective MOR radiotracer, and the application of real tDCS was associated with 
significant changes in thermal pain thresholds. Those preliminary findings suggested that clinical 
outcomes observed with tDCS could be positively associated with activation of the MOR system, which 
has been similarly reported in placebo studies [44]. Furthermore, we have recently measured with MR 
spectroscopy that GABA, Glx, and NAA play an important role in the pathophysiology of chronic pain and 
its modulation by tDCS.  Both the sham and active tDCS phases of a trial with fibromyalgia patients 
resulted in significant alterations in the brain metabolites for various pain-related structures in the brain, 
including the ones described in our previous PET study.  In fact, baseline Glx levels in the anterior cingulate 
predicted response to treatment.  These findings encourage further work to pursue targeted cortical 
therapy with tDCS for head and neck cancer induced pain, especially associated with the 
chemoradiotherapy. 
Studies using tDCS have been performed on well over 100 patients, including healthy patients and 
patients with stroke [45], spinal cord injury [46], depression [47], multiple sclerosis [48], fibromyalgia [49], 
chronic migraines [50], and trigeminal neuropathic pain [43]. No significant adverse outcomes were seen.   
The portable size, ease of application, and consistent cortical effects make tDCS a potentially 
powerful cancer therapy in the palliative clinical setting. One case report has demonstrated this benefit 
in pancreatic cancer, by relieving pain and decreasing rescue medication usage. [12]  tDCS modulation has 
shown significant results in different types of chronic pain [51] and to be more effective in increasing pain 
tolerance than other forms of transcranial stimulation [52]. This may be explained by our forward analysis, 
which predicated significant electric current in neighboring inner cortical structures linked to chronic pain 
pathophysiology. This was later confirmed by our subsequent study where we applied the M1-tDCS during 
the neuroimaging session in multiple subjects. Our results confirm the activation of those pain-related 
structures, directly or indirectly, with concurrent analgesia. [43]  
Lefaucheur et al [53] reviewed the literature for both rTMS and tDCS and found several studies 
that support the analgesic potential of this non-invasive therapy on acute, experimentally induced pain 
perception. [54] [55] [56] [57] [58] [59] [60] [61] It has been shown that stimulation using tDCS 
immediately affects the mu-opioid system [43] and that repetitive stimulation, in as few as 5 daily 
sessions, has significant pain improvement that then lasts for weeks after the end of treatment. [11, 62] 
Previous studies have been reported that accumulative tDCS sessions are required to improve 
clinical outcomes. Recently, the remotely supervised tDCS (RS-tDCS) protocol was implemented to provide 
an extension of in-clinic tDCS sessions and to facilitate patients’ compliance and retention during multiple 
visits [63-65]. Besides that, the RS-tDCS marks a major step in the tDCS field, mainly when lead to 
conditions that promote distinct deficits on the patients, such as multiple sclerosis and palliative care 

6 
 
patients [63-66]. Hence RS-tDCS may also be helpful to progress in clinical trials.  
More recently, simultaneous tDCS/EEG evaluation of cortical mechanisms can elucidate valuable 
information regarding the immediate tDCS effects on the brain. Furthermore, an emerging technology has 
been used for brain imaging. Functional near-infrared spectroscopy (fNIRS) has become a reliable and 
objective tool to evaluate cortical activity of patients by measuring changes in blood oxygenation within 
different layers of tissue, similar to functional MRI (67, 68, 69). Interestingly, a recent study reported the 
use of  concurrent EEG/fNIRS to clarify hemodynamic changes presenting clusters of infantile spasms. 
(70). Hence, in order to optimize our understanding of the central analgesic mechanisms of 
neuromodulation, our study will examine the human cortices responses through EEG and also fNIRS 
related to electrical stimulation on the brain to reduce odinophagia and pain due to mucositis. This will 
be performed in patients with locally advanced head and neck cancer undergoing definitive 
chemoradiotherapy or radiation therapy.  
2. HYPOTHESES/OBJECTIVES 
The goal of this randomized Phase II study is to investigate the effectiveness of tDCS as a novel pain 
relief modality for odynophagia due to mucositis in patients with locally advanced head and neck cancer 
undergoing definitive chemoradiotherapy or radiation therapy.  The hypotheses and specific aims of this 
investigation are: 
 
Primary Aim: To compare the effect of TDCS versus standard care on patient-reported odynophagia. 
Hypothesis: tDCS will result in reduced patient-reported odynophagia at middle and final timepoints 
(10th, and 20th sessions). 
 
Secondary Aim 1: To compare the effect of tDCS versus standard care on weight loss during 
radiotherapy. 
Hypothesis: tDCS will relieve odynophagia thereby improving oral intake and reducing weight loss during 
radiotherapy at middle and final time-points (10th, and 20th sessions). 
 
Secondary Aim 2: To compare the effect of tDCS versus standard care on narcotic pain medication 
requirements due to odynophagia and mucositis. 
Hypothesis: tDCS will relieve odynophagia and mucositis pain thereby reducing narcotic pain medication 
use during radiotherapy at middle and final time-points (10th, and 20th sessions). 
 
Secondary Aim 3: To compare the effect of TDCS versus usual care on the need for feeding tube 
placement during radiotherapy. 
Hypothesis: tDCS will relieve odynophagia thereby improving oral intake and reducing the need for 
feeding tube placement during radiotherapy. 
 
Secondary Aim 4: To investigate whether tDCS neuromodulation alters the quality of odynophagia and 
mucositis pain during head and neck radiotherapy. 
Hypothesis: tDCS will alter the quality of odynophagia and mucositis pain such that the pain is less 
noxious. 
 
Secondary Aim 5: To compare the effect of tDCS on overall (unprovoked) mucositis pain compared with 
standard care. 
Hypothesis: tDCS will reduce the intensity of unprovoked mucositis pain. 
 

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Secondary Aim 6: To compare changes in diet with tDCS during head and neck radiotherapy compared to 
standard care. 
Hypothesis: tDCS will result in less significant diet changes. 
 
Secondary Aim 7: To compare EEG changes with tDCS compared with standard care during head and 
neck radiotherapy. 
Hypothesis: alpha amplitude will be significantly higher in response to active-tDCS and correlated with 
pain relief compared to standard care. 
 
Secondary Aim 8: To compare fNIRS changes with tDCS compared with standard care during head and 
neck radiotherapy. 
Hypothesis: cortical activity will be significantly higher in response to active-tDCS compared to standard 
care 
 
3.0 ELIGIBILITY/EXCLUSION CRITERIA 
 
Patient Standard of Care: Definitive treatment is usually over 7 weeks, delivering 2 Gy per day, 5 
days a week, to a total of 7 weeks. Many of these patients receive concurrent chemotherapy, usually 
every Monday during the 7 week treatment time. Some of these patients can decrease the amount of 
Gy and weeks of the treatment. Patients receiving postoperative radiation therapy (RT) get 60 Gy to the 
high-risk tumor bed, with or without chemotherapy (chemo is delivered if positive margins or ECE). 
There are patients that have g-tubes placed prospectively.  There is not a strict line that is used clinically, 
but they generally have already lost 5-10% body weight and are not eating anything.  
 
The control group will consist of patients receiving the Standard of Care and no 
neuromodulation. 
 
