Boston-Harvard Burn Injury Model System: Cortical Modulation With Transcranial Direct Current Stimulation (tDCS) for Neuropathic Symptoms Following Burn Injury
Phase: NA
Conditions: Burn Injury, Chronic Pain, Pruritus, Itching
Sponsor: Spaulding Rehabilitation Hospital

Detailed Protocol 1 
 
ORGANIZATION OF DETAILED PROTOCOL 
 
Title: Boston-Harvard Burn Injury Model System: Cortical modulation with transcranial direct 
current stimulation (tDCS) for neuropathic symptoms following burn injury.  
Protocol #: 2012-p-001996 
Date: 03/21/2016 
 
I. 
BACKGROUND AND SIGNIFICANCE 
 
Pain and itch are two major long-term neuropathic symptoms that occur after burn injury, reported 
in as high as 70% of burn survivors with large burn injuries  (illustrated by collaborators Ryan[1] 
and Schneider[2], and others [3-11]). Psychological symptoms, including depression, anxiety, and 
PTS, are also a significant burden, affecting nearly 50% of burn survivors[12]. Furthermore, all 
the above complications play a large role in functional, psychosocial, and occupational outcomes 
[12-20], as illustrated by several of our collaborators [21-23]. Pain, itch, and psychological 
symptoms are primary causes of disability as well as significant barriers affecting burn survivors’ 
return to work, with 28% not employed at long term follow-up[15, 21]. The high prevalence rates 
of these complications underscore the ineffectiveness of current treatments [10, 24]. Additionally, 
there is a wide range of complications associated with current therapeutic approaches to pain, itch, 
and psychological symptoms, particularly with long-term use of narcotics and other medications 
[10, 24-28]. Thus there remains an unmet clinical need for safe and effective long-term treatments 
of these common burn injury problems.  
 
Pain, itch, and psychological symptoms are processed by common neural circuits, despite having 
distinct underlying mechanisms. Each is associated with a disruption of normal brain processing 
and they can affect one another[29, 30]. For example, psychological symptoms often increase 
when pain is present[31-37]. Furthermore, specific neural areas have been identified that impact 
pain, itch, and emotional processing[38-40]. Thus, treatments that target these common circuits 
offer a new potential therapeutic avenue for treatment of these refractory symptoms.  A recent Burn 
Care State of the Science review discusses the significant impact of pain, itch, depression, PTS, 
and community reintegration on burn injury patients and identifies the need for additional research 
in these areas[41]. 
 
There are clinical and neurophysiologic associations between pain, itch and psychological 
impairments [31, 32, 34-36, 42]. From a clinical perspective, investigators determined that chronic 
pain patients were often depressed or anxious, depressed and anxious patients often experienced 
chronic pain, and anxious pain patients were often already depressed; these associations suggest 
the interconnected nature of these problematic outcomes commonly found in burn survivors [35, 
36]. 
 
From a neurophysiological perspective, the connections between these symptoms are due to 
common neural structures that are highly activated in pain, itch, and psychological impairments. 
The insula, prefrontal cortex, anterior cingulate cortex, and amygdala are examples of neural areas 
associated with each condition. Several studies indicate this. For instance, Bar and colleagues [43] 
illustrated that there is a neural connection between emotional processing and pain; they assessed 
the effect of applied thermal pain on 13 patients with Major Depressive Disorder and 13 healthy 

Detailed Protocol 2 
 
controls. In comparison to healthy controls, depressed patients displayed significantly greater 
activation in their MRI scans in specific areas of the brain (Dorsolateral Prefrontal Cortex 
(DLPFC), Ventrolateral Prefrontal Cortex, thalamus, and insula) and a strong increase in blood 
flow to these areas. Itch pathways are also shared with emotional and pain processing pathways 
[38]. In a study of 6 healthy subjects with clinically induced itch sensations on their forearms, MRI 
scans revealed significant activation of the primary sensory cortex areas, an area also associated 
with emotional processing. [38] These studies illustrate the common neural circuits of pain, itch 
and psychological symptoms. In summary, burn injury is associated with plastic changes in the 
brain that cause neural dysfunction (see figure); the presence of pain, itch, and/or psychological 
problems can amplify processing of each other due to shared neural structures. It is because of this 
dysfunction that current treatments are limited, as they do not directly target these shared areas of 
the brain [44, 45].  
 
 
                                                                                                                                                               
The development of a safe and powerful method of noninvasive brain stimulation for treatment of 
pain using transcranial direct current stimulation (tDCS) can have beneficial effects in these 
clinical outcomes that have a significant impact on the burn population. Prior research has also 
shown its beneficial effects on neuropathic [46] (i.e. pain and itch) and psychological symptoms 
[47-53]. Our laboratory is a world leader in noninvasive brain stimulation methods, particularly 
for rehabilitation populations [47, 48, 50-52, 54-64]. This safe, low-cost technique reverses some 
of the maladaptive brain changes described above. Numerous studies, including many from our 
group, have confirmed the safety of this technique [51, 52, 54, 55, 65-70] and its effect to reduce 
pain[54-56, 60, 62]. We also performed a pilot study examining tDCS in burn patients with pain 
and found the intervention to be a safe, well-tolerated, and feasible intervention in this population 
Dysfunction of Neural Pathways in Burn 

Detailed Protocol 3 
 
[46]. Finally, we have shown using EEG assessments that tDCS induces measureable changes in 
the brain (as proposed in this protocol)[59].  
 
Contributions to the Field of Burn Injury Rehabilitation: Given encouraging preliminary results 
and a burgeoning interest in burn injury outcomes [5, 71, 72], there is a pressing need to assess the 
effects of tDCS on burn pain, itch, and psychological symptoms in an appropriately-designed 
clinical trial. The degree and duration of pain reduction itch reduction, and psychological symptom 
improvement after tDCS treatment remains unknown in this population, as well as the effects of 
repeated applications of tDCS. Additionally, there are no studies measuring the effects of tDCS on 
functional outcomes such as employment, community integration, and quality of life. This study 
will seek to fill these gaps in knowledge, and in the process will develop this device for clinical 
use. This study may also lead to future testing for portable use, such as at home. This would provide 
a cheap, simple, and safe noninvasive treatment for these common complications of burn injury. 
 
