Neuromodulation as a New Treatment for Post-Traumatic Stress Disorder in Veterans: Evaluating the Effectiveness of Trigeminal Nerve Stimulation
Phase: NA
Conditions: Post-Traumatic Stress Disorder
Sponsor: University of California, Los Angeles

 
VA Project#: 0006- -Neuromodulation as a New Treatment for Post-Traumatic Stress Disorder in 
Veterans: Evaluating the Effectiveness of Trigeminal Nerve Stimulation 
Principal Investigator: Andrew F. Leuchter, M.D. 
Study Sites: UCLA, VA Greater Los Angeles 
 
Contents 
Title…………………………………………………………………………………………….………1 
Personnel…………………….…………………………………………………………………………1 
Study Staff Qualifications……………………………………………………………………………...1 
Funding…………………………………………………………………………………………………1 
Description of Research/Objectives……………………………………………………………………1 
Background Justification……………….………………………………………………………………2 
Research Study Sites……………………......………………………………………………………….3 
Study Site Contacts……………………………………………………………………………..…3 
Study Site Roles………………………………..……….…..…………………………………..…3 
Methods of Communication and Documentation………...…………………………………….…4 
Subject Population……………………………………………………………………………...........…5 
Recruitment process……..………………………………………………………….……….…….5 
Consent Process……………………...…………………………………………………….……...6 
Eligibility Screening………………………………………………………………….………...…7 
Inclusion Criteria………………………………………………………….……………...…7 
Exclusion Criteria………………………………………………………….……………..…8 
Methods and Procedures………………………………………………………………………...……10 
        Overview…………………………………………………………………………………..….…11 
        Randomization………………………………………………………………………………..…11 
                   Sham Vs. Active Treatment……………………………………………..…………….…11 
Screening procedures and Instruments………………………………………………………….…….12 
Table for Study procedures and visits………………………………………………………...………15 
TNS Stimulation Procedures……………………………………………………………………….…16 
Conduct of Study……………………………………………………………………….…….…….…17 
Compensation…………………………………………………………………………………………18 
Cost to participant……………………………………………………………………………….……18 
Medical Devices………………………………………………………………………………………18 
Biological Samples……………………………………………………………………………...….…20 
Anonymity of Confidentiality.………………………………………………………………….….…20 
Foreseeable risks of participation…………………………………………………………………..…21 
Management of the Risks of Participation……………………….………………………………...…22 
Labeling…………………………………………………………...……………………..………22 
IRB Approval………………………………………………………………………………….…22 
Informed Consent………………………………………………………………………………..22 
Monitoring………………………………………………………..…………………….……..…22 
Records………………………………………………………..…………………………..…..…22 
Reporting…………………………………………………………...……………………..…..…23 
 
Serious Adverse Events…………………………………………….………………..….….…23 
 
     Medical Monitor………………………….……………………….……………….....……24 
 Safety Monitoring Committee……….……………………….………………...…..…...…24 
Benefits………………………………………………………………………….………………….…25 
Assessment of Risk:Benefit ratio…………………………………………………………….….....…25 
  
 
 
 
 

  
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RESEARCH PROTOCOL 
         04 December 2018 
 
1. Protocol Title: Neuromodulation as a New Treatment for Post-Traumatic Stress Disorder in 
Veterans: Evaluating the Effectiveness of Trigeminal Nerve Stimulation 
PERSONNEL  
2. Principal Investigator: Andrew F. Leuchter, M.D. 
 
3. Co-investigator(s): Mark Barad, M.D., Aimee M. Hunter, Ph.D., and Bruce Kagan, M.D.  
4. Study Staff:  
Michelle Abrams (Research Nurse/Study coordinator) 
Sarah Chang (Study staff) 
Nikita Vince-Cruz (Study Contact) 
Thomas Belin (Data Analyst) 
Robert Pynoos (Consultant) 
David Krantz (Medical Monitor) 
 
5. Investigator Qualifications:  Each study team member has prior experience and is fully qualified 
to fulfill their assigned roles. Drs. Leuchter, Kagan and Barad are licensed physicians and 
qualified to counsel distressed subjects enrolled in research on PTSD. Study coordinators have 
several years of experience in researching mood disorders and administering 
questionnaires/assessments. All persons in contact with the subjects are trained in dealing with 
adverse events and the suicide protocol.  
FUNDING  
6. Sources of Support for this project pending,  
 
• Indicate internal and/or external funding source: Department of Defense/ USAMRAA 
• Grant/contract number: N/A 
• HRPO Log Number: A-18040 
• Proposal Log Number: 12041006 
• Name of PI on Grant: Andrew F. Leuchter, M.D. 
• Grant title: Neuromodulation as a New Treatment for Post-Traumatic Stress Disorder in 
Veterans: Evaluating the Effectiveness of Trigeminal Nerve Stimulation 
 
DESCRIPTION OF RESEARCH  
7. Description of Research:  
In this project, we propose to use this clinical trial to test Trigeminal Nerve Stimulation (TNS) as 
a new treatment for Post Traumatic Stress Disorder (PTSD) in veterans. This study is a 
collaboration between VA GLA and UCLA. The project’s scientific aims will be accomplished 
by testing hypotheses using data collected from a clinical trial, so that all tasks and milestones are 
tied to the two hypotheses.  The achievement of these aims breaks into three phases of work: (1) 
activities prior to the clinical trial, (2) the trial itself, and (3) data analysis and reporting.  The 
tasks and subtasks will be accomplished within the framework of these three phases, which 
occupy a 1) 6 month period, 2) 36 month period, and 3) 6 month period, respectively.  This 
project is a collaboration between the VA and UCLA.  Subjects will be identified in the PTSD 

  
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Clinic or the Domiciliary Care Program at the VA, where they will be consented for participation.  
Funding for the project is provided by the Department of Defense to UCLA, and this funding will 
be used to cover study costs.  The VA will not be covering any of the costs for personnel, study 
visits, devices, or procedures associated with this study. 
  
An emerging method for treatment of mood and anxiety disorders is neuromodulation, or 
stimulation of the brain to adjust nervous system function.  Newer forms of neuromodulation can 
be performed at little or no risk to the subject and can relieve mood or anxiety symptoms without 
the side effects of medication.  TNS is a novel method for neuromodulation that holds promise for 
the treatment of mood and anxiety disorders (DiGeorgio et al., 2011).  The trigeminal nerve is the 
largest of the cranial nerves and carries nerve impulses from the forehead and face to locations 
throughout the brainstem, the limbic system, and the cortex.  Through placing two electrodes on 
the forehead just above the eyes, it is possible to pass low-voltage, high frequency electrical 
impulses through the trigeminal nerve to the brain.  This method of brain stimulation has shown 
promise for the treatment of Major Depressive Disorder (MDD) (Schrader et al., 2011).  The 
treatment is very easy to use; subjects simply apply the two electrodes to their forehead, and the 
stimulation is provided through wires attached to a stimulator about the size of a deck of cards.  
Subjects sleep with the stimulator on for approximately eight consecutive hours per night. The 
stimulator should be used while asleep but may also be used while awake.  In early trials, subjects 
reported no significant adverse events and that the treatment is convenient and acceptable to them 
(Schrader et al., 2011).  We have conducted preliminary, open-label studies of TNS in subjects 
with PTSD and have shown that the treatment is well-tolerated and is associated with a significant 
improvement in PTSD symptoms.   
 
Eventually, TNS has the potential to be of significant benefit to most Veteran and non-Veteran 
patients suffering with PTSD.  It is non-invasive, very easy treatment to administer, appears to be 
well-tolerated with minimal side-effects, and therefore would be a very useful adjunctive 
treatment for PTSD. Our preliminary data indicates that patients see significant improvement in 
general PTSD symptoms, as well as depressed mood, within eight weeks.  TNS has the potential 
to complement existing therapies for PTSD:  it is a non-pharmacologic treatment that can be 
delivered in the home, and it is administered at night with a low-cost device while the patient 
sleeps.  TNS could constitute a unique and useful addition to the treatment armamentarium for 
PTSD.   
 
8. Background Justification:  
PTSD is a major public health problem for our nations veterans.  It has been estimated that up to 
31% of personnel deployed to Iraq and Afghanistan, respectively, manifest symptoms of PTSD 
upon returning home (Sundin et al., 2010).  Recent PTSD rates among active troops have been 
estimated at 16.7%, and even higher among reservists at 24.5% (Milliken et al., 2007).  The 
impact of PTSD upon warriors, veterans, and their families is overwhelming.  Those suffering 
from PTSD are at six-fold greater risk of committing suicide, and greatly increased risk of 
dropping out of school and having marital difficulties (Kessler, 2000).  The costs to society are 
enormous.   
 
Most veterans with PTSD receive a variety of treatments.  There is evidence that psychotherapy, 
sometimes with adjunctive medication, reduces symptoms in most patients.  Although the 
majority of patients improve, most continue to have significant residual symptoms for many years 
following the diagnosis (Bradley et al., 2005).  There is no one treatment that is likely to totally 

  
Page 3 of 26 
alleviate all symptoms of PTSD, and patients are likely to need multimodal therapy involving 
psychotherapy possibly augmented by pharmacotherapy in order to achieve maximal benefit 
(Pratchett et al., 2011).  These findings highlight the need to develop additional treatment 
approaches that, alone or combination, may improve outcome above and beyond existing 
treatment methods.   
 