3.1 Eligibility criteria: 
3.1.1 
Patients with any AJCC stage head and neck malignancy scheduled for definitive 
chemoradiotherapy or radiation therapy, and who are capable of understanding and 
adhering to the protocol requirements. 
3.1.2 
Patients must be willing to comply with the study procedures and visits. 
3.1.3 
Patients aged 18-75 years old 
 
3.2 Exclusion criteria: 
3.2.1 
Substantial dementia. 
3.2.2 
Patients are actively being treated for another cancer at the time of enrollment. 
3.2.3 
Any condition that would prevent use of tDCS including skull abnormality, implanted 
metal, implanted electronic device, seizure disorder, neurologic condition. 
3.2.4 
Use of an investigational drug or device within 30 days of study screening. 
 
 
4.0 PRETREATMENT EVALUATION 
4.1 History and Physical examination 
4.1.1 Hospital Dentistry Evaluation – Performed as part of the normal protocol for these 
patients. 

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5.0 SUBJECT SCREENING, REGISTRATION PROCEDURES, AND REIMBURSEMENT 
Patient registration for this trial will be centrally managed by the Headache & Orofacial Pain Effort 
Laboratory, Biologic & Materials Sciences, School of Dentistry. 
 
A potential study subject who has been screened for the trial and who has signed the Informed Consent 
document will be initially documented by the Department of Radiation Oncology.  After patient 
eligibility has been determined, a copy of the completed Eligibility Worksheet together with all the 
pertinent de-identified source documents will be collected and stored in the Headache & Orofacial Pain 
Effort Laboratory, Biologic & Materials Sciences, School of Dentistry. 
 
The participants and/or his/her caregiver will receive, during the first week of tDCS session in-clinic, a 
proper training with a trained team member regarding remotely supervised tDCS using ElectraRx 
website (https://www.soterixmedical.com/electrarx/login) and provided with a study stimulation 
device and guidelines. After that, the participants will be able to do their stimulation sessions at home, if 
the subjects properly follow the steps to ensure correct electrode preparation and placement, low 
impedance and safe removal of the device.  
During the remotely supervised tDCS session, the participants or his/her caregiver will have remote 
observation through videoconference and the ElectraRX webpage. Each remotely session the participant 
will fill out the steps through the ElectraRx website ahead the remotely session start and then will be 
provide a code that allow the participant to start the neuromodulation session. (Appendix C)  
 
The participant will have choice to be treated either with at the clinic tDCS sessions or at home tDCS 
sessions via videoconference and can adjust the schedule of sessions (tDCS in clinic or RS-tDCS) at any 
moment during the study visits according to patient’s decision.  
 
The participants will be real-time supervised and instructed to abort the RS-tDCS session if reports 
significant discomfort or other adverse event, otherwise needs to discontinue a session, or if study staff 
determines that the session should be discontinued. In addition, the study will be made aware of the 
designated “stop criteria”. If the stop criteria will be met at any time throughout the study, the session 
and/or ongoing study participation will be reviewed. (Figure 1.0) 
 
Patients will not be compensated for their participation in the study.  In cases of financial hardship and 
extended travel situations, funds may be available to reimburse patients for travel to visits that cannot 
be scheduled on days in which they have previously scheduled appointment at UMHS. The study team 
will determine this on a case-by-case basis.  
 
Patients found to be ineligible for participation after being consented will be considered screen failures, 
and documented as such in the Screening and Enrollment Log. These patients will not have study 
identification number assigned to them, and will not receive study treatment. 
 
Data Forms for Quality of Life and Toxicity Assessments will be completed once the patient has signed 
the consent form. When the patient is deemed eligible and enrolled, the data will be entered into the 
research database. In the event that the patient is deemed ineligible/screen failure, the data will not be 
used and the forms will be kept with the ICD in the study record. 
 
Randomization will be conducted by the statistician as outlined in section 8.0 

9 
 
 
 
 
Figure 1.0   STOP CRITERIA. Transcranial direct current stimulations feasible for remotely supervised home delivery in multiple sclerosis. Adapted 
from: Kasschau, M.et al. Neuromodulation. 19: 824-831 (2016) 
 
STOP 1: Does not meet 
eligibility/exclusion criteria
RS-tDCS training 
and Study 
Session 1
STOP 3: Does not tolerate 
tDCS at either dose
STOP 2: Report pain score of 7 
or greater on tolerability test
tDCS tolerability 
test 1
tDCS tolerability 
test 2
RS-tDCS
Session 1
Study technician 
evaluates environmental 
suitability
STOP 4: Failure on 
environmental suitability screen
Study Session 
2-20
Screening/ Pre-
Study Visit
Participant self-reports 
pain at start, midway, or 
immediately, following 
session
Participant places 
headset correctly
Adverse event/ 
tolerability 
questions
Initiates 
scheduled study 
session
Completes session 
and tolerability report
STOP 7: Failure to place 
headset correctly within 15 
minutes at > 1 session
STOP 6: Participant reports 
any events of critical concern
STOP 5: Three session 
reschedules
STOP 8: Reporting pain 
score of 7 or more at any 
point
STOP 9: Reports experiencing 
any event of critical concern

10 
 
6.0 SCHEMA 
 
Study Entry 
Eligibility 
¯ 
Pretreatment 
Patient-reported odynophagia assessment 
Weight measurement 
Narcotic pain medication baseline assessment 
Oral mucositis quality of life assessment 
Diet assessment 
Pain questionnaires 
EEG 
Hospital Dentistry Evaluation  
¯ 
Randomization: Standard Care OR tDCS 
¯ 
Initiation of Chemoradiotherapy/Radiation Thearpy 
¯ 
During Chemoradiotherapy/Radiation Therapy 
tDCS  
 
-  Week 2/3: daily (5x per week) 
 
-  Week 4/5: 3x per week 
 
-  Week 6/7: 2x per week 
Patient-reported odynophagia assessment 
Weight measurement 
Narcotic pain medication assessment 
Oral mucositis quality of life assessment 
Diet assessment 
Pain questionnaires 
Nutritional assessment weekly by Cancer Center Nutrition, including 
feeding tube necessity assessment 
EEG 
fNIRS 
Evaluation of oral mucositis 
¯ 
After Chemoradiotherapy/Radiation Therapy: 1 week and 1 month follow-ups 
Patient-reported odynophagia assessment 
Weight measurement 
Narcotic pain medication assessment 
Oral mucositis quality of life assessment 
Diet assessment 
Pain questionnaires 
Nutritional assessment weekly by Cancer Center Nutrition, including 
feeding tube necessity assessment 
EEG 

11 
 
7.0 Study Design and Calendar 
 
Patients will undergo the intervention on the day of their chemoradiotherapy/radiation therapy 
appointments, prior to receiving treatment when doing tDCS session in-clinic or after doing tDCS session at 
home. This will occur daily (5 days per week) during the second and third weeks of chemoradiotherapy/ 
radiation therapy, three times per week during the fourth and fifth weeks, and twice per week during the 
sixth and seventh week.  If a stimulation appointment cannot occur on a scheduled day (i.e. extended 
chemotherapy, etc.) or is missed (i.e. weather, personal emergency), two stimulations will be given the day 
before or the following day. The first stimulation will occur in the morning and the second in the afternoon, 
depending on the patient’s schedule. 
 