tDCS: A Powerful Tool to Induce Plastic Changes in the Brain:  tDCS is a noninvasive method of 
brain stimulation, based on the application of a weak direct current to the scalp, which runs 
between an anode and cathode electrode . During tDCS treatment low amplitude direct current, 
applied via scalp electrodes, enters the brain. A sufficient current penetrates the brain to modify 
the potential of neurons to fire, despite shunting of current by the scalp and skull[73]. tDCS thus 
influences the level of cortical excitability and modulates the firing rate of neurons in targeted 
areas of the brain. When applied for a sufficient duration, tDCS can alter brain function beyond 
the stimulation period [74], creating lasting and cumulative effects. Recent human studies have 
confirmed that anodal stimulation increases cortical excitability while cathodal stimulation 
decreases it [66, 74, 75].  
 
tDCS offers many advantages as a therapeutic tool: (1) Small-sized electrodes and stimulator 
allows portable home use for immobile patients unable to travel to appointments or those living in 
remote locations; (2) tDCS is a simple and inexpensive technique that can easily be translated for 
use in clinical practice; (3) tDCS induces current in cortical areas [73, 76, 77] that result in 
significant modulating effects. For instance, 13 minutes of tDCS stimulation can modify brain 
excitability for up to 2 hours[74, 78]; (4) tDCS is a safe technique; (5) Compared to 
pharmacological approaches, tDCS treatment targets focal brain areas, avoiding systemic adverse 
effects[79]; and (6) Anodal tDCS of a single brain region, the DLPFC, can induce clinically 
significant effects on three major symptom groups relevant to the burn population: pain, itch, and 
psychological symptoms. 
 
EEG is another common noninvasive technique used for measuring electrical activity of the brain 
and continuous plastic changes. It provides an objective understanding of the effects of electrical 
activity on different areas of the brain, such as those induced by tDCS. EEG only measures brain 
activity and does not induce electrical current. This technique is noninvasive and has been used 
extensively in clinical practice for diagnosis of neurological conditions. There are no risks 
associated with EEG other than mild discomfort caused by the tightness of the net holding the 
electrodes in place, which can be easily adjusted 
 

Detailed Protocol 4 
 
Given the critical need to develop new therapeutic approaches for patients suffering from chronic 
neuropathic pain due to burn injuries, the goal of this proposal is to investigate a novel 
therapeutic approach using brain stimulation to treat these patients. 
 
II. 
SPECIFIC AIMS 
 
The overall goal for this project is to develop a novel treatment using transcranial direct current 
stimulation (tDCS) for patients with neuropathic burn symptoms such as pain or itching. Because 
the interventions to date for this group of patients (mainly drugs) have been marked by limited 
clinical effectiveness [14], the results of this study will represent an initial, significant step toward 
providing a new therapeutic alternative to this group of patients. Finally we will also collect 
neurophysiological data to understand further the mechanistic effects of this novel intervention 
and compare with the use of tDCS for other chronic pain syndromes. 
 
The following aims will be explored in this study: 
 
Aim 1 - To assess the effects of tDCS treatment on neuropathic symptoms: pain or itching – 
following burn injury. We will determine the magnitude of pain reduction with the modified Brief 
Pain Inventory (BPI) and itch severity/activity with the Visual Analog Scale (VAS) and 5-D Scales 
in active tDCS compared with sham tDCS. Our first hypothesis is that active tDCS will be 
associated with a larger pain or itching reduction assessed by BPI and Itch VAS/5-D.  
 
Aim 2 - To assess the impact of tDCS treatment on the psychological outcomes of depression, 
PTS, and anxiety. We will determine the severity of depression with the Beck Depression 
Inventory (BDI), PTS symptoms with the Impact of Event Scale Revised (IES-R), and anxiety 
symptoms with VAS for anxiety, in active versus placebo stimulation.  Our second hypothesis is 
active tDCS will have a greater effect on physiologic outcomes at 12 months as compared to 
placebo tDCS treatment in subjects with burn injury  and psychological symptoms.   
 
Aim 3 - To assess the impact tDCS treatment on functional outcomes, including quality of life, 
community integration, sleep, and employment. Due to its effects on pain, itch, and psychological 
symptoms, we expect that tDCS treatment will result in significant gains in functional outcomes 
such as qualify of life, community integration, and employment. We will determine overall quality 
of life using the veterans RAND 36 Item Health Survey (VR-36), community integration using the 
Community Integration Questionnaire (CIQ), and return-to-work with a simple employment status 
questionnaire. We will evaluate sleep using Pittsburgh Sleep Quality Index (PSQI), Insomnia 
Severity Scale (ISS), VAS sleep scale, and a short sleep diary. We will look at the difference 
between active versus placebo stimulation. Our hypothesis is if active tDCS will have a greater 
effect on functional outcomes at 12 months compared to placebo tDCS in subjects with burn injury 
pain. 
 
Aim 4 - To determine the measurable brain changes that occur in burn pain and how they are 
impacted by tDCS vs. placebo treatment, using a device that quantifies cortical activity (EEG). We 
will examine brain plasticity changes with auditory and somatosensory Event Related Potentials 
(ERPs), using the EEG device as a neural activity marker. The somatosensory ERP will be the 
third secondary outcome. We hypothesize that active tDCS will decrease somatosensory ERP 

Detailed Protocol 5 
 
amplitudes as compared to placebo in patients with burn pain and that changes in ERPs will 
correlate with other primary outcomes. 
 
Aim 5 - To assess the cost/effectiveness of the impact of a 10-and 5 day period of tDCS treatment 
on cost per quality adjusted life saved using the pain visual analogue scale and VR-6D/VR utility 
metric as compared with sham tDCS. 
 
III. 
MEDICAL MONITOR 
 
 
 
Responsibilities of the Medical Monitor 
 
 
The medical monitor is required to review all unanticipated problems involving risk to subjects or 
others, serious adverse events and all subject deaths associated with the protocol and provide an 
unbiased written report of the event.  At a minimum, the medical monitor must comment on the 
outcomes of the event or problem and in case of a serious adverse event or death, comment on the 
relationship to participation in the study.  The medical monitor must also indicate whether he/she 
concurs with the details of the report provided by the principal investigator.   
This person must also be available by pager during the course of each study session. 
 