9. Multi-center Study: 2 Study Sites-UCLA and VA GLA 
 
a) Name and FWA number of each participating institution:  
 
1) Laboratory of Brain, Behavior and Pharmacology 
     Semel Institute  
     University of California, Los Angeles 
     FWA:00004642 
 
2) VA Greater Los Angeles 
11301 Wilshire Blvd.  
Los Angeles, CA 90073 
FWA:00000734 
 
a)  PTSD Clinic  
                 Building 256, 2nd Floor 
 
b)  Domiciliary Care Program 
  
      Building 217, 2nd Floor 
 
 
 
b) Contact name and information for the Investigator(s) at each participating institution: 
 
Contact for both sites: 
Andrew Leuchter, M.D. 
Semel Institute at UCLA 
760 Westwood Plaza, Suite 57-456 
P (310) 825-0207 
F (310) 825-7642 
E: afl@brain.ucla.edu 
 
c) Role of each participating institution (e.g., recruitment, sample/data collection, sample/data 
analysis, etc.):  
VA GLA --  Identification, recruitment, and consenting of the total 74 participants at the VA 
GLA PTSD Clinic or Domiciliary Care Program. Week 0 (baseline), week 4 and 
week 8(final) visits will be performed at the VA. Additional study visits may 
take place at the VA GLA. 
UCLA – All other study visits including Weeks 1-3, weeks 5-7 and the follow up visit may be 
conducted at UCLA depending on subjects’ preference. 
 
d) Contact name and information for IRB of record at each participating institution: 
 
Contact for both sites (UCLA and VA GLA): 
 

  
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UCLA IRB of Record: 
UCLA Office of the Human Research Protection Program 
The Medical Institutional Review Boards 1, 2, & 3 (MIRB) 
11000 Kinross Ave, Suite 211 
Box 951694 
Los Angeles, CA 90095 
  
Telephone: (310) 825-5344 
Email: mirb@research.ucla.edu  
 
Nikita Vince-Cruz 
Research Administration 
UCLA Semel Institute 
760 Westwood Plaza 
Suite 57-430 
P (310) 825-4781 
F (310) 825-7642 
E: nikita@brain.ucla.edu 
 
e) Method for assuring all participating facilities have the most current version of the protocol: 
 
Study staff at UCLA and VA GLA will be notified via lab or office email of any protocol 
changes, and provided with the updated versions of study materials as soon as they are IRB 
approved.  Personal emails will not be used to communicate any information regarding study 
activities, protocol or participants.  
 
f) Method for confirming that all amendments and modifications in the protocol have been 
communicated to participating sites: 
 
Study staff (investigators and research coordinators who have contact with subjects) will be 
notified via lab or office email and specifically asked to acknowledge receipt and use of 
amended or modified study materials.  Personal emails will not be used to communicate any 
information regarding study activities, protocol or participants. 
 
g) Method for communicating to participating facilities any serious adverse events and 
unanticipated problems involving risks to subjects or others:  
 
David Krantz, Ph.D., M.D. is appointed as the research monitor and will also act as chair of 
the Safety Monitoring committee (SMC) for this study.  He will use his expertise to assess all 
reported adverse events and report all serious adverse events (SAEs) regardless of the effect 
on study procedures or protocol.   All SAEs will be reported to the IRBs as required by 
procedure as well as to all investigators by lab or office e-mail.  
 
h) Method of communicating regularly with participating sites about study events: 
Lab and office e-mail will be used to communicate regularly with all investigators and 
research assistants about study events that occur both at VA GLA and UCLA.  This will 
ensure that all staff who are involved in execution of the protocol are updated in a timely 
manner about protocol changes.   

  
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i) Approval letters from all the IRB of record for all participating sites (or indicate that they are 
pending and provide upon receipt): UCLA IRB approved this study on 13 JAN 2014. UCLA 
IRB# 13-001670 
 
j) Confirm that the PI at GLA will maintain documentation of all correspondence between 
participating sites and their IRBs of record: 
 
The Principal Investigator for both UCLA and VA GLA, Dr. Andrew Leuchter, will maintain 
documentation of all correspondence between participating sites and their IRBs of record for 
UCLA, VA GLA and the Department of Defense/USAMRAA. 
 
10. Subject Population 
We plan to enroll a total of 74 subjects for this study.  We will identify the 74 subjects from 
the VA GLA Healthcare System who are currently in treatment and have received treatment-as-
usual (TAU) for the last 3 months in the PTSD Clinic or the Domiciliary Care Program.  TAU 
may consist of medication and/or group psychotherapy.  In addition to TAU, Veterans who have 
begun a structured, evidence-based therapy such as cognitive behavior therapy (CBT), cognitive 
processing therapy (CPT), or Prolonged Exposure (PE) therapy at least 6 weeks prior to beginning 
the study, and who continue to receive therapy, may also be eligible.  Subjects will be enrolled 
into an eight-week treatment protocol in which they will be assigned to one of two treatment 
groups:  1) active TNS plus TAU; or 2) sham TNS plus TAU.  Study activities will be performed 
at the VA GLA and the Semel Institute at the University of California, Los Angeles. 
 
Participants will be recruited as described below from the PTSD Clinic (Leslie Martin, 
LCSW, Director) and the Domiciliary Care Program (Beverly Haas, Ph.D., Director) of the VA 
GLA Healthcare System.   
 
 
PTSD Clinic:   
The PTSD Clinic caseload includes over 1,800 veterans with PTSD, including approximately 
400 veterans from Iraq or Afghanistan (OIF/OEF/OND).  The clinic receives an average of 25 
referrals a week.   
  Subjects will be recruited from those who are enrolled in TAU in the PTSD Clinic.  This 
program is staffed by four UCLA psychiatry residents, each of whom treats veterans under the 
direct weekly supervision of Drs. Kagan and Barad, who are co-investigators in this study.  The 
average score on the Clinician-Administered PTSD Scale (CAPS-5) of subjects entering the 
program is approximately 108, and patients experience on average a 34-point improvement in 
symptoms, such that at the end of treatment they are significantly improved but still quite 
symptomatic (median CAPS-5 score of 78).  Because many of these patients remain significantly 
symptomatic, are motivated to receive new treatment, and are relatively stable as evidenced by 
stable medications and the absence of a substance abuse diagnosis for a month prior to treatment, 
they constitute an excellent population from which to recruit for this study.   
Drs. Kagan and Barad, co-investigators on this study, are the primary attending physicians in 
the Clinic, and will coordinate efforts with the appropriate mental health staff to refer patients to 
the study.  All subjects will be informed that Drs. Kagan and Barad are investigators in the study 
as well as treating physicians in the PTSD Clinic.  If patients have any questions and would like 
to speak with someone who is not part of the study, they also will be afforded the opportunity to 

  
Page 6 of 26 
speak with Ms. Martin or other study staff who are not part of the study.  The study will be 
explained to all PTSD Clinic staff who will be asked to mention the study and provide veterans 
with a study brochure.  Patients will be asked by clinic staff for permission to be contacted by the 
study coordinator.  Any patient who gives permission will then be contacted by the coordinator 
and a screening will be scheduled.   
 
Domiciliary Care Program (DOM):  
Director Beverly Haas, Ph.D. and staff at the Domiciliary provide a supportive residential 
rehabilitation and treatment service center for Veterans.  The program combines a wide range of 
programs for Veterans to solve the immediate issues of mental health and substance abuse while 
continuing long-term support in their transition to stability and housing independence.  Dr. Haas 
and staff (including Gilad Dakik, LCSW, and Binyamin Amrami, M.D.) will support this study by 
facilitating the identification and recruitment of potential subjects.  
The DOM caseload from which we will be recruiting currently includes an estimated 40 
Veterans with PTSD who would meet study criteria.  The typical length of stay within the DOM 
program is 5-6 months.  Subjects undergoing TAU will be identified by their treating physician as 
eligible for the study and then will be invited to participate voluntarily in the study.  Patients in 
the DOM are required to be sober and undergo weekly drug testing and are breathalyzed when 
they return from pass.  Many patients from the identified DOM caseload of PTSD patients are 
combat veterans who have already been screened and accepted into the program based on the 
same entry criteria as for the PTSD Clinic, namely:  1) meet DSM-IV criteria for PTSD; 2) not 
meet DSM-IV criteria for a substance abuse disorder for at least one month; 3) not have been 
diagnosed with significant traumatic brain injury (TBI); 4) be able to commit to, attend, and 
tolerate weekly psychotherapy sessions in the clinic; and, 5) if receiving psychotropic 
medications, have been on stable doses for at least one month.  These patients therefore constitute 
an appropriate population from which to recruit for this protocol. 
 
11. Consent Process 
Potential subjects who are referred by clinic staff will speak with the study coordinator who will 
provide information (goal of the study, treatment conditions, risks and benefits of participating, 
use of double-blind random assignment, time commitment, compensation for participation, and 
schedule of payments) allowing them to decide whether they want to participate.  Staff will make 
clear to the subjects that their participation in the study is strictly voluntary and that their refusal 
to participate in the study will in no way prejudice their ongoing care in the PTSD Clinic or 
Domiciliary Care Program. Those who are interested will have an appointment scheduled. All 
participants will receive a copy of the Subject’s Bill of Rights prior to discussions of consent to 
participate.  Discussions will take place in a private office to ensure the confidentiality of the 
discussions and safeguard the privacy of the participants.  The consent form outlines procedures, 
potential risks and anticipated benefits, right to withdraw, and confidentiality; it will be read with 
each participant, allowing time for questions.  The research coordinator will review the consent 
form to ensure that all subjects comprehend the requirements and procedures of the study, and 
will ask the potential subjects questions about the protocol after they have explained it to ensure 
that they truly comprehend the nature and procedures of the study.  All potential participants will 
be offered time to decide if they want to participate and the opportunity to take a copy of the 
consent form home to read and discuss with family or friends before giving their consent.  When 
subjects are prepared to consent, they will review the procedures of the study with one of the co-
investigators who will obtain the subjects’ consent.  Participants who qualify after passing 
screening will be randomized as a subject to a treatment condition.  Those who do not pass 

  
Page 7 of 26 
screening will be referred for continued treatment as usual in the PTSD Clinic or Domiciliary 
Care Program.  Only subjects who are capable of giving consent themselves will be eligible to 
participate in this study.  Participants may withdraw from the study at anytime without any 
consequences or impact on other services or medical care they may be receiving.  No procedure 
beyond notification to the study staff is necessary on the part of the subjects to withdraw from the 
project.  We will inform study staff of any subjects who withdraw from the study so that they can 
assess them as indicated to determine if there has been any significant change in the subjects’ 
clinical status, and take appropriate action. 
 