Study Calendar 
 
Pre-
Stu
dy 
Chemoradiotherapy/Radiation Therapy Week 
 
One 
month 
post-
treatm
ent 
1 
2 
3 
4 
5 
6 
7 
One 
week 
follow
-up 
tDCS in-clinic 
 
 
Daily 
(M,T,W,T,F) 
 
 
Last 
session 
on  week 
 
Last 
session 
on week 
 
 
Remotely 
supervised tDCS (at 
home) 
 
 
 
Daily 
(M,T,W,T,
F) 
3 
times 
per 
week 
Twice 
per week 
Twice 
per 
week 
Once a 
week 
 
 
Patient-reported 
odynophagia 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Narcotic pain 
medication 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
H & N Quality of life 
assessment 
X 
 
 
 
 
 
 
X 
X 
X 
Diet assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nutritional (feeding 
tube) assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pain Questionnaires 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EEG 
X 
 
Twice 
(M and F)  
 
 
Last 
session 
on 
week 
 
Last 
session 
on 
week 
X 
X 
fNIRS 
X 
 
First 
session 
 
 
Last 
session 
a week 
 
Last 
session 
 
 
Oral mucositis and 
quality of life 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

12 
 
Positive and 
Negative Affect 
Schedule (PANAS-X) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
tDCS Procedure 
Detailed step-by-step information of the tDCS/EEG and RS-tDCS procedure also provided in the 
following 
video-article: 
http://www.jove.com/video/50426/simultaneous-eeg-monitoring-
during-transcranial-direct-current  
https://www.jove.com/video/53542/a-protocol-for-use-remotely-supervised-transcranial-direct-
current 
 
1) Materials: check if all materials are available before starting the following steps: 
a) The cap has 27 holes representing EEG positions based on the 10/20 system. In our study we will 
use C3 or C5, depending on the location of the cancer, (motor cortex) and F4 (frontal cortex) for 
the tDCS stimulation. 
b) The electrodes have 2 different uses; they can be used for the EEG (six channels) and for tDCS 
(two channels for sponge-electrodes, the anode and the cathode). 
c) The variation of the tDCS electrodes size leads to a variation of focal effects. In this study, sponge-
electrodes of 25 cm2 will be used. 
d) All the electrodes will be connected to the Control Box device through the wires. The device will 
be charged periodically using the Control Box Battery charger.  
e) The USB for Bluetooth connection will be needed to pair the Control Box to the laptop/computer 
(see below). 
2) Skin Preparation 
a) We will inspect the skin for any pre-existing lesions – to avoid electrical stimulation/EEG recording 
over damaged skin or over skull lesions. 
b) To increase conductance, we will move hair away from the site of electrical stimulation/EEG 
registering and place plastic hair clips to keep hair away, clean the surface of the skin to remove 
any signs of lotion, dirt, grease, etc. and allow it to dry. 
3) Head Measurements 
a) We will find and mark the localization of the Vertex or Cz, by measuring the distance of nasion to 
inion and marking halfway using a skin marker. 
4) Electrodes Positioning in the Cap 
a) We will put saline solution on the tDCS sponge-electrodes. The sponge-electrodes will be soaked 
with saline solution before wearing the head cap. It is important to periodically refill the sponge-
electrode with saline solution. 
b) The EEG and the tDCS electrodes will be fixed in the cap before the subject is physically wearing 
it. 
c) For further details on general tDCS electrodes preparation and positioning please check the 
following link: (http://www.jove.com/details.php?id=2744) 
5) Wearing the Cap and Fixing the Control Box on it 
a) We will make sure the subject is seated comfortably. 
b) We will place the cap in a way that the Vertex (measured on the head) matches the Cz point on 
the cap.  
c) We will fill the EEG electrodes with gel using a curved syringe. 
d) We will Connect EEG and tDCS electrodes to the Control Box wires. The Control Box will be fixed 
to the posterior part of the cap. We use channels 1 and 2 for stimulation and the remaining ones 
for EEG recording. The anodal tDCS contralateral to the pain set up will be displayed: anode = M1; 

13 
 
cathode = Supraorbital contralateral. For this montage, connect the anode (red sponge-electrode) 
to the C3 or C5 and the cathode (black sponge-electrode) to F4. 
e) We will put the reference electrodes to one of the mastoids making sure they do not touch one 
another and attached them to the wires (CMS, Common Mode Sense and DRL, Driven Right Leg) 
from the Control Box. 
6) Stimulation and Recording Set Up 
a) In order to configure parameters of stimulation and check recording, the software will be installed 
according to the manufacturer's instruction. 
b) Press "STIMULATION" in the horizontal bar on upper screen. 
c) Select the option "EDIT" in the upper screen and choose "tDCS" or "sham". 
d) Choose the total duration of the electrical stimulation, in this study 20 min and at intensity of 
2mA.  
e) We will configure tDCS and EEG channels according to the experimental approach. The reference 
electrodes are labeled as DRL and CMS. Label the active stimulation electrode as "anode" or 
"cathode" and its reference as "return". 
f) In the bar menu located in the lower part of the screen choose the duration of the ramp down 
and ramp up period for 30 sec. During this step we will also select the duration of pre- and post 
EEG recordings. The EEG recording is not dependent on the stimulation and will be programmed 
to start 5min before, during tDCS, and 2min after the end of the tDCS. 
g) To check electrode impedance we will press "STIMULATION" in the upper part of the screen and 
then "MOUNT" in the left side of the screen and then "START IMPEDANCE CHECK" 
7) Start the Device 
a) The subject will be placed in a relaxed and comfortable position during the procedure. 
b) Press "LAUNCH" in the lower part of the screen. 
c) Check if the vertical gray bar is moving forward before, during and after the tDCS. 
d) Re-check electrode impedances. 
e) Press "Abort" to suspend the stimulation at any moment, if needed. 
8) Record EEG Data 
a) We will press "EEG" in the upper screen to check if the EEG signals are visible and without any 
artifacts. The signals will be filtered from in order to clarify the EEG traces. 
b) EEG recording will start automatically as soon as the icon LAUNCH is pressed. 
 
Assessment Measures 
Patient-reported odynophagia assessment 
A Visual Analog Scale (VAS) will be used to assess patient-reported odynophagia at weekly Radiation 
Oncology on-treatment visits (OTVs).  The VAS is a traditional pain assessment tool that has been used 
and validated widely in both clinical and research settings, including studies of oral mucositis 
pain.[31,71-73]  This simple tool offers a straightforward method that can be completed quickly by the 
patient.  Baseline pain will be established at the enrollment visit, and Area Under the Curve above this 
baseline will be calculated from the weekly OTV assessments. 
 
 
 

14 
 
Oral Mucositis Assessment:   
The WHO scale will be used for grading Oral Mucositis and including both visual and functional 
assessments (Table 1.0)1. Assessments will be made prior to treatment, weekly during treatment, one 
week and one month post treatment.   
 
Grade 
Description 
Additional Guidance 
0 
none 
None 
1 
Soreness, erythema 
May include buccal scalloping 
with or without erytherma. 
Patient can swallow a solid diet. 
2 
Erythema, ulcers, ability to eat 
solid foods 
Must include ulcer +/- 
erythema. Patient can swallow a 
solid diet. 
3 
Ulcers, requiring liquid diet 
Must include ulcer +/- extensive 
erythema. Patient can swallow a 
liquid diet but not a solid diet. 
4 
Alimentation not possible 
If total parenteral nutrition is 
started for reasons other than 
mucositis, a determination of 
the patient’s ability to swallow 
must be made using the above 
criteria.  
 