Medical Monitor:   
Nevena Zubcevik, DO 
Professor, Department of Physical Medicine and 
Rehabilitation, Harvard Medical School 
 
 
IV. 
SUBJECT SELECTION 
 
We will select 60 subjects that have burn injury and meet the following criteria: 
 
Inclusion Criteria: 
1. Providing informed consent to participate in the study 
2. Age 18 or older 
3. Burn injury with pain and/or itch that is moderate to severe (at least 4 on the visual analogue 
scale during the previous 3 weeks)  
4. Burn injury occurred at least 3 weeks prior to enrollment. Patient must be discharged from 
acute inpatient care.  (Patient can be enrolled in either inpatient rehabilitation and/or 
outpatient care) 
 
Exclusion Criteria: 
1. Subjects with burns in scalp in the area of electrode placement (i.e. within 4 cm of the 
DLPFC and the reference site) as the electrode may cause irritation to the injuries 
2. Psychiatric disorders that have led to hospitalization within the past 6 months or signs of 
suicidality 
3. Learning disorders that may affect the patient’s ability to complete assessments. 
4. Unstable conditions preventing travel to the study site 

Detailed Protocol 6 
 
5. Current use of any anti-epileptic medications or dopaminergic medications known to 
reduce or inhibit the benefits of tDCS treatment: carbamazepine, oxcarbazepine, phenytoin 
6. Contraindications to tDCS including implanted metal plates in the head or implanted brain 
medical devices 
7. Pregnancy 
8. History of other neurological conditions associated with structural anatomical changes (i.e. 
stroke, brain injury, Parkinson’s)  
 
All subjects receiving outpatient and inpatient care at SRH are eligible for the study and will be 
sought to participate through publicity flyers. SRH provides outpatient services to the Boston area 
so we anticipate our recruitment procedures will reflect the distribution of races/ethnicities in the 
surrounding communities.  
 
The safety of tDCS in the pregnant population has not been assessed and therefore pregnant women 
will be excluded. Women of child-bearing potential will be required to take a urine pregnancy test 
during screening process as well as at the end of each week of stimulation. If a subject becomes 
pregnant during the course of the study, she will be withdrawn from the study. 
 
Concurrent Pain Medication Use: Although pain medications can confound the effects of tDCS, 
we consider it to be unethical to require subjects to discontinue pharmacologic treatment for pain 
over the course of the study as a criterion for enrollment. In addition, to increase generalizability, 
it is important to recruit subjects using pain medications. Therefore, we will require subjects (who 
enroll as an outpatient) to maintain stable doses of pain medications for at least 1 month prior to 
beginning the study and to not introduce new drugs during the trial. For those who enroll in the 
study as an inpatient, we understand that it may not be possible to keep stable doses of medications. 
Thus, we will notify the patient’s physician and nurses of his/her participation in the study to 
facilitate participation. We will track any medication changes as they may occur.  We will not 
withdraw the subject if he/she must change medications/dosage. However, if any subject begins 
on any medications as listed above in the exclusion criteria, he or she will be withdrawn from the 
study. 
 
 
 
V. 
SUBJECT ENROLLMENT 
 
Potential subjects will be identified by the following sources: 
 
1. Attending physicians may refer their neuropathic burn pain or itching patients to the study. 
Patients should not be in acute care hospital; subjects may be recruited from inpatient 
rehabilitation and outpatient care. We will provide collaborating physicians with study 
information sheets and flyers.  
• Medical records may be pre-screened to identify potential subjects to be seen by 
collaborating physicians in-office, such that the approved recruitment materials can 
be provided to the physician (i.e., study letter and information summary sheet) prior 
to the scheduled appointment. Study staff will not contact potential subjects 
directly.  Collaborating physicians will provide the prospective subjects with the 

Detailed Protocol 7 
 
approved study material, and encourage prospective subjects to contact a co-
investigator on this study, if they have interest or questions regarding the trial. 
2. Flyers posted in the outpatient specialist clinics, and around the Boston area. 
3. Internet advertisements posted on websites. 
4. Via the Partners Research Patient Data Registry (RPDR)  
5. We will register this study on ClinicalTrials.gov. 
6. Patients who agree to be contacted for research through the National Database portion of 
the BH-BIMS Model System 
7. Email distribution lists 
 
 
Eligible subjects will contact or give permission to be contacted by a co-investigator to obtain 
more information about the study and give informed consent. At the first point of contact (usually 
a phone call), study co-investigator will administer a phone screening questionnaire, which will 
involve some sensitive medical information. Once the phone screening process is complete, the 
information gathered by the co-investigator will be taken to the PI of the study for further review. 
Additionally, the consent form and other study materials will be sent to the subject in advance, so 
that they may consider the details of the study prior to enrollment. Once the PI agrees that the 
subject is thus far eligible, the subject will then again be reached to schedule their first visit. Data 
obtained from screening will be stored in a locked filing cabinet in the lab. 
 
Informed consent will be obtained by an investigator (not involved in the subject’s care) at SRH. 
The subject will meet with a co-investigator. The test procedures will be described and the 
testing equipment will be shown to the subject. A co-investigator will clearly explain all the 
procedures and risks of the testing outlined in the consent form. The study will be divided into 
three parts: Part I (Visit 1), Part II (Visit 2-14), and Part III (Visit 15-23). Subjects will consent 
to participate to each part one at a time. It will be explained to them that they will have the 
option to enroll in later parts of the study if they desire. Completion of each preceding part of the 
study will be required prior to enrollment into the next part.  
 
A separate consent form will be needed for each three parts of the enrollment. For each part, the 
subject will be given an hour to consider their decision and will be encouraged to ask questions, 
both during the initial interview and throughout the study. The PI or a co-investigator will 
answer any questions regarding the study at the time consent is given.  Once enrolled, the subject 
may pause or terminate his/her participation at any time during the study. 
 
Informed Consent Procedure: 
 
The following outlines the consenting process (also see diagram in following page): 
 
• Part I: Subjects will be first presented with the option to enroll into Part I (Visit1) only of 
the study. They will be explained that at the completion of Part I, they retain the ability to 
decline or further enroll into Part II (Visits 2-14) and then Part II (Visits 15-23). The study 
visit of Part I will be fully explained as well as a summary of what will happen in Parts II 
and III should they decide to continue and the overall purpose of the study. They will sign 
a consent form for this phase of the study (Part I) 

Detailed Protocol 8 
 
• Part II: For subjects continuing to Part II, they will be told at this completion of this part, 
they retain the ability to decline or further enroll into Part III (Visits 15-23). Each study 
visit of Part II will be fully explained as well as a summary of what will happen in Parts III 
should they decide to continue and the overall purpose of the study. They will sign a 
separate consent form for this phase of the study (Part II). 
• Part III: At the completion of Part II, subjects will again be presented to either decline 
further participation or enroll into Part III (V15-V23) of the study. The study visits of Part 
II will be fully explained and the overall purpose of the study. They will sign a separate 
consent form for this phase of the study (Part II. 
 