All study personnel are well trained in subject protection and consent procedures.  All study 
personnel have completed the Collaborative Institutional Training Initiative (CITI) Biomedical 
Course in the Responsible Conduct of Research Protection of Human Research Subjects 
(http://www.citiprogram.org).  CITI training is considered a national best practice for those 
involved with research and review.  The CITI course is composed of online tutorials and 
quizzes.  The average time needed to complete the Basic Course is between 2-4 hours, and 
Certificates of Completion are granted after satisfactory completion each of the quizzes.  This 
course provides excellent training regarding the history and application of The Belmont Report 
and the current Code of Federal Regulations (CFRs) that govern human subjects 
research.  Training in the protection of confidentiality and the details of the Health Insurance 
Portability and Accountability Act (HIPAA) has been completed similarly through online 
programs, the “HIPAA Clinical Research Training Course” (http://www.training.arc.ucla.edu/) at 
UCLA and the "VA Privacy Awareness Training" through the Veterans Administration Learning 
Management System (LMS) at VA GLA (https://www.lms.va.gov). 
 
12. Eligibility Screening:     
 
Potential participants will be recruited from the VA GLA PTSD Clinic and the Domiciliary Care 
Program.  Drs. Kagan and Barad, co-investigators on this study, are the primary attending 
physicians in the PTSD clinic, and will coordinate efforts with the clinic staff to refer patients to 
the study.  Directors of the recruiting VA GLA programs will coordinate efforts with the staff to 
refer potential subjects to the study.  The study will be explained to all PTSD Clinic and 
Domiciliary Care Program staff who will be asked to mention the study and provide potentially 
eligible veterans with a study brochure.  The brochure will explain in lay language the goals of 
the study, the procedures and time commitment, and that compensation will be provided.  Simple 
one-page flyers also will be prepared that can be left in the clinic waiting room.  These will 
contain a brief lay language summary of the study and the telephone number for research staff to 
call for further information.  The brochure and flyer will not be coercive or offer any undue 
inducements for participation, and will be approved by the IRB prior to distribution.   
 
Inclusion criteria:  In order to be included in the study, subjects must:   
1) 21-65 years old and be a patient in the PTSD Clinic or the Domiciliary Care Program at the VA 
GLA; 
2) have experienced trauma while serving in a war zone in the following U.S.Military conflicts; 
Multinational Force in Lebanon (1982-1984) 
Invasion of Grenada (1983) 
Invasion of Panama (1989-1990) 
Gulf War (1990-1991) 
Iraqi No-Fly Zone (1991-2003) 

  
Page 8 of 26 
Somali Civil War (1992-1995) 
Intervention in Haiti (1994-1995) 
Bosnian War (1994-1995) 
Kosovo War (1998-1999) 
War in Afghanistan (2001-present) 
Iraq War (2003-2011) 
3) meet DSM-V criteria for current warzone-related PTSD with a duration of at least 3   
    months;  
4) currently receiving treament as usual (TAU) and have received TAU treatment for the last 3 
months, and may be receiving structured, evidence-based therapy such as Prolonged Exposure 
therapy (PE), Cognitive Processing Therapy (CPT), or Cognitive Behavior Therapy (CBT), so 
long as the therapy was not initiated within 6 weeks of beginning the TNS protocol; 
5) significant residual PTSD symptoms as evidenced by a CAPS-5 (Clinician-administered PTSD 
scale) score > 50; 
5) consent to be randomized to active or sham TNS treatment; 
6) if receiving medication for depression, anxiety, sleep, or mood stabilization, must have   
    been on stable dose for at least six weeks prior to randomization.   
 
We have minimized exclusion criteria in order to support inferences applicable to as broad a mix 
of patients presenting with PTSD as practicable.  In order to avoid confounds that might make it 
impossible to interpret findings from the study due to a lack of exchangeability of experimental 
subjects, we will not include patients who exhibit:   
 
Exclusion Criteria: 
1) current substance abuse disorder not in remission for at least 3 months; 
2) a history of bipolar, schizophrenia, other psychotic disorder, or dementia; 
3) current suicidal or homicidal ideation requiring hospitalization, or suicide attempt  
within six months; 
4) report of severe TBI with coma duration (30 minutes or more) at time of screening interview 
and/or duration of post-traumatic amnesia (1hour or greater) on the Post-traumatic Amnesia 
Questionnaire (PTAQ); 
5) reported use (by patient or clinic staff) of antidepressant, antianxiety, antipsychotic, or mood-
stabilizer medication where the dose has not been stable for a minimum of six weeks prior to 
entering the randomization; 
6) reported participation (by patient or clinic staff) in psychosocial or medication treatment 
through a clinic or facility other than the VA GLA PTSD Clinic or the Domiciliary Care 
Program;    
7) infection or loss of integrity of skin over the forehead, where the electrode pads will be placed.   
 
We will exclude participants who are receiving treatment for PTSD outside of the VA GLA 
PTSD Clinic or Domiciliary Care Program because such treatment may deviate from accepted 
treatment as usual (TAU), and the details of such treatment may not be available to the 
investigators.  We will not exclude participants who are currently in TAU for PTSD at the VA 
GLA with the exception of the initiation of or change in medication status (i.e., starting or 
changing dose) occurring within the prior six weeks.  Subjects, as well as staff providing 
treatment, will be informed that TAU may not change during the eight week blinded study period 
if the subject wishes to remain enrolled in the study.  If a change in TAU is indicated based upon 
the subject’s clinical situation, the subject will be withdrawn from the study and the clinic staff so 

  
Page 9 of 26 
informed.  This exclusion is designed to reduce the confounding effects of changes in 
concomitant treatment with those of TNS.  Because of the relative stability of this patient 
population after 3 months of TAU, we anticipate that this exclusion will affect only a small 
number of patients.  Although a blanket exclusion of subjects receiving medication would avoid 
certain complexities in the assessment of TNS efficacy, given the frequency with which these 
medications are prescribed, excluding such individuals could be expected to negatively affect not 
only recruitment success but also generalizability.   
 
We have chosen not to exclude subjects who may be initiating naturalistic psychosocial treatment 
through the PTSD Clinic or the Domiciliary Care Program.  There are a number of outpatient 
group treatments available including:   
 
OEF/OIF group - Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) 
combat Veterans, discussions of issues pertaining to readjustment hack to civilian life;    
 
Combat Trauma group - 12-week class discussion of issues related to combat trauma;  
 
PTSD/Substance Abuse group - helps veterans remain safe in their behavior and manage 
emotions;   
 
Grief Group - helps veteran who have experienced losses;   
 
Anger Management - a 12-week program that teaches understanding of anger and coping 
skills;  
 
Emotional Management - 12-week program teaches how to negotiate emotionally  
charged situations;   
 
Strategies for Living – 12-week program that teaches how to more effectively use  
 cogntive  resources. 
 
We are allowing these treatments for two reasons.  First, the subjects in this study will be 
significantly symptomatic, and it could be impractical or unsafe, and correspondingly unethical, 
to deny them access to some type of psychosocial intervention for their ongoing symptoms.  
Second, all subjects will be receiving TAU which may include a combination of treatments 
including medications, breathing exercises, and talk therapy.  While a course of another 
psychosocial treatment through the PTSD Clinic or the Domiciliary Care Program may provide 
valuable support and some symptomatic relief, we believe that it is unlikely that one of these 
treatments would result in a significant magnitude of symptom reduction that would confound the 
study results.  We will require that all non-study treatments be provided through the VA GLA 
PTSD Clinic or Domiciliary Care Program which will make it possible for us to carefully record 
any non-study medication or psychosocial treatments that the subjects are receiving for their 
PTSD.  We will use uncontrolled treatment as a covariate in analyses if indicated due to 
unbalanced frequency or intensity of treatments received between the active and sham TNS 
groups.   
 
Individuals with Major Depressive Disorder (MDD) will not be excluded if they meet the 
inclusion and exclusion criteria.  MDD often is comorbid with PTSD, so that excluding these 

  
Page 10 of 26 
subjects would limit generalizability of results.  Individuals with active substance dependence, 
bipolar or other psychotic disorders, or severe TBI will be excluded because TNS may not work 
in the same manner or achieve the same degree of effectiveness in such individuals compared 
with patients who do not have these conditions.  In this initial blinded efficacy study, we believe 
that it is important to eliminate these potential confounds.  We do not anticipate that many 
subjects will be excluded because of bipolar or psychotic disorders because such patients 
generally have been identified prior to their registration in the PTSD Clinic or Domiciliary Care 
Program and are being treated elsewhere in the VA GLA.  Some patients will have suffered or 
will suffer from an active substance use disorder, and these subjects will be excluded from the 
study.   
 
Similarly, we do not anticipate exclusion of many subjects because of TBI because patients with 
significant TBI would have been identified and referred to another clinic in the VA GLA system.  
Nevertheless, we recognize that we need to make provision for identification of such subjects who 
may not have been identified by usual clinical screening and may have entered treatment in the 
PTSD Clinic or Domiciliary Care Program:  PTSD and TBI are highly comorbid in recently 
returning veterans (Hoge et al., 2008) and both conditions share cognitive (e.g., inattention, 
memory impairment), physical (e.g., sleep disturbance, reactivity/sensitivity to sensory stimuli), 
and emotional (e.g., increased irritability, depressive symptoms) sequelae (Belanger et al., 2009; 
Luethcke et al., 2011; Qureshi et al., 2011).  It would not be ideal to utilize neuropsychological 
testing of symptom screening measures in an attempt to identify severe TBI because of the 
overlapping symptoms.  Therefore, to help ensure that our sample is primarily suffering from the 
effects of PTSD and not TBI, we will utilize the Post-traumatic Amnesia Questionnaire 
(McMillan et al., 1996).  Any individuals who report a history of coma duration 30 minutes or 
more and/or duration of post-traumatic amnesia of 1 hour or greater resulting from any one 
episode of TBI will be judged to have suffered severe TBI and will be excluded from the study.  
We will rely on subjects’ reports of TBI for this screening.  We considered excluding subjects 
with lesser degrees of TBI from the study, but decided not to do so for two reasons.  First, 
traumatic injuries are extremely common in this population, and it could be difficult to reliably 
identify lesser degrees of TBI because of the overlap in symptoms between PTSD and TBI.  
Second, a history of mild TBI is common in patients with PTSD, and eliminating such subjects 
could make it difficult to recruit sufficient numbers of subjects to conduct the study.  Third, 
because of the possibility that significant numbers of veterans will have mild degrees of TBI, it is 
important to include such subjects in this study in order to have a representative sample of PTSD 
patients.  If this initial efficacy study is positive, it will be important in future studies to more 
systematically evaluate the effectiveness of TNS in patients suffering from different degrees of 
TBI.   
 