Adapted from: Miller, AB, Hoogstraten B, Straquet M et al, Reporting results of cancer treatment. 
Cancer 47: 207-214, 1981.  
Weight 
Patient weight will be measured regularly as an objective measure of nutritional status, and has been 
used in numerous head and neck radiotherapy trials, including oral mucositis mitigation trials.[4, 6, 23, 
74,75]  Weekly weight measurement is standard practice in the Radiation Oncology clinic, and therefore 
no additional infrastructure is needed to collect this data.  The Area Under the Curve (AUC) of weight, 
using the baseline weight at the enrollment visit as baseline, will be compared between the groups. 
Narcotic pain medication requirement 
Narcotic pain medications are often required to relieve oral mucositis pain and odynophagia.  As such, 
the level of narcotic pain medication required offers a somewhat objective proxy measure of the level of 
oral mucositis pain and odynophagia that is often used in head and neck cancer trials.[19,76-78]  
Narcotic pain medications will be managed by the Medical Oncology service that is blinded to the 
randomization assignment.  At weekly on-treatment visits with Radiation Oncology, the amount of 
narcotic pain medicine used over the previous week will be recorded.  Amounts will be converted to 
milligram oral morphine equivalents for comparison among various narcotic medications.  If the patient 
has chronic narcotic use due to other conditions that preceded the head and neck cancer diagnosis, the 
researchers will attempt to determine the pre-cancer usual amount of narcotic pain medication.  The 
weekly amounts of narcotic pain medications during treatment will be used to calculate the AUC, with a 
                                                             
 
 

15 
 
baseline of zero or the pre-cancer baseline amount.  The AUCs will then be compared between the two 
groups. 
Feeding tube placement 
Severe nutritional deficiency during chemoradiotherapy/radiation therapy due to severe odynophagia 
requires placement of a feeding tube, and therefore offers another objective measure of odynophagia 
that has been used in many head and neck cancer trials.[4-6, 33,77]  The number of patients in each 
group requiring feeding tube placement will be recorded.  Nutritional assessment and determination of 
need for feeding tube placement will be conducted by the Medical Oncology service, which is a usual 
part of our multidisciplinary practice.  The Medical Oncology service will also be blinded to the 
intervention randomization. 
Oral Mucositis Quality of Life 
Numerous tools have been developed to assess the overall quality of life related to oral mucositis pain 
due to chemoradiotherapy/radiation therapy.  The Oral Mucositis Weekly Questionnaire for Head and 
Neck Cancer (OMWQ-HN) has been validated for this purpose, and has been used in several trials.[29, 
79,80]  The OMWQ-HN will be administered weekly including pre-study and one month post-treatment.  
Individual and overall scales will be compared between the tDCS and Standard Care patient groups. 
Photographs may be taken at middle, end, and follow-up appointments. These photographs will be used 
in “adjunct” with the OMWQ-HN to examine objective and subjective pain as reported by the patient. 
The physician will interpret oral mucositis, as graded using the scale above, clinically, and without any 
use of the photographs.    
A multicenter, longitudinal study to assess the validity, reliability, and feasibility of the OMWQ-HN was 
performed by Epstein et al 2007, and found the questionnaire to be valid, reliable, and feasible.  
 
Diet 
Severe odynophagia during chemoradiotherapy/radiation therapy prompts changes in diet that 
contribute to nutritional deficiency.  Diet changes can be assessed quickly with simple categorization of 
the patients’ diet, such as full/unrestricted, minimally restricted, soft, liquid, and minimal or no oral 
intake.[2] This simple assessment will be considered on an ordinal scale as levels of restriction and will 
be performed at the enrollment visit, the weekly Radiation Oncology OTVs during 
chemoradiotherapy/radiation therapy, and 1 month after treatment completion, as is standard practice 
in the Radiation Oncology clinic. The AUC will be calculated against the baseline diet level at the 
enrollment visit, and will be compared between the tDCS and Standard Care patient groups. A score at 
each follow up time point based on number of levels changed from baseline will also be analyzed. For 
example a patient who was at baseline only eating soft foods but during treatment was assessed as 
minimal or no intake will be scored -2 during treatment; at one month follow-up, if that patient is 
assessed fully/unrestricted their score at that time-point will be +2.  
H & N Quality of Life 
Numerous tools have been developed to assess the overall quality of life related to pain due to 
chemoradiotherapy/radiation therapy.  The Head and Neck Quality of Life Weekly Questionnaire and 
University of Washington QOL Questionnaire have been validated for this purpose, and have been used 
in several trials. [53, 54] The Washington QOL is one of the most frequently reported health-related QOL 
questionnaires in head and neck cancer. Laraway et al 2010, published a structured review and found 19 
papers discussing the development and validation of this questionnaire. [81]  

16 
 
The H&N QOL and UW QOL will be administered during the pre-treatment session, one week and one 
month post-treatment.  Individual and overall scales will be compared between the tDCS and Standard 
Care patient groups. 
 
EEG 
EEG evaluation of cortical mechanisms can elucidate valuable information regarding the immediate tDCS 
effects on the brain. EEG recording will be taken at the pre-study visit, the first stimulation visit, last 
stimulation on first week of tDCS session, and the fifth and seventh week of treatment (both on the last 
session on week), as well as the follow-up appointment.  
 
 
fNIRS 
fNIRS is an important tool for clinical monitoring of tissue oxygenation and measurement of cortical 
activity, thereby appear that an advancement in brain imaging. (80) fNIRS will taken at the pre-study 
visit, first stimulation visit, at the fifth week of treatment and the last stimulation visit. 
 
Pain Questionnaires 
Patients will complete 3 forms regarding their current pain levels immediately before and after 
stimulation: the McGill Short Form, the HOPE Pain Assessment, and the GeoPain App. These forms will 
be used to assess patient pain both during treatments and from beginning to end of the tDCS 
stimulation.  The McGill Short Form was shown to be valid with the following articles: Pain. 1987 
Aug;30(2):191-7; The short-form McGill Pain Questionnaire. Melzack R. The HOPE Pain Assessment was 
shown to be valid using DaSilva AFM, Granziera C, Tuch D, Snyder J, Hadjikhani N. “Interictal Alterations 
of the Trigeminal Somatosensory Pathway and PAG in Migraine”. Neuroreport – March; 2007, 18: 301-
305.  DaSilva AFM, Granziera C, Snyder J, Hadjikhani N. “Thickening in the Somatosensory Cortex of 
Migraine Patients”. Neurology – Nov 20, 2007; 69(21):1990-5. Granziera C *, DaSilva AFM*, Snyder J, 
Tuch DS, Hadjikhani N. “Anatomical Alterations of the Visual Motion Processing Network in Migraine 
with and without Aura”. * Equal contribution. PLoS Medicine, 2006 Oct 17;3(10). Sceintific Abstract: 
DaSilva AFM, Loder E, Sorensen AG, Hadjikhani, N. Development of a Craniofacial Pain Map for use in 
Neuroimaging Studies, 11th International Headache Society Congress, Rome, Italy, 2003.The PainTrek 
App is a free and interactive mobile application developed by our laboratory (H.O.P.E.) and the 3DLab at 
the University of Michigan. It allows our researchers to track, display and analyze facial pain information 
acquired from the patients during our research protocol (www.youtube.com/watch?v=CP8tvz2nmpY). 
PainTrek was awarded first prize in the last University of Michigan Mobile App Challenge, and it is now 
available in the Apple App Store for patients to download and use for free. The app changed the name 
to GeoPain and can record and analyze headache and facial pain intensity, pain area, percentage 
dermatomes affected, descriptors ratings, signs, symptoms, and so forth. No identifying information is 
stored on the iPad. The participant can also fill out through the internet using Soterix platform 
integrated with GeoPain. All information is deidentified. DosSantos MF, Martikainen IK, Nascimento TD, 
Love T, DeBoer M, Maslowski E, Monteiro AA, Vincent MB, Zubieta JK, DaSilva AF. "Reduced Basal 
Ganglia μ-Opioid Receptor Availability in Trigeminal Neuropathic Pain: A Pilot Study". Mol Pain. 2012 Sep 
24;8:74. DaSilva AF*, Nascimento TD*, Love T*, DosSantos MF, Martikainen IK, Cummiford CM, DeBoer 
M, Maslowski E, Smith YR, Zubieta JK, “3D-Neuronavigation In Vivo Through a Patient's Brain During a 
Spontaneous Migraine Headache”. JVisExp.2014 Jun 2;(88) PMID:24962460 *Equal contribution.  DaSilva 
AF, Nascimento T, DosSantos M; Lucas S; Van Holsbeeck H, DeBoer M, Maslowski E, Love T, Martikainen 
I, Koeppe R, Smith Y, Zubieta, JK. “μ-Opioid activation in the prefrontal cortex in migraine attacks – brief 
report I." Ann of Clin and Transl Neurol. 2014 1(6): 439-444.  