 
 
VI. 
STUDY PROCEDURES 
 

Detailed Protocol 9 
 
We will select sixty participants that have burn injury and meet the inclusion criteria proposed. 
Study visits will take place at either Spaulding Rehabilitation Hospital (SRH) or Spaulding 
Rehabilitation Network Research Institute (SRN-RI). Subjects will be thoroughly informed of their 
study visit location prior to enrollment. 
 
Please note: for subjects who enroll as inpatient into the study, we will coordinate with the 
appropriate care outlets to ensure that the procedures of the study will not interfere with their 
standard of care. This includes, but is not limited to: physicians, therapists and nurses working 
with the patient. We will schedule inpatients as their clinical schedule allows – preferably after 
3pm – unless the patient specifies otherwise. We will also attempt to target patients toward the 
end of their rehab stay when they are less medically complicated (ex. fewer changes in 
medications/treatments etc.) and may be more independent in their travel. When 
possible/feasible, we will also complete study visits in the patients’ room in order to limit time 
off of the floor. 
 
Subjects will receive either (i) active tDCS; or (ii) sham tDCS in a randomized double blind 
design. Randomization assignment will be kept in a locked cabinet accessible only to the unblinded 
study investigator.  
 
The study will occur in three parts, where the subject consents to Part I (Visit 1), then if they 
choose to continue, they may consent to Part II (Visits 2-14). After completion of Part II, they 
may then choose to consent to Part III (Visits 15-23).  
 
If the subject receives sham stimulation over his/her participation, he/she may re-enroll to an open-
label portion of the study to receive 10 sessions of active tDCS stimulation. 
 
Part I Study Flow: 
o 1 Visit (Baseline) only  
 
Part II Study Flow: 
o 10 sessions of tDCS stimulation over 2 weeks 
o 3 Follow-up visits (over a period of about 2 months) – at approximately 2, 4 and 8 
weeks after the first 10 sessions of stimulation 
 
Part III Study Flow: 
o 5 sessions of tDCS over 1 week 
o 3 Follow-up visits (over a period of about 2 months) – at approximately 2, 4, and 
8 weeks after the final 5 sessions of stimulation. 
o 1 Final Follow-up visit at about 12 months after you enroll in Part I of the study. 
 
 
Pre-screening Procedures: 
During the pre-screening process, the subject will contact a co-investigator of the study by phone. 
During this call, the co-investigator will discuss in greater depth the details of the study. In the 
privacy of the laboratory, the co-investigator will ask the subject questions from the following: 
1) Phone screening questionnaire 

Detailed Protocol 10 
 
2) tDCS contraindications checklist 
 
If a subject indicates feelings of suicide during screening (responds yes to the question “Do you 
have feelings of suicide?”), the subject will be provided with information on how to contact the 
MGH ED Acute Psychiatry Service.  
 
Once this information is collected, the co-investigator will consult with the principal investigator, 
who will give final approval for the subject to come to Spaulding for the screening procedure. The 
pre-screening process will last approximately half an hour. 
 
 
Detailed Study Outline: 
 
Part I Visit (V1) 
 
Visit 1 (approx. 2 hours) 
Screening and Baseline 
 
Screening Procedures: a review of inclusion/exclusion criteria will be conducted to determine the 
subject’s eligibility for enrollment. Study procedures will be reviewed with the subject, and 
documentation of informed consent for Part I will be obtained. During screening the following 
procedures will be completed: 
 
• 
Discuss study-specific procedures with the subject  
• 
Review inclusion and exclusion criteria  
• 
Obtain a signed and dated consent form. 
• 
Urine pregnancy exam (if applicable) 
• 
Randomization  
 
Randomization: Subjects will be randomized to either receive active or sham tDCS treatment 
through a randomization approach using random blocks of 4 and 6.  
Stimulation assignment will be concealed from patients, clinicians, and research staff. 
 
Baseline Assessment: If the subject is found to be eligible through the screening and consent 
process, and enrolls in the study, the following baseline assessments will take place during this 
visit: 
 
o Demographic Data Collection 
o Visual Analog Scale (VAS) for anxiety 
o Brief Pain Inventory (BPI) 
o Visual Analog Scale (VAS) for itching severity and activity 
o For patients reporting itch, we will also use the Questionnaire for pruritus assessment 5-D 
Itch scale [80]  
o Beck Depression Inventory (BDI) 
o Impact of Event Scale  Revised (IES-R) 
o Veterans RAND 36 Item health survey (VR-36) 

Detailed Protocol 11 
 
o Community Integration Questionnaire 
o Primary and Secondary Employment status 
o Pittsburgh Sleep Quality Index (PSQI) 
o Insomnia Severity Scale (ISS) 
o VAS Sleep 
o Measurement of brain changes using EEG to quantify the cortical activity 
 
Part II Visits (V2 through V14) 
 
Visit 2-11 (approx. 1 hour) 
Stimulation Visits 
 
Before the stimulation session, the subject will complete:  
o Explain and give the subjects a pain medication diary which they will keep for the duration 
of the study 
o Review Pain Medication Diary [Visit 11 only] 
o Review Sleep, pain and/or itch Diary [Visit 11 only] 
o Visual Analog Scale (VAS) for anxiety  [Visit 11 only] 
o Brief Pain Inventory (BPI) [Visit 11 only] 
o For patients reporting itch, we will also use the Questionnaire for pruritus assessment 5-D 
Itch scale [Visit 11 only] 
o Beck Depression Inventory (BDI) [Visit 11 only] 
o Visual Analog Scale (VAS) for itching severity and activity [Visit 11 only] 
 
Stimulation Session: 
- Subjects will be randomly allocated to receive either active or sham tDCS 
• Active Transcranial Direct Current Stimulation (tDCS): Stimulation will occur with the 
anodal electrode placed over the primary motor cortex (contralateral to the most (or 
predominant) painful side) and the cathode will be placed over the contralateral supra-
orbital area. The primary motor cortex will be localized using the 10/20 EEG system (C3 
or C4) and this is a reliable method for the technique of tDCS [54]. This is the montage 
that had positive results in two trials using tDCS to treat chronic pain [54, 81]. In active 
tDCS, 2 mA of transcranial direct current stimulation will be applied for 20 minutes. The 
electrodes will have the size of 35cm2 each. Furthermore, current intensity will be 
gradually increased at the beginning of the session, and decreased at the end of the 
session to diminish its perception. 
• Sham tDCS: For sham tDCS, the same montage will be used; however current will be 
applied only for 30 seconds – It should be noted that less than 3 minutes of tDCS induces 
no effects on cortical excitability (Nitsche et al., 2000) and also using 30 seconds of sham 
is a reliable method of blinding as shown by a randomized controlled study [82]. 
 