13. Methods and Procedures 
 Overview:  
This is a 74-subject study designed to examine the use of TNS as an adjunctive treatment for 
adults with PTSD.  Subjects undergoing Treatment as Usual (TAU) in the PTSD Clinic or the 
Domiciliary Care Program at the VA GLA will be identified and referred by their treating 
physician as eligible for the study, and only then will be invited to participate voluntarily in the 
study.  The study population will consist of 74 male and female Veterans who meet diagnostic 
criteria for PTSD on the basis military service in a war-zone.  Veterans are the most appropriate 
population for this preliminary study because research has shown suboptimal outcomes for 
combat veterans using existing treatments (Bradley et al., 2005), indicating a need for improving 

  
Page 11 of 26 
treatment options for this population.   
 
This is a collaboration between the VA GLA and UCLA.  All study activites will will be 
performed at the VA Greater Los Angeles or UCLA as determined by the Principal Investigator, 
in consultation with the PTSD Clinic and Domiciliary Care Program directors, as well as the 
subject’s preference.  Identification, recruitment and consenting of subjects for participation will 
be performed at the VA GLA PTSD Clinic or the Domiciliary Care Program.  The baseline visit, 
Week 4 visit, and Week 8 visit will be conducted at the VA GLA PTSD Clinic or Domicialiary 
Care program without exception.  All other study activities and visits will be performed at UCLA, 
or at the VA GLA PTSD Clinic or Domiciliary Care Program.   If subjects prefer that visits be 
performed at the VA, the clinic director approves such visits, and space is available in the clinic, 
these visits will be performed at the VA GLA PTSD Clinic or the Domiciliary Care Program.  
Subjects will be randomized to treatment with either active or sham TNS for a period of eight 
weeks.  Subjects will be randomly assigned in a double-blind manner (n=37 in each group); all 
subjects and the research staff who interact with them will be blinded to assignment, and a 
separate UCLA staff member of the research team who has no contact with subjects will program 
the TNS device settings.  Subjects assigned to the sham treatment condition will receive a TNS 
stimulator that will look identical to the active treatment stimulator, and will follow identical 
procedures for the use of this stimulator.  The sham unit, however, will deliver no actual nerve 
stimulation (i.e., it will pulse at 0 Hz).  It will be explained to all subjects that they may or may 
not feel any sensation while using the device and any sensations or lack there of is not indicative 
of which treatment they are receiving. There is no noise associated with the device.  The TNS 
device is equipped with a lighted display which will turn on to indicate to the patient when 
stimulation is being administered. The display on the sham device will turn on when stimulation 
is given at 0 Hz to avoid the appearance of a difference between the sham and active treatment. 
 
Subjects will be followed weekly with ratings of PTSD symptoms, mood and anxiety, as well as 
examinations for risk of suicidality.  Week 8 endpoint measures will include severity and 
frequency of PTSD symptoms, quality of sleep, and quality of life measures.  The primary 
endpoint measure is the change in symptom severity at the week 8 visit.  The week 8 time point 
will be used to compare changes in symptoms between subjects who were randomly assigned to 
the active vs. sham TNS treatment condition.  Subjects also will be interviewed an additional 4 
weeks after the conclusion of the sham controlled treatment, and their mood and anxiety 
symptoms assessed, to examine the durability of any symptom change that subjects experienced 
during the initial 8 weeks. At the end of week 8, subject improvement will be assessed and those 
showing a ≥ 25% improvement from baseline at the end of 8 weeks of treatment will be eligible 
to participate in the 42-month extension phase to monitor and observe possible benefits of 
prolonged TNS in responders. Subjects who participate in the extension phase will remain 
blinded. Subjects complete the PCL-M and BDI monthly during their participation in the 
extension phase. The PCL-M monthly score determines on-going inclusion in this phase. Subjects 
will be withdrawn in the case of adverse events, or symptom worsening (quantified as > 25% 
worsening in symptoms after one month as compared to the beginning of the extension phase as 
assessed using the PCL-M total score). Subjects way also voluntarily withdraw from the 
extension phase at any time.  
 Subjects who do not participate in the extension phase will be unblinded and told whether they 
received the active or sham-controlled treatment after all study and follow-up visits have been 
completed. This includes completion of the eight-week double-blind treatment phase and four-
week follow-up phase for a total of 12 weeks in this study. Data will be examined for differences 

  
Page 12 of 26 
between active and sham treatment, as well as safety and acceptability of the treatment.  If 
positive, this preliminary study will serve as the basis for a larger pivotal trial of effectiveness.   
 
Screening Procedures and Instruments:  After signing the consent form, the research coordinator 
will interview subjects to ask about demographic data and assess for possible exclusion criteria.  
The instruments listed below will be used to determine eligibility for the study and assess 
symptom severity.  Instruments will be administered on the schedule shown in Table 1 below. 
Clinician-Administered PTSD Scale for DSM-V (CAPS-5-5) (Blake et al., 1995; Weathers et al., 
2001):  The CAPS-5 will be used both to establish eligibility for inclusion in the protocol and as 
an outcome measure. This 30-item structured interview assesses the presence, frequency, and 
severity of symptoms of PTSD.  It provides a continuous score of frequency and severity for each 
symptom, with overall severity characterized by summing the total score for the individual items.  
The CAPS-5 has good psychometric properties across a wide variety of clinical populations and 
research settings (Weathers et al., 2001).  We first will determine using the CAPS-5-5 whether the 
subject has at least one Criterion A stressor related to warzone exposure.  If the subject meets this 
criterion, the remainder of the CAPS-5-5 will be administered to confirm the presence of PTSD 
and assess severity.   Frequency and severity of symptoms are rated separately on a 0-4 scale.   
 
Mini International Neuropsychiatric Interview for DSM-IV, Version 5.0 (MINI) (Sheehan et 
al.,1998):  The MINI is a short yet accurate structured diagnostic interview used to diagnose 
current and lifetime Axis I disorders according to DSM-IV criteria. The assessment takes 
approximately 15 minutes to administer (Sheehan et al., 1998) We will specifically assess current 
substance dependence, current and/or history of psychosis, bipolar disorder, and to assess possible 
presence of exclusion criteria through use of relevant modules from the MINI.  We also will 
utilize this instrument to determine the presence of Major Depressive Disorder (MDD); subjects 
will not be ruled-out because of the presence of MDD, but the presence of the illness will be used 
as a covariate. If presence of MDD appears to affect outcome, we may perform a subgroup 
analysis in subjects with comorbid MDD.   
 
Post-traumatic Amnesia Questionnaire (PTAQ) (McMillan et al., 1996) will be used as a screen 
to identify subjects who may have suffered significant TBI.  This questionnaire will be 
administered only to those potential subjects who report a history of TBI.  It is unlikely that many 
such individuals will be in the population of subjects eligible for screening for this study because 
such individuals will generally have been identified clinically and referred elsewhere in the VA 
GLA system.  This simple questionnaire will be used, however, to help ensure that no subjects 
with significant TBI are enrolled in this study.  The PTAQ estimates the severity of TBI based 
upon the length of time that individuals report coma or amnesia following injury.  Subjects with 
coma duration 30 minutes or more and/or duration of post-traumatic amnesia 1 hour or greater 
will be excluded from the study.  The PTAQ shows good psychometric properties.  It has a strong 
association (0.87) with prospective assessment post-traumatic amnesia (McMillan et al., 1996).   
PTSD Checklist (PCL-5) (Wilkins et al., 2011):  The PCL is a 20-item self-report measure of the 
20 DSM-V symptoms of PTSD.  We will use this instrument to track changes in PTSD symptoms 
on a weekly basis throughout the study.  It is a self-report measure that can be completed by 
patients in the waiting room in approximately 5-10 minutes. There are no corresponding PCL-5 or 
PCL-C versions of PCL-5. The PCL has demonstrated strong psychometric properties. Estimates 
of internal consistency (Cronbach's alpha) range between .94 (Blanchard et al, 1996) to .97 
(Weathers et al. 1993).  

  
Page 13 of 26 
Beck Depression Inventory-II (BDI-II) (Beck et al. 1988):  This 21-item self-rated questionnaire 
will be used to assess characteristics and severity of depression.  We will use this instrument on a 
weekly basis to track changes in depressive symptoms throughout the study.  Each item is rated 
on a 4-point scale (0 = not present; 3 = present in the extreme). This questionnaire will be used to 
rate the severity of depressive symptoms and any improvement during the course of the trial. The 
total score ranges from 0 to 63.  Psychometric properties of the instrument are good.  Beck and 
Steer (1984) demonstrated internal consistency of .86, while Gallagher, Nies, and Thompson 
(1982) reported high internal consistency of .91.   
 
Addiction Severity Index (ASI) (McLellan et al., 1992):  This standardized clinical interview will 
be used to assess severity and functional impact of substance use for each subject.  We will 
exclude subjects who meet criteria for a current substance dependence disorder, but because of 
the high prevalence of substance use in this population, we will assess the severity of current use.  
In addition to providing data on substance use in the previous thirty days, the ASI assesses 
functional impact and use severity in seven specific areas, including drug use, alcohol use, family-
social, medical, and psychological functioning, employment, and legal involvement.  The 
instrument has good psychometric properties.  Concurrent and interrater reliabilities are strong 
(.74-.93) and validity is acceptable (Kosten et al., 1983; McLellan et al., 1983). 
 