17 
 
Nascimento T, DosSantos M; Lucas S; Van Holsbeeck H, DeBoer M, Maslowski E, Love T, Martikainen I, 
Koeppe R, Smith Y, Zubieta, JK, DaSilva AF. "μ-Opioid activation in the midbrain during migraine 
allodynia – brief report II". Ann of Clin and Transl Neurol. 2014;1(6) 445-450. PMCID: PMC3522528 
 
In addition, patients will also complete a tDCS Side Effects assessment after each stimulation. This 
assessment will objectively gauge any adverse events the patient undergoes as a direct result of the 
stimulation.  This assessment has been used multiple studies by our lab. 
 
Positive and Negative Affect Schedule (PANAS-X) 
Patient mood will be measured using the Positive and Negative Affect Schedule (Watson D, Clark LA, 
Tellegen A: Development and validation of brief measures of positive and negative affect: the PANAS 
scales. Journal of personality and social psychology 1988, 54:1063-70) (Nemanick RC, Jr., Munz DC: 
Measuring the poles of negative and positive mood using the Positive Affect Negative Affect Schedule 
and Activation Deactivation Adjective Check List. Psychological reports 1994, 74:195-9) —a scale that 
consists of sixty words describing different feelings and emotions to assess both positive affect (PA) and 
negative affect (NA). The PANAS-X scale has high reliability and validity, is strongly correlated with 
commonly used state affect measures and current psychiatric symptomology, and many studies indicate 
the scale is sensitive to short-term mood fluctuation (Watson D, Clark LA, Tellegen A: Development and 
validation of brief measures of positive and negative affect: the PANAS scales. Journal of personality and 
social psychology 1988, 54:1063-70). Patients will complete this questionnaire at week 1, to establish a 
baseline, before and after each stimulation session (or once a week for patients in the standard care 
group), and at one-week and one-month follow-up. Mood changes throughout the study and before and 
after each stimulation will be analyzed, in addition to comparing the results between the tDCS and 
Standard Care patient groups. 
8.0 STATISTICAL CONSIDERATIONS 
Allocation 
Participants who successfully complete baseline testing are then allocated into one of the two 
intervention groups: active tDCS or Standard care, using a minimization scheme for age (<60 vs. >60) 
and gender.[82]  The minimization scheme ensures balance between treatment groups over these 
prognostic variables.  
Data analysis 
Subjects who are missing more than 2 odynophagia VAS timepoints will not be included in this primary 
analysis. Comparison of odynophagia between the 2 treatment groups (primary aim and hypothesis) will 
be performed with a simple 2 sample t-test comparing the AUCs from the VAS. If necessary, a log or 
other transformation will be applied to the endpoints before statistical tests performed. We will 
perform both intent-to-treat (ITT) and per-protocol analyses, and the degree of compliance will be 
summarized at each study week.  
 
Analysis for the secondary and exploratory aims will be performed in a similar manner using two sample 
comparisons (t-tests for continuous or chi-square for categorical variables) between the treatment 
groups for Oral Mucositis assessments, weight, narcotic pain medication requirements, OMWQHN, 
HNQOL, UW QOL, feeding tube requirement, and diet.   

18 
 
Treatment groups should be similar at baseline with respect to potential confounding variables due to 
the randomization, eligibility and exclusion criteria, therefore no covariate adjustment is planned in the 
analysis comparing treatment groups. Descriptive statistics will however be used to compare the 2.   
Sample size justification 
Over a two year period, 40 patients will be randomized into active tDCS group (n=20) or standard care 
group (n=20). Based on previous experience with impaired populations, we may have attrition as high as 
25%, leaving 16 participants in each group for analyses of 1 month post-treatment data. With a total 
sample of 32 patients, and a between group standard deviation of 1.5, there is 79% power to detect a 
mean absolute difference of 25%.  This power calculation is based on a 2-sided t-test at .05 level. 
Regardless of whether this trial achieves statistical significance, a larger study will be needed to confirm 
any findings. Such a trial will be run only if the results of the present study are sufficiently promising. The 
present trial will provide reasonable estimates of effect size and between subject variability to use in 
designing and powering a larger randomized Phase III trial. 
Timeline 
Sessions will occur daily for the initial two weeks, every other day the following two weeks, and two 
days per week during the last two weeks. Processing and analytic model development will be ongoing so 
that results will be available soon after completion of the study. 
Criteria for Discontinuation 
Patients unwilling or unable to complete more than 75% of study assessments, or who miss more than 1 
session in the first two weeks. (those enrolled and unable to meet this requirement will be taken out of 
study and replaced).  
Study strengths 
This study brings together expertise in HNCa treatment with expertise in tDCCS central pain 
neuromodulation and assessments of participants with an active medical condition under treatment. 
The intervention is directed at relieving odynophagia, a major driver of anorexia, malnutrition, and QoL, 
in HNCa. The outcomes are commonly performed and readily analyzable. 
Study limitations 
Patients undergoing HNCa treatment are likely to experience fatigue due to the disease, treatment side-
effects, and the numerous treatment appointments, and therefore may have difficulty complying with 
all study interventions and assessments. 
Future plans 
Findings from the pilot, including operational and effect size issues, will be used as the basis for external 
funding for a large randomized Phase III study. 
Significance of the study 
Odynophagia is a major driver of definitive chemoradiotherapy/radiation therapy morbidity in HNCa.  
Significant relief of odynophagia is expected to reduce narcotic pain medication requirements, which 
also carry significant side-effect morbidity.  In the ideal setting, odynophagia relief with tDCS would 
improve nutritional oral intake enough to reduce weight loss and the need for feeding tube placement.  
Based on these effects, relief of odynophagia with tDCS would have a major impact in HNCa. 

19 
 
9.0 REPORTING ADVERSE EVENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  Data on adverse 
events will be collected from the time of the initial investigational intervention administration through 
the end of the study calendar. Serious Adverse Events (SAEs) will continue to be followed until 
resolution or clearly determined to be due to a patient’s stable or chronic condition or intercurrent 
illness(es). 
 
Mild or benign adverse side effects, such as a mild headache, have been reported in a small number of 
patients. It has been demonstrated that no significant side effects in cognitive changes have been 
reported including by NIH researchers, and they can be avoided if the safety guidelines are followed ([39]). 
Patients will be closely monitored, and any adverse outcomes will be managed appropriately and 
reported immediately to the PI. 
 
The investigator is responsible for the detection and documentation of events meeting the criteria and 
definition of an AE or SAE. The definitions of AEs and SAEs are given below. It is the responsibility of the 
principal investigator to ensure that all staff involved in the trial is familiar with the content of this 
section. 
 