After the stimulation, the subject will complete: 
• 
tDCS Side Effects Questionnaire 
 
Visit 12-14 (approx. 1 ½ hour) 

Detailed Protocol 12 
 
Follow-up Visits – will occur at 2 weeks (+/- 7 days), 4 weeks (+/- 10 days), and 8 weeks (+/- 10 
days) post-stimulation 
 
During these visits, the subject will complete: 
o Review Pain Medication Diary 
o Review Sleep Diary [Visit 12 only] 
o Visual Analog Scale (VAS) for anxiety   
o Brief Pain Inventory (BPI) 
o Visual Analog Scale (VAS) for itching severity and activity   
o For patients reporting itch, we will also use the Questionnaire for pruritus assessment 5-D 
Itch scale 
o Beck Depression Inventory (BDI) 
o Veterans RAND 36 Item health survey (VR-36) 
o Impact of Event Scale  Revised (IES-R) 
o Community Integration Questionnaire 
o Primary and Secondary Employment status 
o Pittsburgh Sleep Quality Index (PSQI) [Visit 12 only] 
o Insomnia Severity Scale (ISS) [Visit 12 only] 
o VAS Sleep [Visit 12 only] 
o EEG 
 
Part III visits (V15 through V23) 
 
Visit 15-19 (approx. 1 hour) 
Stimulation Visits 
 
Before the stimulation session, the subject will complete: 
o Review Pain Medication Diary [Visit 19 only] 
o Visual Analog Scale (VAS) for anxiety  [Visit 19 only] 
o Brief Pain Inventory (BPI) [Visit 19 only] 
o Beck Depression Inventory (BDI) [Visit 19 only] 
o Visual Analog Scale (VAS) for itching severity and activity  [Visit 19 only]  
o For patients reporting itch, we will also use the Questionnaire for pruritus assessment 5-D 
Itch scale [Visit 19 only] 
 
Stimulation Session: 
The subject will undergo 20 minutes of tDCS stimulation (either active or sham) 
 
After the stimulation session, the subject will complete: 
o Adverse Effects Questionnaire Validation of blinding [Visit 19 only] 
o tDCS Side Effects Questionnaire 
 
Visit 20-23 (approx. 1½ hour) 
Follow-up Visits – will occur at 2 weeks (+/- 7 days), 4 weeks (+/- 10 days), and 8 weeks (+/- 10 
days) post-stimulation. Visit 23 occurs 52 weeks post-enrollment (+/- 1 month). 
During these visits, the subject will complete: 

Detailed Protocol 13 
 
o Review Pain Medication Diary 
o Visual Analog Scale (VAS) for anxiety   
o Brief Pain Inventory (BPI) 
o Visual Analog Scale (VAS) for itching severity and activity   
o For patients reporting itch, we will also use the Questionnaire for pruritus assessment 5-D 
Itch scale 
o Beck Depression Inventory (BDI) 
o Veterans RAND 36 Item health survey (VR-36) 
o Impact of Event Scale  Revised (IES-R) 
o Community Integration Questionnaire 
o Primary and Secondary Employment status 
o EEG 
 
Summary of Study visits 
 
Part I 
Part II of Trial 
Part III of Trial 
Baseline 
Stimulation 
Follow-
up 
Stimulation 
Follow-
Up 
V1 
V2-
10 
V11 
V12-14 
V15 -
18 
V19 
V20-23 
Consent/Screening,  
Demographic data 
X 
 
 
 
 
 
 
Visual Analog Scale for anxiety 
X 
 
X 
X 
 
X 
 
Brief Pain Inventory 
X 
 
X 
X 
 
X 
X 
Visual Analog Scale for itch severity 
and activity (for patients reporting 
itch only ) 
X 
 
X 
X 
 
X 
X 
5-D scale (for patients reporting 
itching only) 
X 
 
X 
X 
 
X 
X 
Beck Depression Inventory (BDI) 
X 
 
X 
X 
 
X 
X 
Impact of Event Scale Revised (IES- 
R) 
X 
 
 
X 
 
 
X 
Veterans RAND 36 item Health 
Survey (VR-36) 
X 
 
 
X 
 
 
X 
Community Integration 
Questionnaire (CIQ) 
X 
 
 
X 
 
 
X 
Primary and Secondary Employment 
status 
X 
 
 
 
X 
 
 
X 
Pittsburgh Sleep Quality Index 
(PSQI) 
X 
 
 
X 
 (V12 only) 
 
 
 
Insomnia Severity Index 
X 
 
 
X  
(V12 only) 
 
 
 
VAS Sleep 
X 
 
 
X  
(V12 only) 
 
 
 
Sleep, pain and/or itch diary (to 
review) 
 
X 
X 
X 
 (V12 only) 
 
 
 
Medical History Form 
X 
 
 
 
 
 
 
tDCS stimulation & Side Effects 
 
X 
X 
 
X 
X 
 
Blinding Assessment 
 
 
 
 
 
X 
 
Pain Medication Diary (to review) 
X 
 
X 
X 
 
X 
X 
Assessment of cortical activity 
(EEG) 
X 
 
 
X 
 
 
X 
Approximate Visit Time 
2 hours 
1 hour 
1 ½ 
hours 
1 hour 
1 ½ 
hours 

Detailed Protocol 14 
 
 
DESCRIPTION OF ASSESSMENTS 
 
Demographic Assessment: We will record the following baseline characteristics: age, sex, 
race/ethnicity and level of education. 
 
VAS for Anxiety: This is a self-evaluation scale that ranges from 0 to 10, where 0 means no 
anxiety and 10 means the worst anxiety ever. This scale is used extensively in our tDCS studies 
[46, 54-56, 60, 62]. 
 