36-item Short Form Health Survey (SF-36) (Ware and Sherbourne, 1992):  This scale is widely 
used to assess the effects of health on quality of life (QoL).  It recently has been used in OEF/OIF 
veterans to assess the impact of PTSD on QoL (Pittman et al., 2011).   It consists of 36 questions 
covering eight health domains:  physical functioning, bodily pain, role limitations due to physical 
problems, role limitations due to emotional problems, general health perceptions, mental health, 
social function, and vitality.  Each domain is scored by summing the individual items and 
transforming the scores into a 0 to 100 scale, with higher scores indicating better health status or 
functioning.  Two summary scores are constructed based on the eight domains.  The SF-36 was 
constructed to satisfy minimum psychometric standards necessary for group comparisons.  It has 
been extensively evaluated and has robust psychometric properties (http://www.sf-
36.org/tools/sf36.shtml#MODEL).   
 
Pittsburgh Sleep Quality Index (PSQI) (Buysse et al., 1989):  The PSQI measures the quality and 
patterns of sleep.  Because TNS is administered at night, this scale will be used specifically to 
assess the effects on sleep.  It will provide a more comprehensive assessment of subjects' sleep 
patterns than the other scales.  It can be used to differentiate "poor" from "good" sleep with seven 
measures: subjective quality, sleep latency, duration, habitual sleep efficiency, sleep disturbances, 
use of sleeping medication, and daytime dysfunction over the last month. The client self-rates 
each of these seven areas of sleep on a 0 to 3 Likert scale.  Each area can be examined 
independently, and a summary score is calculated with 5 or greater indicating a "poor" sleeper.  
The scale has good psychometric properties.  It has strong internal consistency, with Cronbach's 
alphas 0.80 across groups and moderate to high correlations between global and component 
scores (Carpenter and Andrykowski, 1998).  Assessment of safety, compliance, and tolerability 
will be performed at the weekly subject visits.  All subjects will be provided with a log booklet 
with space to record any treatment-emergent adverse events, how long they were able to wear the 
TNS system each night, and whether they encountered any problems.  The research coordinator 
will examine this booklet each week and record any specific adverse events as well as the degree 
of compliance.  In addition, subjects will be asked to rate tolerability of treatment-emergent 
adverse events by completing the Systematic Assessment for Treatment Emergent Events-Specific 

  
Page 14 of 26 
Inquiry (SAFTEE-SI) (Levine and Schooler, 1986), an easy to use 55-item self-report (with an 
additional overall severity item) that rates most commonly reported side effects expected with the 
clinical study interventions.  While developed for medication studies, it is applicable to device 
studies as well, and will be used to describe side effects associated with treatment.  The SAFTEE-
SI will be administered at enrollment and at each follow-up visit, to detect treatment-emergent 
events or events which worsen during treatment.  The SAFTEE-SI will be supplemented by an 
open-ended question ("general inquiry") to capture any adverse reactions not enumerated in the 
SAFTEE-SI items.  Events will be categorized using the Medical Dictionary for Regulatory 
Affairs (MedDRA), a clinically validated terminology that applies to all phases of drug and 
medical device development, and developed by the International Conference on Harmonisation 
(ICH) as a successor to the earlier COSTAR ("Coding Symbols for Thesaurus of Adverse 
Reaction") nomenclature. 
 
Scales from the Deployment Risk and Resilience Inventory-2 (DRRI-2) (baseline) 
 
This 'Trauma and Adversity Exposure' protocol includes the following four self-reported, 
deployment-related subscales from the Deployment Risk and Resilience Inventory-2 (DRRI-2) 
(Vogt et al., 2013): Difficult Living and Working Environment (14 items); Combat 
Experiences (17 items); Aftermath of Battle (13 items); and Perceived Threat (12 items).  Items 
are rated on Likert-style scales and added together to give a score for each scale. 
See: http://www.ptsd.va.gov/PTSD/professional/assessment/deployment/index.asp 
 
Difficult Living and Working Environment Scale (14 items) DRRI-2 Section: C; Survey Label: 
"Deployment Environment."  This scale assesses exposure to events or circumstances 
representing repeated or day-to-day irritations and pressures related to life during military 
deployment. These personal discomforts or deprivations may include the lack of desirable 
food, lack of privacy, poor living arrangements, uncomfortable climate, cultural difficulties, 
and constraints to performing one's duties.  
 
Combat Experiences Scale (17 items) DRRI-2 Section: D; Survey Label: "Combat 
Experiences."  This scale covers exposure to combat-related circumstances such as firing a 
weapon, being fired on, being attacked or witnessing an attack (e.g., encountering an explosive 
device), encountering friendly fire, and going on special missions and patrols that involve such 
experiences. This war-zone factor refers to objective events and circumstances and does not 
include personal interpretations or subjective judgments of the events or circumstances.  
 
Aftermath of Battle Scale (13 items) DRRI-2 Section: E ; Survey Label: "Postbattle 
Experiences."  Assesses exposure to the consequences of combat, including observing or 
handling human remains, interacting with detainees or POWs, and observing other 
consequences, such as devastated communities and homeless refugees. This factor is 
conceptualized as cataloging more objective war-zone events and circumstances.  
 
Perceived Threat Scale (12 items) DRRI-2 Section: G; Survey Label: "Deployment Concerns."  
Assesses fear for one's safety and well-being during deployment, especially as a response to 
potential exposure to warfare (e.g., attacks by enemy combatants, encountering explosive 
devices), as well as nuclear, biological, and chemical agents (NBCs) in the war zone (e.g., 
depleted uranium in munitions, pesticides, or other routinely used chemicals). This factor 

  
Page 15 of 26 
reflects emotional or cognitive appraisals of situations that may or may not accurately represent 
objective or factual reality.  
 
The Life Events Checklist for DSM-5 (LEC-5) (baseline) 
LEC-5 is a self-report measure designed to screen for potentially traumatic events in a 
respondent's lifetime. We will use the LEC-5 as it is typically used, i.e., to facilitate 
identification of an index trauma for assessment of PTSD symptoms with the CAPS-5-5. 
 
PTSD Treatment History and Effectiveness (baseline) 
The Emory Treatment Resistance Interview for PTSD (E-TRIP) (Dunlop et al., 2014) is a 
combination self-administered questionnaire and interview that includes a PTSD Medication 
Treatment Record, a PTSD Psychotherapy Treatment Record, and a Treatment Resistance 
Interview for PTSD.  The time required to administer the E-TRIP ranges from one minute for 
treatment-naïve patients to 20 minutes for more extensively treated patients.  Mean time to 
administer the instrument was 6.41 ± 5.47 minutes (Dunlop et al., 2014). 
 
 
Visit Type 
Week 0 
(Baseline) 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 8 
Visit Length 
*6 hrs 
2 hrs 
2 hrs 
2 hrs 
4 hrs 
2 hrs 
2 hrs 
2 hrs 
4 hrs 
Questionnaire
/Survey: 
  
  
  
  
  
  
  
  
  
MINI 
X 
  
  
  
  
  
  
  
  
CAPS-5 
X 
  
  
  
X 
  
  
  
X 
PTAQ 
X 
  
  
  
  
  
  
  
  
PCL-M 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BDI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ASI 
X 
  
  
  
  
  
  
  
X 
SF-36 
X 
  
  
  
X 
  
  
  
X 
PSQI 
X 
X 
X 
  
X 
  
  
  
X 
SAFTEE-SI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DRRI-2 (4 
scales) 
X 
  
  
  
  
  
  
  
  
LEC-5 
X 
  
  
  
  
  
  
  
  
E-TRIP 
X 
  
  
  
  
  
  
  
  
Treatment 
Blinding 
Questionnaire 
  
  
  
  
  
  
  
  
X 
Safety and 
Compliance 
  
X 
X 
X 
X 
X 
X 
X 
X 
Study 
Procedures: 
  
  
  
  
  
  
  
  
  
Urine Test 
X 
  
  
  
  
  
  
  
  
Pregnancy Test 
(Females only) 
X 
  
  
  
  
  
  
  
  
Simulation Log 
Check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Device Setting 
Adjustments 
X 
  
  
  
X 
  
  
  
  
Table 1  Schedule for administration of diagnostic and rating instruments in the main study 
 
 
 

  
Page 16 of 26 
 
 
 
 
 
 
 
 
 
Visit Type 
Monthly 
Final 
visit 
Visit Length 
30 mins 
4 hrs 
Questionnaire/Survey: 
  
  
MINI 
 
X 
CAPS-5 
 
X 
PTAQ 
 
X 
PCL-M 
X 
X 
BDI 
X 
X 
ASI 
 
X 
SF-36 
 
X 
PSQI 
 
X 
SAFTEE-SI 
 
X 
DRRI-2 (4 scales) 
 
X 
LEC-5 
 
X 
E-TRIP 
 
X 
Treatment Blinding 
Questionnaire 
 
  
Safety and Compliance 
X 
X 
 
Table 2: Schedule for administration of diagnostic and rating instruments in the extension phase 
 
MINI Version 5.0: Mini International Neuropsychiatric Interview for DSM-IV  
CAPS-5: Clinician-Administered PTSD Scale for DSM-V 
PTAQ:  Post-traumatic Amnesia Questionnaire  
PCL-5:  PTSD Checklist for DSM-V 
BDI:  Beck Depression Inventory  
ASI: Addiction Severity Index  
SF-36: 36-item Short Form Health Survey 
PSQI: Pittsburgh Sleep Quality Index  
SAFTEE-SI: Systematic Assessment for Treatment Emergent Events–Systematic Inquiry 
LEC-5: Life Events Checklist for DSM-5, self-report  
E-TRIP: Emory Treatment Resistance Interview for PTSD  
Treatment Blinding Questionnaire: Survey to assess what treatment is thought to be received 
DRRI-2 Section C, Deployment Environment: 14-item scale assesses exposure to events or 
circumstances representing repeated or day-to-day irritations and pressures related to life during 
military deployment.  
DRRI-2 Section D, Combat Experiences: 17-item scale assesses exposure to combat-related 
circumstances.  
DRRI-2 Section E, Postbattle Experiences:  13-item scale assesses exposure to the consequences of 
combat.  