Any medical condition or laboratory abnormality with an onset date before intervention administration 
is considered to be pre-existing in nature. Any known pre-existing conditions that are ongoing at time of 
study entry should be considered medical history. 
 
All adverse events occurring from the initial investigational intervention administration through the end 
of the study calendar must be recorded as an adverse event in the patient’s source documents 
regardless of frequency, severity (grade) or assessed relationship to the investigational intervention.   
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of a pre-existing 
condition that occurs after the patient begins the investigational intervention is also considered an 
adverse event. 
 
All adverse events specified in the Case Report Form Completion Guidelines will be recorded in the 
study database (Microsoft Excel). 
 
 
9.1 Definitions 
Adverse event 
Adverse event means any untoward medical occurrence associated with the use of a medical treatment 
or procedure regardless of whether or not considered related to the medical treatment or procedure.  
An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the medical 
treatment or procedure, without any judgment about causality. 
Unexpected 
An adverse event is considered “unexpected” if specificity or severity that has been observed is not 
described in the protocol, informed consent document or published medical literature. 

20 
 
Serious Adverse Event 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or sponsor (UNIVERSITY OF MICHIGAN), it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
o A congenital anomaly/birth defect. 
o Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Previously planned (prior to signing the informed consent form) surgeries should not be reported as 
SAEs unless the underlying medical condition has worsened during the course of the study. Preplanned 
hospitalizations or procedures for preexisting conditions that are already recorded in the patient’s 
medical history at the time of study enrollment should not be considered SAEs. 14 
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for example, for the 
administration of study therapy or other protocol-required procedure) should not be considered SAEs. 
However, if the preexisting condition worsened during the course of the study, it should be reported as 
an SAE. 
Life-threatening 
An adverse event is considered “life-threatening” if, in the view of either the investigator or sponsor, its 
occurrence places the patient or subject at immediate risk of death. It does not include an adverse event 
that, had it occurred in a more severe form, might have caused death. 
9.2 Adverse Event Characteristics 
CTCAE term 
Adverse events [83] will use the descriptions and grading scales found in the revised National Cancer 
Institute [12] Common Toxicity Criteria for Adverse Events (CTCAE).  A copy of the CTCAE version 3.0 can 
be downloaded from the CTEP home page: http://ctep.info.nih.gov/reporting/ctc.html 
Attribution of the AE 
The investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the investigational intervention. 
Probable – The AE is likely related to the investigational -intervention. 
Possible – The AE may be related to the investigational -intervention. 
Unlikely – The AE is doubtfully related to the investigational -intervention. 
Unrelated – The AE is clearly NOT related to the investigational -intervention. 

21 
 
9.3 Reporting Procedures 
Serious adverse Events (SAEs) that are unexpected and definitely, probably or possibly related to 
protocol therapy should be reported to the Principal Investigator within 48 hours of awareness of the 
event. 
Principal Investigator: Alexandre DaSilva, DDS, DMedSc 
Phone: 734-763-5280 
Fax: 734-647-4130 
E-mail: adasilva@umich.edu 
 
Follow-up information must also be reported within 48 hours of receipt of the information. 
SAEs and/or unanticipated problems will also be reported concurrently to the IRBMED within 48 hours 
of awareness of the event. 
 
 
9.3.1 Exceptions to SAE Reporting 
The following adverse events are excluded from SAE reporting: 
• 
Hospitalization secondary to expected cancer morbidity 
• 
Admission for palliative care or pain management 
• 
Planned hospitalizations for surgical procedures either related or unrelated to the patient’s 
cancer. 
10.0 STUDY MONITORING 
10.1 Data and Safety Monitoring Procedures 
 
The principal investigator, co-investigator(s), data manager and study coordinator and other members 
of the study staff involved in the conduct of the trial will hold quarterly meetings to discuss matters 
related to: 
• 
Enrollment rate relative to expectations, characteristics of participants 
• 
Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
• 
Adherence to protocol (protocol deviations) 
• 
Completeness, validity and integrity of study data 
• 
Retention of study participants 
 
These meetings are to be documented by the data manager or study coordinator using the Protocol 
Specific Data and Safety Monitoring Report (DSMR), signed by the site principal investigator or co-
investigator, and submitted quarterly to the Rogel Cancer Center Data and Safety Monitoring 
Committee.  
 
Similarly, protocol deviations are to be documented using the Notice of Protocol Deviation Form and 
requires the signatures of both the data manager or study coordinator and the principal investigator or 
co-investigator.  These reports will be collected by the Headache & Orofacial Pain Effort Laboratory, 
Biologic and Materials Sciences, School of Dentistry, and on a quarterly basis with a Protocol Specific 
Data and Safety Monitoring Report.  The Headache & Orofacial Pain Effort Laboratory, Biologic and 
Materials Sciences, School of Dentistry will provide the Data and Safety Monitoring Reports to the Data 
Safety Monitoring Committee. 

22 
 
10.2 Clinical Monitoring Procedures 
Clinical studies coordinated by The University of Michigan Rogel Cancer Center must be conducted in 
accordance with the ethical principles that are consistent with Good Clinical Practices (GCP) and in 
compliance with other applicable regulatory requirements. 
 
Additionally, patients receiving tDCS will fill out a “tDCS Side Effects” Questionnaire after each session 
they received the treatment, including on remotely supervised tDCS session. This data will be used to 
assess patient safety and any adverse events per the patient.  This questionnaire was developed by a 
neuromodulation group at Harvard University and used by several other centers. Our team has 
conducted several tDCS trials, most of them combined with neuroimaging, including fibromyalgia, 
migraine, neuropathic pain, and temporomandibular disorders. We've had no report of significant side 
effects or incidents with any of our patients and healthy controls. However, in case of any incident, we 
will report it to IRB immediately. 
 
 
10.3 Data Monitoring and Confidentiality 
Subjects will provide information in a secluded area. This information will then be kept in confidential 
locked offices, including cabinet or storage units and secured laptops, within the Molecular and 
Behavioral Neuroscience Institute.  Data will not be provided to a repository. Individual identifiable 
sensitive data will no be accessed, collected, used, maintained, or disclosed in this study. 
 
No information will be generated that, if revealed, will place the subjects at risk of personal safety, 
liability, employability, or reputation.  
 
At the conclusion of the study, the data will be retained at the MBNI for record keeping purposes. They 
will be retained for at least 2 years in locked cabinets in a locked office or storage room.  These areas 
will only be accessible by study team members, who frequently monitor. 
 
 
 
 
 
 
 

23 
 
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83. Baez, C.F., et al., Detection of Merkel cell polyomavirus in oral samples of renal transplant recipients 
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27 
 
 
53.  Hunter KU, Schipper M, Feng FY, Lyden T, Haxer M, Murdoch-Kinch CA, Cornwall B, Lee CS, Chepeha 
DB, Eisbruch A. Toxicities affecting quality of life after chemo-IMRT of oropharyngeal cancer: prospective 
study of patient-reported, observer-rated, and objective outcomes Int J Radiat Oncol Biol Phys., 2013. 
85(4): p. 935-40. 
 
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61-70. 
 
 
 

28 
 
12.0 APPENDICES 
Appendix A: Visual Analog Scale 
 
 
 
Source: hospiceworld.org 
 
 
 

29 
 
Appendix B: Questionnaires 
 
Oral Mucositis Weekly Questionnaire for Head and Neck cancer (OMWQ-HN) 
 
 
 
 
! HUM00078942!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Patient!ID:!______________________!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Week:!______________________!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Date:!______________________!
!
Oral!Mucositis!Weekly!Questionnaire!
!