Modified Brief Pain Inventory (BPI) – main outcome: The BPI is a short self-assessment 
questionnaire that provides information on various dimensions of pain including how pain 
developed, the types of pain a patient experiences, and time of day pain is experienced, as well as 
current ways of alleviating pain [83]. The BPI also consists of the VAS Pain scale, a simple 10- 
point scale (0 = ‘‘no pain’’, 10 = ‘‘pain as bad as you can imagine’’) measuring a patients’ worst 
pain and least pain, on average and at present time. The Brief Pain Inventory provides information 
on the intensity of pain (the sensory dimension) as well as the degree to which pain interferes with 
function (the reactive dimension). According to several previous studies on pain in spinal cord 
injury, the BPI is an effective measure, as shown by both our group [54] and other studies [84] 
 
Itching Severity: We will measure severity of itching using a VAS for itching severity. This is a 
0 to 10 scale, where 0 indicates no intensity and a 10 indicates unbearable intensity of itching. This 
scale has been previously used in a study investigating treatment of refractory itching in burn 
patients. We will also have subjects keep a record of itching/pain severity using this scale in a 
diary through visit 12. 
 
Itching Activity: We will also measure scratching activity using VAS for scratching activity. This 
is a 0 to 10 scale, where 0 indicates no activity of scratching and a 10 indicates frequent scratching 
activity. This scale has been previously used in a study investigating treatment of refractory itching 
in burn patients. We will also have subjects keep a record of itching/pain activity using this scale 
in a diary through visit 12.  
 
5-D Itch scale: We will use this scale to measure five dimensions of itch: degree, duration, 
disability, and distribution. It is a valid and reliable for measuring itch and changes in itch over 
time 
 
Beck Depression Inventory (BDI): The Beck Depression Inventory (BDI) is a 21-item test 
presented in multiple-choice format that measures the presence of and the degree of depression in 
adults [85]. If an enrolled subject gives a response of a of 1, 2 or 3 on question 9 on the BDI, the 
subject will be withdrawn from the study and the medical coverage will be contacted immediately 
by research staff to provide further evaluation and action to protect the subject (i.e. if the subject 
needs to be escorted or referred to the MGH ED Acute Psychiatry Service). 
 
 
Impact of Event Scale Revised (IES-R): This 22-item scale is designed to measure severity of 
PTS symptoms associated with a traumatic event. These symptoms correspond to the symptoms 

Detailed Protocol 15 
 
contained within the DSM-IV. Subjects are asked to rate their level of distress associated with the 
event on a 0-4 scale (0 means not at all distressed, 4 means extremely distressed). This scale has 
been extensively validated[86] 
 
Veterans RAND 36 Item Health Survey (VR-36): The VR-36 was developed by our 
collaborators [87]. This survey was developed from the Veterans Health Study and includes both 
physical and psychological domains as a measure of overall quality of life. There are eight domains 
total including: bodily pain, role limitations due to physical problems, physical functioning, 
general health perception, vitality, social functioning, and role limitations due to mental health 
issues. This measure is valid and reliable[87].  
  
Community Integration Questionnaire (CIQ): This instrument measures home integration 
competency, social integration, and productive activity[88]. It assesses levels of independence and 
interdependence. It includes questions about leisure activities, social interactions, travel/mobility, 
and daily activities; it contains a rating scale of how easily these items are accomplished (i.e. 
often/never, done alone/done with someone else, full time/not applicable).  This assessment has 
been validated for use[88]. 
 
Primary and Secondary Employment Status: As part of the vocational sub-aim of this study, 
we will assess the employment status, and in particular the intention to seek employment, of each 
subject. Codes include: unemployed, unemployed but searching for work, part time or full time 
student, employed, or retired. These are the same employment rating scale codes used already in 
the model systems database. 
 
Sleep Assessments: We will measure sleep outcomes using the Pittsburgh Sleep Quality Index, 
Insomnia Severity Scale, and VAS for sleep. We will also have the subjects keep a very short diary 
looking at sleep for the first 4 weeks of the study. 
 
Medication Use Questionnaire and Diary: We will obtain a medication use history at study entry 
using a standardized questionnaire similar to that used in our prior tDCS studies, and update this 
information at each subsequent visit. We will also monitor patient medication throughout the 
course of the study using a subject Medication Diary. Participants will be required to record 
medications daily in a pain medication diary. Participants will be instructed to keep the pain 
medication diary throughout the baseline, treatment, and follow-up period. This diary will be 
maintained until completion of the study. 
 
tDCS Stimulation Side Effects Questionnaire: At each stimulation session, subjects will 
complete a questionnaire to evaluate potential adverse effects of tDCS (tingling, burning sensation, 
headache, neck pain, mood alterations) on a 5-point scale. The scale will also be administered at 
follow-up. Subjects will be asked whether they have experienced any side effects in an open-ended 
manner and they will be specifically asked about headache, neck pain, scalp pain, burning 
sensation, tingling, skin redness, sleepiness, trouble concentrating, and acute mood change. If any 
side effects are reported, the degree of relatedness to the tDCS intervention will be assessed. 
 

Detailed Protocol 16 
 
Validation of blinding: This questionnaire asks the rater and subjects whether treatment was sham 
or active tDCS. Respondents will rate their level of confidence for their response on a scale of 0 
to 5, with 0 representing no confidence and 5 representing total confidence. 
 
Cortical activity assessment with electroencephalogram (EEG): EEG activity will be assessed 
in all participants using standardized procedures EEG will be sampled using an electrode cap, 
which places the electrodes in the standard 10-20 international placement system.  Ground 
electrode is built into the cap and will be at site AFZ.  All electrodes are recorded as active so that 
various montages may be examined post recording for accuracy of data inclusion.  EEG analysis 
will be performed with a linked ear reference montage and a weighted average reference montage.  
In addition to baseline data, the subject will complete two tasks for measurement of event related 
potentials. 
 
 
VII. 
STATISTICAL ANALYSIS 
 
As study outcomes will be measured at baseline and several timepoints up to 12 months (post-
enrollment), continuous and categorical outcomes will be analyzed by methods of longitudinal 
analysis using generalized estimating equations with an unrestricted covariance matrix, to estimate 
model parameters and test hypotheses. Tests of equality of the change from baseline to 12 months 
in the two treatment groups will be based on the estimate of the time (12 months versus baseline) 
by treatment interaction. This will allow participants who are seen at some follow-up visits but not 
at 12 months to contribute to the analysis. Time to event variables such as time to return-to-work 
will be analyzed by proportional hazards regression and Kaplan Meier estimation of time to event 
distributions. 
Midway through the study, a power analysis will be performed to reassess the sample size needed 
to successfully complete this project. In this analysis, we will only look at the variability 
parameters (variance) and compare it to the one estimated before the study. We will not look at 
the effect estimates and therefore do not anticipate Type I error increase.  This power analysis will 
be performed by a staff member (Co-Investigator) not involved with the analysis and conduct of 
the study. All blinded staff members will remain blinded. 
The primary endpoint for this study is pain intensity as measured by the BPI. The study will have 
three secondary endpoints: itch as measured by the VAS scale, depression as measured by BDI 
and neural activity changes measured by somatosensory ERPs. These secondary outcomes 
represent three domains in which tDCS are anticipated to be effective. The same analytic approach 
will be employed in the analysis of the primary and secondary outcomes. For the outcomes, 
exploratory univariate analysis comparing active vs. placebo tDCS will be conducted. If a 
significant treatment effect is detected, similar adjusted longitudinal regression analysis will be 
performed; however these analyses will be considered hypothesis generating a p values interpreted 
cautiously given the increased likelihood of a false positive result given the false positive problem. 
 