  
Page 17 of 26 
DRRI-2 Section G, Deployment Concerns: 12-item assesses fear for one's safety and well-being 
during deployment.  
Safety and Compliance: Assessment will be performed by the research coordinator to assure the 
device is being used safely and as directed. 
 
 
Assessment instruments will be administered by the study coordinator (Michelle Abrams, R.N., 
Dr. Aimee Hunter and Sarah Chang).  Ms. Abrams has over 20 years experience in assessment of 
psychiatric patients in clinical trials.  She will undergo standardized refresher training in 
conducting the MINI interview, and in administering or supervising completion of the instruments 
utilized in this study.  She will undergo training in administering the CAPS-5 through the Trauma 
Psychiatry Program at UCLA (Robert Pynoos, M.D., Director).  Training will include practice 
interviews and feedback from trainers designed to calibrate to a consistent acceptable standard of 
administration.   
 
 TNS stimulation procedure.  TNS will be performed using a CE-mark approved neurostimulator, 
the Monarch eTNS SystemTM (NeuroSigma, Inc., Los Angeles CA); in August 2012, NeuroSigma 
received CE mark certification for use of the Monarch for adjunctive treatment in epilepsy and 
MDD in adults and children age 9 and older.  The Monarch comprises two elements: the electrical 
pulse generator and the hypoallergenic, self-adhering custom electrodes for delivery of the signal 
to the supraorbital and supratrochlear branches of the V1 division of the trigeminal nerve.  The 
system offers features not available in off-the-shelf transcutaneous nerve stimulators, such as 
limiting the applied current to known safe ranges and two levels of lock-out codes to prevent the 
device from being used by others or reprogrammed by the subject.  As well, the composition and 
geometry of the electrodes has been engineered to provide the optimal amount of adhesion to be 
worn for 7-9 hours with a gel devoid of volatile compounds that are present in most surface 
electrodes used for nerve stimulation and that lead to skin irritation.   
 
The stimulators are the same device for the active and sham treatment conditions; the only 
differences are the frequency at which the device is set to deliver stimulation, the pulse width, and 
the duty cycle.  The programming will be set at the UCLA site prior to the baseline visit and the 
week 4 visit by a member of research staff who has no contact with subjects to deliver TNS in a 
double-blind manner at one of two frequencies of stimulation, active (120 Hz) or sham (0 Hz); 
these are the active and sham stimulation conditions previously described in epilepsy studies 
(DeGiorgio et al., 2003; 2006; 2009; in press) as well as in MDD (Schrader et al., 2011).  
Preliminary data indicate that subjects report comparable perceptions of being stimulated in the 
two stimulation conditions.  Once the device is programmed, the user will not be able to change 
the stimulation parameters.  Current can be adjusted within a narrow range for the comfort of the 
subject.  Preliminary data (reviewed above) indicate that in the treatment of epilepsy, a 120 Hz 
stimulation frequency had a significantly greater effect than 2 Hz on mood under double-blind 
treatment conditions.  In both conditions, the current will be adjusted to maintain comfortable but 
perceptible levels of stimulation.  TNS will be performed for approximately 8 hours each night, a 
protocol that subjects found acceptable in the pilot work.   
 
Conduct of the study.  After subjects are consented and qualify to enter the study, the full 
assessment of symptoms will be performed.  The estimated time for all these procedures at the 
baseline visit is approximately 3 hours.   
 

  
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Following the baseline assessment, subjects then will be randomized to one of the two treatment 
conditions.  Treatment assignment will be randomized within cells defined by gender, symptom 
severity, and presence of current medication treatment to provide a degree of balance on key 
underlying characteristics that otherwise would have the potential to confound the interpretation 
of study findings.  Specifically, there will be eight strata for randomization defined by the 2 x 2 x 
2 combinations of gender (male or female), symptom severity (lower or higher defined by 
whether the CAPS-5 score on entry is less than 78, the median value for this sample, versus being 
78 or greater), and presence of current medication treatment (yes or no).  Within these strata, 
randomization will occur in blocks of two, so that after every two patients with a given 
combination of stratum-defining characteristics, there will be one patient assigned to the active 
intervention and one to the control arm.  The randomization will be carried out by associating 
strata with rows of the random-number table in Cochran (1977, p. 19).  For the first member of 
each successive pair of patients presenting with a given set of stratum-defining characteristics, if 
the next number in the row is in the range of 5 through 9, then the patient will be assigned the 
active intervention, else the patient will be assigned to the sham.  If the first subject was assigned 
the active intervention, then the next subject would be assigned the sham, and vice versa; for the 
next subject after that, the random-number table will be used in the same way.  The pairing in the 
design could be considered in the analysis, and we will plan to do so using a permutation-test 
approach for purposes of being complete.  The core motivation for the pairing, however, is 
to ensure that treatment assignment remains balanced across arms rather than because we believe 
that there is anything scientifically important about whether the subject arrives at an odd or an 
even number in the sequence.  For our primary analysis, we will use a randomized-block ANOVA 
that accounts for the 2 x 2 x 2 stratification in the design but does not reduce the error degrees 
of freedom on account of the pairing. 
 
Following randomization, subjects will be scheduled to come back for a second visit when they 
will be given a pre-programmed stimulator, a supply of electrodes, and instructions on how to 
apply the electrodes and use the device.  No more than one week will elapse between the first and 
second baseline visits.  Baseline measures will not be repeated at the second baseline visit except 
for the CAPS-5, PCL-5, and BDI measures, which will be repeated in order to have PTSD, 
anxiety, and depression severity measures immediately prior to the start of treatment. Subjects 
will return to UCLA or the VA GLA for weekly visits and will undergo assessment of symptoms 
with instruments as specified in Table 1 above.  The research coordinator will assess compliance, 
ensure that the device continues to be in good working order and that the subject has a sufficient 
supply of electrodes, and encourage continued compliance.  In addition, the research coordinator 
will assess the subject for safety, inquiring specifically about any suicidal ideation and evaluate 
the results of scheduled assessments.  If the research coordinator has any concerns about subject 
safety, she will immediately contact a study physician who will interview the subject and perform 
an independent assessment.  Subjects will be removed from the study and hospitalized for any 
safety concerns per the procedure in the Human Subjects section.   
 
At the conclusion of the main study (week 8 visit or sooner if the subject drops out or is removed 
from the study), subject improvement will be assessed and those showing a ≥ 25% improvement 
from baseline at the end of 8 weeks of treatment will be eligible to participate in the 42-month 
extension phase to monitor and observe possible benefits of prolonged TNS in responders. 
Subjects who participate in the extension phase will remain blinded and will be asked to complete 
the Beck Depression Inventory(BDI) and the PTSD checklist during a monthly phone visit. 
Subjects who do not participate in the extension phase will be unblinded and told whether they 

  
Page 19 of 26 
received the active or sham-controlled treatment after all study and follow-up visits have been 
completed. The device will be collected from the subject and the subject will be continue 
treatment in the PTSD Clinic or the Domiciliary Care Program.  A summary of the results for 
each subject in the study will be provided to the clinic staff with the subject’s permission.   
 
Four weeks after the week 8 endpoint, all subjects who did not participate in the extension phase 
will be contacted again and interviewed to examine the durability of any symptom changes that 
they experienced during the eight-week double-blind controlled trial period.  All of the 
instruments from the week 8 time point will be administered again to determine if symptom 
improvement persists after discontinuation of the device, whether symptoms have returned, and 
whether any adverse events have resolved. 
 
14. Compensation:  
Compensation will be provided in the amount of $200.00 plus reasonable expenses for travel 
costs (bus fare, mileage, etc.) for all participants who complete the study.  The amount of $200.00 
reflects payments commensurate with the amount of time the subjects will be spending in the 
study ($40 for the screening visit, plus $20 for each subsequent study visit in the 8-week main 
study).  This level of compensation is standard for studies at the VA GLA for this level of time 
commitment, and has been deemed to be fair and non-coercive in other outpatient research 
protocols at the VA GLA.  Participants who voluntarily withdraw or are involuntarily removed 
from the study will be compensated by check for completed study visits and transportation at the 
conclusion of each research visit.  
 
15. Cost: There will be no costs to the participants enrolled in this study. 
16. Medical Devices 
The medical device used in the study is the NeuroSigma Monarch eTNS System manufactured 
by NeuroSigma, Inc.   
The UCLA MIRB-3 Committee has reviewed NeuroSigma’s Monarch eTNS System for use in 
protocol 11-002580 “Trigeminal Nerve Stimulation for Epilepsy” and decided that it met criteria 
for non-significant risk. Please see also our attached document “Abbreviated IDE Materials - TNS 
as NSR Device” for discussion. TENS units are FDA cleared for use in the treatment of pain by 
stimulating peripheral nerves. As per our protocol, we will use TNS units for stimulating 
peripheral nerves cutaneously, but for effects on the symptoms of major depression rather than of 
pain. Please see our attached documents for information about the risks associated with this 
offlabel use in prior and on-going research studying trigeminal nerve stimulation. Regarding 
reporting of the data to FDA, if this study finds that there are therapeutic benefits in PTSD and/or 
depression symptoms from TNS, then it is likely that data from this study may be reported to the 
FDA.   
TNS is a relatively new treatment, so there are limited published data from sham-controlled 
studies.  All data available to date, however, show a pattern of consistent efficacy for TNS in 
alleviating mood and anxiety symptoms in patients with epilepsy, MDD, and PTSD (Cook et al., 
2014).  Significant improvements in mood have been described with TNS in an open-label study 
of subjects with MDD (Schrader et al., 2011; Cook et al., 2013) and a controlled trial of epilepsy 
(DeGiorgio et al., 2011).  