30 
 
 
 
 

31 
 
University of Washington Quality of Life Questionnaire (UW-QoL) 
 
Study #__________ 
Initials___________ 
Date of questionnaire______________ 
 
Each of the following items lists different numbered statements.  Think about what each statement says, then 
place a circle around the one statement that most closely describes how you have been feeling during the 
past week, including today.  Please circle only one statement for each item.   
 
 
 
I.  PAIN (General) 
 
A.     General 
10     I have no pain. 
20     There is mild pain not needing medication. 
30     I have moderate pain--requires regular medication (codeine or non-narcotic). 
40     I have severe pain controlled only by narcotics. 
50     I have severe pain not controlled by narcotics. 
 
B.     Mouth 
10     I have no pain in my mouth. 
20     I have mild pain but it is not affecting my eating. 
30     I have moderate pain which is affecting my eating. 
40     I have severe pain and need medication in order to eat. 
50     I have severe pain and cannot eat even with the medication. 
 
C.     Throat   
10     I have no pain in my throat. 
20     I have mild pain but it is not affecting my eating. 
30     I have moderate pain which is affecting my eating. 
40     I have severe pain and need medication in order to eat. 
50     I have severe pain and cannot eat even with the medication. 
 
 
II.  DISFIGUREMENT 
 
10     There is no change in my appearance. 
20     The change in my appearance is minor. 
30     My appearance bothers me but I remain active. 
40     I feel significantly disfigured and limit my activities due to my appearance. 
50     I cannot be with people due to my appearance. 
 
 
III.   ACTIVITY 
 
10     I am as active as I have ever been. 
20     There are times when I can't keep up with my old pace, but not often. 
30     I am often tired and I have slowed down my activities although I still get out. 
40     I don't go out because I don't have the strength. 

32 
 
50     I am usually in a bed or chair and don't leave home. 
 
 
 
 
IV.  RECREATION/ENTERTAINMENT 
 
10     There are no limitations to recreation at home and away from home. 
20     There are a few things I can't do but I still get out and enjoy life. 
30     There are many times when I wish I could get out more but I'm not up to it. 
40     There are severe limitations to what I can do, mostly I stay home and watch T.V. 
50     I can't do anything enjoyable. 
 
 
V.   EMPLOYMENT 
 
10     I work full time. 
20     I have a part time but permanent job. 
30     I only have occasional employment. 
40     I am unemployed. 
50     I am retired (circle one below) 
    51     not related to cancer treatment 
    52     due to cancer treatment 
 
 
VI.   EATING 
 
A.     Chewing 
10     I can chew as well as ever. 
20     I have slight difficulty chewing solid foods. 
30     I have moderate difficulty chewing solid foods. 
40     I can only chew soft foods. 
50     I cannot chew soft foods. 
 
B.     Swallowing 
10     I swallow normally 
20     I cannot swallow certain solid foods. 
30     I can only swallow soft foods. 
40     I can only swallow liquid foods. 
50     I cannot swallow. 
 
 
VII.  SALIVA 
 
A.  Amount 
10     I have a normal amount of saliva 
20     I have a mild loss of saliva 
30     I have a moderate loss of saliva. 
40     I have a severe loss of saliva. 
50     I have no saliva. 

33 
 
 
 
 
 
B.  Consistency 
10     My saliva has normal consistency. 
20     My saliva is slightly thicker. 
30     My saliva is moderately thicker. 
40     My saliva is extremely thicker. 
50     I have saliva that dries in my mouth and/or on my lips. 
 
 
VIII.   TASTE 
 
10     I can taste food normally. 
20     I can taste most foods normally. 
30     I can taste some foods normally. 
40     I can taste few foods normally. 
50     I cannot taste any foods normally. 
 
 
IX.   SPEECH 
 
10     My speech is the same as always. 
20     I have difficulty with saying some words, but can be understood over the phone. 
30     I have moderate difficulty saying some words, and cannot use the phone. 
40     Only family and/or friends can understand me. 
50     I cannot be understood. 
 
 
X.   MUCUS OR PHLEGM 
 
A.     Amount 
10     I have a normal amount of mucus. 
20     I have a mild amount of mucus 
30     I have a moderate amount of mucus. 
40     I have a severe amount of mucus. 
50     I have no mucus. 
 
B.     Consistency 
10     My mucus has normal consistency 
20     My mucus is slightly thicker 
30     My mucus is moderately thicker 
40     My mucus is extremely thicker 
50     I have no mucus 
 
 
 
Comments:______________________________________________________________________________ 
________________________________________________________________________________________ 
 

34 
 
Patient Name ____________________________________   Reg No. ________________ 
Hospital ________________________________________ 
 
Date of Questionnaire _____________________________ 
 
Below are several questions that will help describe the dryness in your mouth and how that dryness 
affects your daily life.  Please encircle the number that corresponds to your condition during the last 
week in each of the following questions: 
 
1. 
Rate the discomfort of our dentures due to dryness (if you do not wear dentures please check 
_____) 
 
0           1           2           3           4           5           6           7            8           9           10 
     Comfortable  
 
 
 
 
 
Extreme discomfort 
 
2.  Rate the difficulty you experience in speaking due to dryness of your mouth and tongue: 
 
0           1           2           3           4           5           6           7            8           9           10 
      Easy  
 
 
 
 
 
 
Extremely Difficult 
 
3.  Rate the difficulty you experience in chewing food due to dryness: 
 
0           1           2           3           4           5           6           7            8           9           10 
     Easy  
 
 
 
 
 
 
Extremely Difficult 
 
4.  Rate the difficulty you experience in swallowing food due to dryness: 
 
0           1           2           3           4           5           6           7            8           9           10 
     Easy  
 
 
 
 
 
 
Extremely Difficult 
 
5.  Rate the dryness your mouth feels when eating a meal: 
 
0           1           2           3           4           5           6           7            8           9           10 
     No Dryness  
 
 
 
 
 
Extremely Dryness 
 
 
6.  Rate the dryness in your mouth while not eating or chewing: 
 
0           1           2           3           4           5           6           7            8           9           10 
     No Dryness  
 
 
 
 
 
Extremely Dryness 
 
 
 
 
 
7.  Rate the frequency of sipping liquids to aid in swallowing food: 
 
0           1           2           3           4           5           6           7            8           9           10 

35 
 
     None required 
 
 
 
 
 
Extremely Frequent 
 
 
8.  Rate the frequency of fluid intake required for oral comfort when not eating: 
 
0           1           2           3           4           5           6           7            8           9           10 
     None required 
 
 
 
 
 
Extremely Frequent 
 
9.  Rate the frequency of sleeping problems due to dryness: 
 
0           1           2           3           4           5           6           7            8           9           10 
     None          
 
 
 
 
 
 
Extremely Frequent 
 
10.  Does your mouth feel dry when eating a meal? 
 
 
 
Yes / No 
 
11.  Are you thirsty? 
 
 
 
 
 
 
 
Yes / No 
 
12.  Does the amount of saliva in your mouth seem to be: 
 
 
_____  Too little 
 
_____  Too much 
 
_____  Don’t notice it 
 
13.  Do you have difficulties swallowing any food? 
 
 
 
Yes / No 
 
14.  Do you sip liquids to aid in swallowing dry food? 
 
 
Yes / No 
 
15.  Have you smoked in the last week?  
 
 
 
Yes / No 
 
 
If yes, how many packs? _______ 
 
16.  Do you drink alcohol more than twice a week? 
 
 
 
Yes / No 
 
17.  Do you have any medical problem/disease for which you take  
       medication? 
 
 
 
 
 
 
 
Yes /No 
 
 
Which pills/medication do you take? 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_________________________________ 
 
 

36 
 
Head and Neck Quality of Life Questionnaire 
 
 
INSTRUCTIONS:  This survey is designed to assess how much you are bothered by your Head and Neck 
condition and/or treatment.  Please answer every question by marking one box.  If you are unsure 
about how to answer, please give the best answer you can. 
 