The sample size was chosen to test the null hypothesis of no treatment on the BPI with a power of 
0.8 to detect a clinically meaningful treatment effect. We specified a two sided Type 1 error rate 
of 0.05 for all analyses. Assuming that the between-patient standard deviation of BPI from baseline 

Detailed Protocol 17 
 
to 12 months will be 1.2, a completed sample size of 52 will achieve power of 0.8 to detect a 
difference in mean change of BPI between treatment groups of 0.96, that is, an effect size of 0.8. 
Anticipating that retention will be sufficient to achieve at least 85% of the precision provided by 
complete follow-up of all participants, the study will enroll 60 participants. For the secondary 
endpoints, assuming no adjustment for multiple comparisons, the study will again have power of 
0.8 to detect effect size of 0.8. 
 
All primary analyses will employ the intent-to-treat approach.  If there is appreciable non-
adherence to the tDCS treatment protocol, exploratory analyses based on per-protocol methods 
will also be performed.  In multivariate analysis, we will adjust for important baseline variables, 
including medication use, age and baseline clinical severity using regression models.  
 
In exploratory analyses, we will employ structural equation modeling[89] to investigate the extent 
to which effects of treatment on pain, itch, and psychological outcomes are mediated through 
shared pathways represented by latent variables.  Mediation analysis[90] will be employed to 
investigate whether changes in pain are due to direct effects from tDCS or indirect tDCS-induced 
changes in psychological and functional outcomes (see figure, regarding Mediation Analysis—
MacKinnon 2007[90]). A direct effect of tDCS on pain is implied if the treatment effect (active 
vs. placebo tDCS) cannot be substantially explained by changes in psychological or functional 
outcomes. 
    
Data forms and questionnaires will be coded in a standardized manner, and double-entered into 
the Research Electronic Data Capture (REDCap). The PI will oversee quality assurance of forms 
and study databases. Analyses will be conducted using SAS 9.3 and Stata 11. 
 
We plan to calculate an incremental cost-effectiveness ratio (ICER) of the costs in dollars per unit 
of health gained or QALY gained for each of the arms. We can compare the difference of the 
differences of the two arms using the ICER for the RCT (tDCS treatment as compared with Sham 
tDCS). Separate stratified analysis also will be done for a 10- and a 5-day period of tDCS treatment 
versus the SHAM tDCS.  We plan to use dual boot strap analysis to assess stochastic variation 
along with a Bayesian sensitivity analysis to assess additional sources of error or bias in outcomes 
and cost.  If, as is likely, tDCS treatment compared to SHAM tDCS  therapy offers better outcome 
at higher cost, at least in some of the replicates in the sensitivity analyses, then the question will 
arise as to whether tDCS treatment is cost-effective.  This would seem to be the cost if most of the 
time the ICER is below an agreed to society threshold.  However, such a formal threshold does not 
exist, and is a policy rather than a societal question.  This can be addressed in a cost-effectiveness 
acceptability curve (Briggs et al. 1998).  In this analysis the threshold for a service being 
considered cost-effective is varied on the x axis and the probability of being cost effective on the 
y axis.  This graph can be formed for both the dual bootstrap analysis and the Bayesian sensitivity 
analysis (Claxton et al. 2005). This will permit us to determine the probability that tDCS treatment 
offers good value for any threshold for an ICER to be considered cost-effective. 
 
 
VIII. RISKS AND DISCOMFORTS 
 
Transcranial Direct Current Stimulation 

Detailed Protocol 18 
 
This is a technique that poses a non-significant risk to subjects. The safety of this technique has 
been addressed and tested by multiple researchers (e.g., Hummel, et al., (Hummel and Cohen, 
2005); Fregni, et. al., (Fregni et al., 2006a, Iyer et al., 2005); Nitsche, et al., (Nitsche et al., 2003c, 
Nitsche et al., 2003b, Nitsche et al., 2003a), (Nitsche et al., 2004); Priori, et al., (Priori, 2003)) 
who have concluded that tDCS, as applied in a manner similar to our proposed protocol, induces 
only temporary mood, cognitive / motor effects, and no negative side effects. More than 30 
research studies involving hundreds of subjects have been published using tDCS. Hundreds more 
subjects have undergone tDCS for unpublished pilot research (Nitsche et al., 2003c). No 
undesirable or long-lasting effects have been reported, nor have any subjects reportedly abandoned 
a study due to discomfort. 
The most common side effects according to a recent consensus are: headache, dizziness, nausea, 
itchy sensation as well as irritation under the area of the electrodes (Nitsche et al., 2008).  
Researchers at the National Institute of Neurological Disorders and Stroke (NINDS), Iyer et al., 
(2005) (Iyer et al., 2005) conducted a safety study on tDCS, investigating 20-minute sessions of 1 
mA and 2 mA current stimulation with healthy controls (n=103). No negative effects were identified. 
Nitsche and colleagues (2004) found no measurable structural changes in brain tissue due to tDCS 
(Nitsche et al., 2004).  
 
Finally, two recent studies showed that several sessions of tDCS are safe to be used in chronic pain 
syndromes such as fibromyalgia and spinal cord injury (Fregni et al., 2006c), (Fregni et al., 2006a). 
Thus, a growing body of research from different laboratories has shown that tDCS is a safe, 
noninvasive and painless technique for modulating neural excitability, with measurable but only 
transient effects. The protocol described here uses stimulation levels that fall well within safety 
limits established by basic research investigating neural tissue damage, as well as numerous studies 
applying tDCS with human subjects (Nitsche et al., 2003c), (McCreery et al., 1990a), (McCreery 
et al., 1990b), (Yuen et al., 1981). In addition, we have performed several studies in PD using 
tDCS and did not find adverse effects associated with this technique [91, 92]. 
 