  
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We recently concluded an open-label trial of TNS in adults with PTSD and comorbid MDD.  
Twelve adults (mean age 52.8 (13.7 s.d.) years, 8F:4M) with median 37 yrs since traumatic 
exposure (range 3-61) and with PTSD and MDD, were studied in an 8-week open label 
outpatient trial. Three of these subjects had PTSD based upon military service.  Current episodes 
were required to be of  at least 4 months duration, with non-response to at least 1 antidepressant 
trial over at least 6 weeks during the current episode (ATHF ≥1), and concomitant use of at least 
1 antidepressant.  All had prominent symptoms at entry, with mean scores on the CAPS-5 of 
80.2 (12.5), PTSD Patient Check List (PCL) of 63.3 (7.8), of  25.8 (4.6) on the 17-item Hamilton 
Depression Rating Scale (HDRS), and of 17.8 (4.0) on the Quick Inventory of Depressive 
Symptomatology (QIDS-C).  Subjects placed stimulating electrodes over the supraorbital 
branches of the trigeminal nerve for at least 8 hours each night, primarily while asleep, with 
current adjusted to maximal comfortable levels. Co-primary outcomes were change in PCL and 
QIDS-C at 8 weeks.  Results show that TNS was well tolerated, with no subjects discontinuing 
treatment because of difficulty or unacceptability of using the device. Decreases in PCL score 
were significant, from 63.3 (7.8) at entry to 43.0 (18.3) at week 8 (2-tail paired t-test p=0.003). 
QIDS-C score decreases were also significant, falling from 17.8 (4.0)  to 8.8 (4.3) (p<0.001), as 
were scores on the HDRS, improving from 17.8 (4.0) to 11.9 (7.3) p<0.001).  All reflect a large 
effect size comparing end-of-trial to start (Cohen's d 1.5 for PCL, 1.8 for QIDS-C, and 2.1 for 
HRSD).  We do not have data on the durability of these effects.   
 
In order to elucidate mechanisms through which TNS may produce therapeutic effects on mood, 
we undertook a functional neuroimaging study to evaluate patterns of regional activation that 
might be relevant to understanding the effect of TNS in mood and anxiety disorders.  We 
examined four adults with nonpsychotic unipolar MDD (2M:2F; all right-handed; age 46.9 + 5.8 
yrs) who had enrolled in a trial of adjunctive TNS.  All subjects had non-response to greater than 
six weeks antidepressant treatment in the current episode at enrollment.  All subjects had 
moderately severe residual symptoms, with mean Hamilton Depression Rating Scale (HDRS17) 
(Hamilton, 1960) scores at entry of 19.5 + 4.4.  A total of 24 [O-15] water PET scans were 
performed at pre-treatment baseline. TNS then was initiated via bilateral supraorbital electrodes 
for periods of 60 sec during the PET scan sequence.  Half of the scans for each subject were 
acquired while receiving 60 sec TNS, and half with the device deactivated.  In device-on scans, 
the TNS system was activated at the time that the [O-15] water bolus was administered 
intravenously.  PET data were analyzed both by standardized volume of interest (sVOI) and 
statistical parametric  mapping (SPM) methods.  Both methods normalized local metabolism to 
whole brain activity.  SPM measured activity values within 240 standardized regions of interest 
that were clustered into 47 volumes.  PET data were contrasted for scans collected with and 
without TNS.  
 
There were significant differences between scans collected with and without TNS.  With only 
brief exposure to TNS, significant increases in regional cerebral blood flow were detected  in 
anterior cingulate gyrus (bilateral BA 32,24) and medial and middle frontal gyri of the DLPFC 
(right BA 6,8, 45, 46), as well as the inferior frontal gyrus (left BA 44,6,22) and parietotemporal 
cortex (bilateral BA 39,40).  All regions had peak voxels showing highly significant differences 
(p<0.0005) and significant cluster size (pcluster corr<0.05).  The largest activation cluster was in the 
left inferior frontal gyrus (pcluster corr=0.008). SPM findings were corroborated with sVOI analyses.  
These findings indicate that several key areas implicated in regulating mood and anxiety are 

  
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affected by TNS.  Future studies may clarify the role of these changes in regional activity in the 
mechanisms underlying symptom improvement with this novel approach to neuromodulation.   
 
Taken as a whole, these data present a compelling picture of the promise of TNS as an innovative 
potential treatment for mood and anxiety disorders.  Because of the limited pilot data available on 
TNS in PTSD, the fact that the sham condition has not been tested in subjects with PTSD, and the 
complex nature of TAU in PTSD, this pilot intervention study is a necessary step in development 
of the technology.   
 
17. Biological Samples 
We will request urine samples to test drug use for all participants and pregnancy in female 
participants. The sample will be discarded immediately after test results are confirmed (5-30 min. 
after sample is given). 
18. Anonymity or Confidentiality 
De-identified demographic, historical, and clinical data will be collected on each subject using the 
clinical and functional rating scales and entered into a secure SQL computer database.  Subjects 
will be identified in the database by a code number that will be stored in a logbook in a locked 
cabinet that will be accessible only to the PI, and the PI will oversee all data access.  No personal 
identifying information will be available to those analyzing data.  The only people who will have 
access to the Informed Consent forms or the data are members of the study research team.  
Informed Consent forms will not be attached to assessment instruments and will be stored in a 
separate locked cabinet from interview data forms.  Assessments will at no time contain names or 
identifiers of participants.  The above data confidentiality plan will be followed exactly as 
described and strictly enforced at all times. The research team and research sponsor (Department 
of Defense/USAMRAA) may use the research report and share it with others to perform more 
research, place it into research database (TNS-related research database, stored at UCLA), use it 
to improve the design of future studies, use it to publish articles or for presentations to other 
researchers, share it with the sponsor, or file applications with U.S. or foreign government 
agencies to get approval for new drugs or health care products. 
  
a) Records of participation in this study may only be disclosed in accordance with federal law, 
including the Federal Privacy Act, 5 U.S.C.552a, and its implementing regulations. DD Form 
2005, Privacy Act Statement - Military Health Records, contains the Privacy Act Statement for 
the records. These records may be examined at by staff from the appropriate IRBs as well as the 
US Army Medical Research and Materiel Command (USAMRMC), and other government 
agencies as part of their duties. These duties include making sure that the research participants are 
protected. Confidentiality of records will be protected to the extent possible under existing 
regulations and laws but cannot be guaranteed. To further protect privacy, a Certificate of 
Confidentiality will be obtained for this study. As required by law the site PI will report any child 
abuse or neglect to the Family Advocacy Program or to local child protective services. Participant 
names will not appear in any published paper or presentation related to this study. Research study 
staff will also abide by the Health Insurance Portability and Accountability Act (HIPAA) Risks. 
 
The physical research records will be stored in locked file cabinets within locked offices. Other 
data will be kept in locked offices on password-protected computers and in locked file cabinets, 
so that only members of the research team will have access to the information. The physically- 
and electronically-secure SQL database server will be employed as the main electronic data 

  
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repository; it will be located behind a dedicated firewall system. Data will be archived to an off-
campus backup server via an encrypted data communications link (e.g., rsync protocol employing 
ssh “tunnel”) to guard against data loss from on-campus catastrophe (e.g., fire, earthquake) and in 
compliance with HIPAA regulations. Research records will be retained for a period of five years 
after the latter of the following two dates: the date on which the investigation is terminated or 
completed and a study report accepted for publication, or the date that the records are no longer 
required for purposes of supporting a premarket approval application or a notice of completion of 
a product development protocol. 
 
Foreseeable risks of participation.  It is possible that some subjects may suffer a worsening of 
symptoms as a result of the assessments or discussing traumatic experiences during the intake 
process.  The assessments are likely to be no more upsetting, however, than standard clinical 
assessments and treatment.  Because subjects will recently have completed a course of PE 
treatment, they will be familiar with discussions of their symptoms and should not suffer any 
significant change in their condition.   
 
The primary risk of this sham-controlled treatment protocol is the potential for lack of clinical 
improvement.  Subjects may suffer some fluctuation or worsening of symptoms in either the 
active treatment arm (if the treatment is ineffective or they are a non-responder) or the sham arm 
(which, like a pill placebo, is designed not to be effective).  Evidence would suggest that the TNS 
procedure itself carries minimal risk.  The external nerve stimulator for TNS in this project is not 
implanted, and the stimulation provided through cutaneous electrodes on the forehead.  The 
procedure is safe and well tolerated, having been performed in more than 100 subjects over eight 
years as an adjunctive treatment for medication-resistant epilepsy (DeGiorgio et al., 2003; 2006; 
2009; Heck et al., 2011), as a treatment for MDD (Schrader et al., 2011; Cook et al., 2013), and 
most recently in our group, in subjects with PTSD or MDD (unpublished data).  It has been 
examined in preliminary studies for its efficacy, tolerability, and safety profile.  For subjects with 
epilepsy, TNS was very well tolerated.  No serious adverse events due to the stimulator or 
stimulation occurred.  Side effects included skin irritation in approximately one-third of subjects 
who were wearing the stimulator continuously in early epilepsy trials, and this adverse effect was 
ameliorated by reducing the duration of stimulation to 12-16 hours per day.  In the current study, 
subjects will wear the stimulator for only 8 hours per day (while they sleep).  The use of 
hydrocortisone 1% cream applied topically also can be helpful with skin irritation.  Some subjects 
reported sensations of tingling, pressure, or headache, and lowering the current of stimulation was 
used to address any discomfort for these individuals.  Vital signs were monitored and there were 
no significant effects on heart rate, systolic blood pressure, or diastolic blood pressure, either with 
acute exposure to stimulation (i.e., first hour of device use) or after six months of daily use.  For 
the subjects who have completed our pilot studies of TNS in PTSD or MDD, none has 
experienced serious adverse events related to the use of the device.  In these studies, none 
developed skin irritation requiring the use of hydrocortisone cream or reduction in the number of 
hours of use each day.  Use of the system was not limited by any sensation experiences, and there 
were no significant effects on vital signs, similar to the findings in subjects using TNS for 
epilepsy as above.  One subject who did not respond to treatment did commit suicide during the 
last week of participation in the current open label PTSD protocol.  This subject had consistently 
denied any suicidal ideation on his bi-weekly symptom ratings.  This adverse event was reviewed 
by the UCLA IRB and was determined not to be related to use of the device.   
 