1.  As a result of your head and neck condition or treatment, over the past FOUR WEEKS how much 
have you been BOTHERED by your… 
 
 
  Not at all   Slightly 
  Moderately 
    A lot 
   Extremely 
 
 
A. Ability to talk to other people 
 
B. Ability to talk on the phone 
 
 
 
 
2.  As a result of your head and neck condition or treatment, over the past FOUR WEEKS how much 
have you been BOTHERED by problems with… 
 
 
 Not at all 
   Slightly 
  Moderately 
     A lot 
  Extremely 
 
A. Volume of your voice 
 
 
B. Clarity of your voice 
 
 
C. Difficulty opening your mouth 
 
 
D. Dryness in your mouth while eating 
 
 

37 
 
2 (continued). As a result of your head and neck condition or treatment, over the past FOUR 
WEEKS how much have you been BOTHERED by problems with… 
 
 
 Not at all 
   Slightly 
  Moderately 
     A lot 
  Extremely 
 
 
E. Chewing food (for example, pain,  
difficulty opening or closing your mouth 
moving food in your mouth, or teeth or 
denture problems) 
 
F. Swallowing liquids 
 
 
G. Swallowing soft foods and/or solids 
 
H. Your ability to taste food (For example, 
loss of taste, and/or loss of appetite due to  
poor taste) 
 
I. 
Pain, burning, and/or discomfort in your  
mouth, jaw, or throat 
 
J. Shoulder or neck pain 
 
 
 
 
3. Over the past  FOUR WEEKS, how often did you take pain medication?... 
 
    Never  
    Rarely 
 Sometimes 
Frequently 
   Always 
 
 
 

38 
 
4. Over the past FOUR WEEKS how much have you been bothered by… 
 
 
 Not at all 
  Slightly 
Moderately 
 A lot 
Extremely 
 
A. Concerns or worries about  
Your appearance related to your head and 
neck condition or treatment 
 
B. Emotional problems related to  
your head and neck condition or treatment 
 
C. Embarrassment about your symptoms 
 
 
D. Frustration about your condition 
 
 
E. Financial worries due to medical problems 
 
 
F. Worries that your condition will get worse 
 
 
G. Physical problems related to your  
head and neck condition 
 
5. Were you working (employed)                           Yes  
 
     No 
prior to being diagnosed with cancer? 
 
 
 
 
 
If no, got to 
question 6 (next page) 
 
 
 
 
 
 
 
 
 
          Yes 
           No 
5A.  If yes, did your doctor declare  
you unable to work due to your head  
and neck condition or treatment? 
6. Have there been other problems related to your head and neck condition that were not 
mentioned?  If so, please write them in the space below and tell us how much this problem has 
bothered you.  (For instance, if your treatment included surgical transfer of tissue from a donor site 
to the head and neck, does the donor site bother you) 
 
 
    Not at 
all 
      Slightly 
  Moderately 
 A lot 
Extremely 
 
 
A. ________________________________ 
 
B. ________________________________ 
 

39 
 
C. ________________________________ 
 
 
7. For the past FOUR WEEKS, please rate 
your OVERALL amount of disturbance  
or BOTHER as a result of your head  
And neck cancer condition? 
 
8. Overall how satisfied are you with 
your Head and Neck cancer care at  
this Hospital? 
 
9. Overall how would you rate your response to treatment? 
 
 
     Poor 
       Fair 
       Good 
Very Good  Excellent 
 
 
 
 
10.  Approximately how long did it take you to answer this questionnaire? 
 
 
 
__________  Minutes 
 
 
 Not at all 
      Slightly 
  Moderately 
 A lot 
Extremely 
11.How difficult was it to complete  
this questionnaire? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

40 
 
tDCS Side Effects Questionnaire – Session_________________________ 
 
Patient Initials:  
 
 
 
Date: 
 
Do you experience 
any of the following 
symptoms or side 
effects? 
Enter a value (1-
4) in the space 
below.             1-
Absent                   
2-Mild                    
3-Moderate             
4-Severe 
If present: 
Is this 
related to 
tDCS?         
1-None       
2-Remote    
3-Possible   
4-Probable  
5-Definite 
Notes 
Headache 
  
  
  
Neck Pain 
  
  
  
Scalp Pain 
  
  
  
Scalp Burns 
  
  
  
Tingling 
  
  
  
Skin Redness 
  
  
  
Sleepiness 
  
  
  
Trouble 
Concentrating 
  
  
  
Acute Mood Change   
  
  
Other (specify): 
  
  
  
 
 
 
 
 
 
 
 

41 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

42 
 
 

43 
 
HOPE Pain Assessment Form 
 
 
 
 

44 
 
GeoPain App on iPad 
 
 
 
 

45 
 
 
 
 
 
 
 
 
 
 
 

46 
 
Positive and Negative Affect Schedule (PANAS-X) 
 
 
 
Subject ID: ______________ 
 
Date: ___________________ 
 
Positive and Negative Affect Schedule (PANAS-X) 
 
This scale consists of a number of words and phrases that describe different feelings and emotions.  Read each item and then mark the appropriate answer in 
the space next to that word.  Indicate to what extent you feel this way AT THIS MOMENT.  Use the following scale to record your answers. 
 
1 
2 
3 
4 
5 
Very slightly/not at all 
A little 
Moderately 
Quite a bit 
 Extremely 
 
  1. _____cheerful  
 
 
16. _____sad 
31. _____active 
46. _____angry at self 
  2. _____disgusted 
 
 
17. _____calm 
 
32. _____guilty 
47. _____enthusiastic 
  3. _____attentive 
 
 
18. _____afraid 
 
33. _____joyful 
48. _____downhearted 
  4. _____bashful 
 
 
19. _____tired 
34. _____nervous 
49. _____sheepish 
  5. _____sluggish 
 
 
20. _____amazed 
35. _____lonely 
50. _____distressed 
  6. _____daring 
 
 
21. _____shaky 
36. _____sleepy 
51. _____blameworthy 
  7. _____surprised 
 
 
22. _____happy 
37. _____excited 
52. _____determined 
  8. _____strong 
23. _____timid 
38. _____hostile 
53. _____frightened 
  9. _____scornful 
24. _____alone 
39. _____proud 
 54. _____astonished 
10. _____relaxed 
25. _____alert 
40. _____jittery 
55. _____interested 
11. _____irritable 
26. _____upset 
 
41. _____lively  
 56. _____loathing 
12. _____delighted 
27. _____angry 
42. _____ashamed 
57. _____confident 
13. _____inspired 
28. _____bold 
43. _____at ease  
58. _____energetic 
14. _____fearless 
29. _____blue 
44. _____scared 
59. _____concentrating 
15. _____disgusted with self 
30. _____shy 
45. _____drowsy 
60. _____dissatisfied 
 
 
 
 
          with self  
 
Watson, D., & Clark, L. A. (1994). The PANAS-X: Manual for the Positive and Negative Affect Schedule-Expanded Form. Ames: The University of Iowa.  

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Appendix C: Screenshot Remotely tDCS website set-up 
 
 

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