Questionnaires 
All questionnaires will be administered in the privacy of a closed lab. If subjects feel uncomfortable 
in answering any of the questions they may stop the study at any time. 
 
Electroencephalography (EEG): 
The EEG test is performed to measure the electrical activity in the brain and to examine the 
dynamic changes. It also allows for better understanding of the effects of electrical activity 
generated in different areas of the brain. EEG only measures brain activity and does not induce 
electrical current in the brain. It is non-invasive and has been used extensively in clinical practice 
for diagnosis or neurological conditions such as epilepsy. There are no risks associated with EEG 
other than a mild discomfort caused by the tightness of the net. The investigator will adjust the net 
to allow for the comfort of the subject. 
 
 

Detailed Protocol 19 
 
IX. 
POTENTIAL BENEFITS 
 
The knowledge will be valuable to burn injury patients and their family members, physicians who 
treat burn patients, and community members. The results of these studies may benefit subsequent 
future subjects if tDCS proves effective in improving the perception of subjects’ neuropathic 
symptoms. We envision that in the near future the information obtained from the proposed research 
will provide a better understanding for chronic burn pain. 
 
 
X. 
MONITORING AND QUALITY ASSURANCE 
 
Safety will be monitored by tDCS Adverse Effects Questionnaire.  Adverse events, data, and 
procedures will be reviewed by Dr Fregni and his team.  All expected and unexpected adverse 
outcomes will be reported to the IRB according to the Adverse Event Reporting guidelines. 
 
A trained co-investigator on the study will administer the tDCS stimulation, sensory exams and 
other evaluations. Prior to performing study procedures, the study staff member was trained in the 
techniques of tDCS as well as all aspects of the evaluations. This study staff member was then 
evaluated by the PI of the study. The PI has given confirmation that the co-investigator is qualified 
to administer the stimulation and the evaluations. 
 
All procedures in the Neuromodulation Center will be performed by research personnel having 
Basic Life Support (BLS) certification.  All staff performing study procedures must have reviewed 
and understand hospital and building 79-96 emergency procedures. 
 
Additionally,  a one-sheet medical information summary, highlighting important medical issues 
(pertinent PMH, medications, allergies, functional limitation/neurologic deficits, emergency 
contact, PCP) will be available for each patient participating as the initial page of their study 
binder. Therefore, in case of emergency, the clinician will have this information easily accessible. 
 
Emergency Procedure Plan 
 
Testing of research subjects in experiments from the Neuromodulation Center will be conducted 
in two sites (79-96 Neuromodulation Center and SRH). Subjects will be preferentially tested at 
SRH when equipment for testing and stimulation allows.  Stimulation sessions will take place in 
79/96 if there is an equipment restriction or scheduling conflict that would affect the scientific 
validity of the protocol (ie, would cause a missed visit during the 2 weeks of daily stimulation 
visits). All assessment based visits will be conducted in 79/96 (under the coverage plan explained 
below) as these tests require sensitive equipment which cannot be moved between 79/96-SRH 
after having already been calibrated and tested here.  
 
79-96 Neuromodulation testing 
 
Testing in the 79-96 building will take place with in-house licensed clinicians available (physician 
or RN). To ensure that coverage is available, one of the coordinators of the Neuromodulation lab 
will send out weekly e-mails to in-house clinicians to confirm their schedules for the following 

Detailed Protocol 20 
 
week.  Additionally, daily e-mails will be sent to all laboratory members with the medical coverage 
schedule for the day. The clinicians will be copied on these daily e-mails, and thus can let the 
Neuromodulation lab know if something has changed in their schedule. Finally, these weekly 
schedules will be posted on a white board in the main reception area of the lab so that all staff may 
readily see who is available when.  
 
Should an emergency arise during stimulation that requires immediate medical attention, the 
investigator will use the established emergency procedures for 79/96. This includes alerting the 
in-house clinician, dialing the emergency number (9-911) and reporting the nature and location of 
the medical emergency. Staff will assist the clinician as directed until EMS arrives. After using 
this system, the investigator will follow the Laboratory and IRB policies for adverse event 
reporting, including notification of the Principal Investigator and the Medical Monitor and filing 
of an adverse event report.  Should any minor incidents occur during stimulation that do not require 
immediate medical attention, the PI or licensed physician will be contacted to assess these issues 
and initiate appropriate action.  
 
SRH testing – Research Floor 
Whenever is possible, testing in SRH will be prioritized especially for patients participating in the 
stimulation sessions, when equipment permits. Coverage for emergencies during hospital testing 
(SRH) is the emergency response team.  The team is activated by dialing 8-6666, giving location 
and type of emergency. 
 
If due to equipment restrictions (ie, sensitive equipment that cannot be moved between 79-96 and 
SRH) or scheduling conflicts prevents subjects from being able to be stimulated in SRH, subjects 
may receive stimulation in 79-96 in accordance with the plan listed above in order to maintain the 
scientific validity of the protocol. 
 
 In addition to this support, the Principal Investigator or a licensed physician familiar with the 
research study will be available either on-site or available by pager, for all stimulation sessions. If 
this PI is unavailable, this licensed physician will be available to assist with identification and 
notification of emergencies.  
 
The Principal Investigator will be responsible for data monitoring, accuracy and completeness of 
data collection, and data storage. Data will be reviewed at completion of each subject’s 
participation in the study. 
 
A Data Safety Monitoring Board will be established for this study, comprised of a clinician with 
expertise in noninvasive brain stimulation (Lotfi Merabet, OD, PhD), a physiatrist with significant 
research experience who specializes in pain (Nitin Jain, MD, MSPH), and a burn injury survivor 
(Diana Tenney). The members of the board will work closely with the human subjects safety board 
(IRB) at BH-BIMS to oversee the welfare of all participants in this clinical trial. The board will 
meet three times over the course of the study, specifically after 20, 40, and 60 patients are enrolled. 
During each monitoring period, the DSMB will report to the IRB and study PI on data integrity, 
protocol adherence, and study participant safety issues. The DSMB will focus on adverse events 
and reasons for loss to follow up, raising any concerns or issues with the PI, and recommending to 

Detailed Protocol 21 
 
the IRB and PI the continuation, modification, or conclusion of the trial, while protecting the 
confidentiality of the trial data.   
 
 
 

Detailed Protocol 22 
 
 
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