  
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We have carefully reviewed FDA guidance, and believe this is a NSR device because (a) it does 
not meet the FDA’s criteria for being a Significant Risk (SR) device (per 21 CFR 812.3(m)) and 
(b) the FDA has previously classified non-implanted TENS devices as NSR devices when used to 
stimulate cutaneous nerves for the treatment of pain in the same general way that this study will 
stimulate cutaneous nerves (branches of cranial nerve V) for a different indication (i.e., a 
psychiatric disorder).  The UCLA IRB has determined that use of the Monarch system to provide 
TNS qualifies as a Non-Significant Risk (NSR) investigational device  under FDA guidelines and 
as such is governed by the provisions of the Abbreviated IDE process.   
 
 Management of the Risks of Participation.  For the project proposed here, we will submit 
requests to the VA GLA and UCLA IRBs to classify the TNS system as non-significant risk  
(NSR) for the purpose of this study.  The NSR process will be administered by the VA GLA and 
UCLA IRBs as delegated by the FDA per 21 CFR 812.2(b), and will involve review and 
concurrence with the investigator-sponsors’ determination that this is an NSR device, and that the 
investigators will adhere to the rules and regulations specified for NSR device studies.  In 
accordance with FDA guidance, we will follow the abbreviated requirements at 21 CFR 812.2(b): 
• 
Labeling:  all devices will be labeled in accordance with §812.5 with the text 
“CAUTION: Investigational device. Limited by Federal (or United States) law to 
investigational use.”  All subjects will also receive a statement concerning relevant 
contraindications, hazards, adverse effects, interfering substances or devices, 
warnings, and precautions (attached). 
• 
IRB approval:  this study will not commence until IRB approval is granted 
• 
Informed consent:  all research subjects will provide informed consent under 21 
CFR 50, and this will be document with the study’s Informed Consent Form, as 
approved by the VA GLA and UCLA IRBs. 
Monitoring:  we will comply with the monitoring methods described in the project 
protocol, including monitoring for any unanticipated adverse device effects; 
adverse events will be reported to the VA GLA and UCLA IRBs in accordance 
with IRB policies. 
• 
Records: records will be maintained regarding use of the devices and will be 
available for VA GLA and UCLA IRBs and FDA inspection [§812.140(b)(4)] as 
needed, including 
o 
the objectives of the investigation;  
o 
a brief explanation of why the device is not a significant risk device;  
o 
the name and address of each investigator;  
o 
the name and address of the VA GLA and UCLA IRBs;  
o 
a statement of the extent to which the good manufacturing practices (21 
CFR 820) were followed in manufacturing the device by the outside 
manufacturer 
o 
records concerning complaints and adverse device effects whether 
anticipated or not [§812.140(b)(5)] 
o 
any other information required by FDA 
• 
Reporting:  the investigators will report to the full research team and the VA GLA 
and UCLA IRBs any unanticipated adverse device effects, changes in IRB 
approval status, protocol deviations, or other events, in accordance with IRB 
policies. 
• Compliance with prohibitions:  §812.7 prohibits promotion or misrepresentation of the device 
and other practices (e.g., any advertisements for recruitment of research subjects will be 

  
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approved by the VA GLA and UCLA IRBs before use; the device will be represented as 
investigational and not as FDA-cleared for this indication). 
 
The overall risks of clinical worsening in this study are mitigated because all subjects will be 
able to receive some naturalistic non-study treatment in the clinic.  Specifically, subjects will be 
permitted to continue to receive medications so long as they have been on a stable dose for at 
least six weeks.  They also will be able to participate in a number of groups or psychotherapies 
while in the study.  All subjects will continue to be followed as regular patients in the PTSD 
Clinic or the Domiciliary Care Program, so that if additional intervention is needed, subjects 
will be called to the attention of the staff who will be available to respond.   
 
We anticipate that any symptom worsening that the subjects would experience due to evaluation 
or ongoing ratings would be short-lived and mild in intensity.  Nevertheless, we will have 
procedures in place to ensure subject safety at all times during evaluation and treatment.  
Participants will be fully advised about all study procedures and risks through the informed 
consent process.   They also will be advised that they can refuse to answer any questions that 
they find intrusive or upsetting or can stop the interview at any time.  Any subject who shows 
significant distress will be observed carefully and will be asked to remain with study personnel 
until safety can be assured.  All subjects also will be reminded at each visit about the 
availability of their study clinician should the subject develop any event of concern, including 
suicidality or adverse events.  PTSD Clinic or Domiciliary Care Program staff will be contacted 
immediately during regular working hours if there are any concerns about the subjects’ 
emotional state or safety.  Because all subjects will be patients of the PTSD Clinic or 
Domiciliary Care Program, they are eligible for emergency services at the VA GLA Healthcare 
System, including inpatient hospitalization on the same station as the Clinic.  If clinic staff are 
not immediately available to handle a subject in need of immediate care, he or she will be taken 
by research staff to the VA GLA Emergency Department (ED) or, as needed, to another 
emergency facility that may be closer to where the subject is located (e.g., if an individual's 
condition deteriorates while at home).  Study physicians may petition the subject to be brought 
involuntarily to the nearest emergency room if necessary, as provided for under state mental 
health laws in California where the study is being conducted.  Physicians will be available 24/7 
on pager for emergencies, and will ensure that appropriate emergency facilities will be used 
after hours and on weekends for sudden worsening of clinical status.   
 
Should an adverse event emerge, the subject will be instructed to contact his/her study physician 
who will assess the clinical significance of the event.  This assessment will categorize the 
serious adverse event (SAE) as emergent or non-emergent.  For non-emergent events, the 
physician will manage as they see fit.  Rapid consultation with the Principal Investigator is 
available at the physician’s request; the PI will be responsible for reporting the event as an SAE 
per study protocol.  If a consultation with the PI is not pursued in real-time, the physician will 
inform the PI of the event within 24 hours of having identified the event.  All reports of adverse 
events will be reported to the relevant Institutional Review Board in accordance with its 
policies, as well as to the Medical Monitor (Dr. Krantz).  Reports for serious events that may be 
related to participations also will be reported to the Army Human Research Protection Office 
(HRPO).   
 

  
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The medical research monitor for this study will be David Krantz, Ph.D.,M.D.  He is 
responsible for overseeing the safety of the research and report observations/findings to the IRB 
or a designated institutional official. The Research Monitor will review all unanticipated 
problems involving risks to subjects or others associated with the protocol and provide an 
independent report of the event to the IRB. The Research Monitor may discuss the research 
protocol with the investigators; shall have authority to stop a research protocol in progress, 
remove individual human subjects from a research protocol, and take whatever steps are 
necessary to protect the safety and well-being of human subjects until the IRB can assess the 
monitor's report; and shall have the responsibility to promptly report their observations and 
findings to the IRB or other designated official and the HRPO. 
  All serious adverse events and unanticipated problems will be reported to the monitor within 
24 hours of occurrence.  He will issue a written opinion on the relationship of study procedures 
to the event and this report will be filed with the IRBs and kept in the subject’s file.  The 
medical monitor will indicate whether he concurs with the details of the event as reported by the 
investigator.  Reports for serious events that may be related to participations also will be 
reported to the Safety Monitoring Committee (SMC) that will be created for this study and the 
HRPO.  If in his professional opinion, the procedures of the study pose a risk to subjects, he will 
have the authority to halt the study at any time.  The SMC will meet every six months or more 
often as deemed necessary by the chair of the Committee, Dr. Krantz, and will be composed of 
three physicians on the UCLA and/or VA medical staff who are unaffiliated with the study and 
without any conflicts of interest regarding this study.  The SMC will review SAEs that occur in 
the study after the medical monitor has reviewed them and will have the authority to halt the 
study at any time for reasons of subject safety.  If this should happen, the relevant IRBs and 
HRPO would be notified.   
 
19. Benefits:  
If TNS proves to be an efficacious treatment, subjects who receive the active treatment may have 
a significant reduction in their symptoms and would benefit from this innovative treatment.  
Subjects in this study will receive a level of interpersonal interaction and follow-up care from a 
research coordinator that is of greater intensity than they ordinarily would receive in the PTSD 
Clinic or Domiciliary Care Program, which may provide some symptom reduction whether or not 
the subject receives some benefit from TNS.   
 
In addition to the possible direct benefits to subjects, this project offers significant benefits to 
patients suffering from PTSD.  This novel treatment could be a safe, non-pharmacologic 
adjunctive therapy for the treatment of PTSD symptoms.  Given the substantial residual 
symptoms that patients have after completing either psychological or pharmacological therapy, 
there is a great need for novel treatments.  TNS could help fill a significant gap in our current 
treatment armamentarium.   
 
20. Assessment of Risk:Benefit ratio 
The objective of this preliminary study is to examine the potential efficacy of TNS as an 
adjunctive treatment in veterans with PTSD.  This method of brain stimulation has shown promise 
for the treatment of MDD (Schrader et al., 2011; Cook et al., 2013).  The treatment is very easy to 
use; subjects simply apply the two electrodes to their forehead, and the stimulation is provided 
through wires attached to a stimulator about the size of a deck of cards.  Subjects will go to bed so 
that they can sleep with the stimulator on for approximately eight consecutive hours per night.  If 

  
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they have difficulty sleeping, subjects may also be awake during the treatment.  In early trials, 
subjects reported no significant adverse events and that the treatment is convenient and acceptable 
to them (Schrader et al., 2011; Cook et al., 2013).  We have conducted preliminary, open-label 
studies of TNS in subjects with PTSD (described above) and have shown that the treatment is 
well-tolerated and is associated with a significant improvement in PTSD symptoms.   
 
The risks for the TNS treatment in this study is categorized as a non-significant risk. We have 
taken all the steps necessary to minimize possible risks/adverse events and have received postive 
results with this device in regards to efficacy and safety. We are confident that the potential 
benefits to participants and society outweigh the risks.