Enhancing Prolonged Exposure Therapy for PTSD With Oxytocin
Phase: PHASE2
Conditions: PTSD
Sponsor: VA Office of Research and Development

V17 8/19/24 
Title of Study: Enhancing Prolonged Exposure Therapy for PTSD with Oxytocin 
NCT04228289 
Document Date: 8/19/2024 
 
 

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Protocol Title: Enhancing Prolonged Exposure Therapy for PTSD with Oxytocin 
PI: Julianne Flanagan, PhD 
 
SPECIFIC AIMS 
Posttraumatic stress disorder (PTSD) is a chronic, debilitating condition and the most common mental 
health disorder among treatment-seeking Veterans1,2. The high rates of disability and healthcare utilization 
among Veterans with PTSD result in substantial economic burden for the individual Veteran, their family, and 
our nation3. Veterans with untreated PTSD are at risk of developing other mental health problems (e.g., 
depression, anxiety, suicidal ideation, and substance abuse), as well as social and occupational impairment. 
Prolonged Exposure (PE) therapy is a highly efficacious, evidence-based, cognitive-behavioral treatment for 
PTSD4,5. In 2007, a nationwide rollout of PE was initiated at the direction of the VA Mental Health Services in 
order to train VA clinicians across the country in the delivery of PE. While the nationwide rollout of PE was an 
important step in reducing the burden of PTSD among Veterans, there is an immediate need for empirical data 
to further enhance PE retention and outcomes. Although PE is one of the most effective treatments for PTSD, 
approximately 30% of patients dropout before treatment completion4,6-10 and a significant proportion of patients 
who do complete PE continue to experience unremitting PTSD symptoms2,11. Furthermore, in comparison to 
civilians, Veterans demonstrate the highest dropout rates and the lowest treatment response to PE7. Thus, there 
is a critical need to develop effective strategies to optimize the delivery of PE and improve outcomes for Veterans 
with PTSD. Building on promising preliminary data, the proposed study directly addresses this 
knowledge gap by testing the efficacy of oxytocin in combination with PE to accelerate reduction in 
PTSD severity and improve treatment retention and adherence.  
Accumulating research indicates that the neuropeptide oxytocin is a promising candidate to augment PE. 
Higher endogenous oxytocin levels are associated with improved fear extinction12, which is a central component 
underlying the positive effects of PE. In addition, preclinical and clinical research show that oxytocin has 
anxiolytic effects13,14 and attenuates fear responses12,15,16. Therefore, converging evidence suggests that 
augmenting PE with oxytocin may simultaneously target the neurobiological and psychosocial underpinnings of 
PTSD, and result in improved treatment outcomes17-20. Our team conducted a proof-of-concept study to examine 
the combination of PE and oxytocin. In this randomized, placebo controlled, double-blind pilot study we found 
that individuals with PTSD who were treated with PE and intranasal oxytocin (40 IU) for 10 weeks demonstrated 
greater reduction in PTSD severity and depression as compared to those treated with PE and placebo. 
Furthermore, the combination of PE + oxytocin was safe, feasible and well tolerated.  
The primary objective of the proposed two-site Phase II study is to evaluate the ability of oxytocin in 
combination with PE to (1) reduce PTSD severity and (2) enhance retention and adherence rates among 
Veterans (N=210) with current PTSD. Secondary objectives are to evaluate oxytocin in combination with PE in 
improving associated areas of functioning (e.g., depression, sleep, aggression). We will also include 
physiological measurements to investigate mechanisms of change and identify prognostic indicators of positive 
treatment response. In order to accomplish this we will employ an intent-to-treat, double-blind, placebo-controlled 
randomized controlled trial that will consist of 10 weeks of PE treatment and intranasal oxytocin (40 IU) or 
placebo medication delivered prior to each PE session. We will also examine standardized, repeated dependent 
measures of: (a) PTSD symptom severity, (b) rate of PTSD symptom reduction and time to diagnostic remission, 
and (c) treatment retention and adherence. The following specific aims are proposed: 
 
Specific Aim 1:  Examine the efficacy of PE + oxytocin vs. PE + placebo in reducing self-report and clinician-
rated PTSD symptomatology.  
Specific Aim 2:  Evaluate the ability of intranasal oxytocin, as compared to placebo, to accelerate PTSD 
symptom reduction (i.e., slope of change) and time to diagnostic remission. 
Specific Aim 3:  Examine the efficacy of PE + oxytocin vs. PE + placebo in improving treatment retention and 
adherence (e.g., number of sessions attended, homework compliance). 
 
The proposed study will address critical questions regarding the potential of oxytocin as an effective 
pharmacotherapy to improve PE outcomes and retention among Veterans. This study has the particular 
advantage of building directly on positive preliminary findings; using a double-blind, placebo-controlled 
randomized design; measuring functioning in related areas, such as depression, suicidality, and aggression and 

V17 8/19/24 
employing a multidisciplinary team of experts who have successfully collaborated in the past and are uniquely 
qualified to implement this type of investigation. This project is directly responsive to the mission of the Veterans 
Health Administration Blueprint for Excellence in that it seeks to advance mental health care for Veterans. The 
findings from this study have the potential to significantly improve the standard of patient care, advance the 
science in the area of PTSD, and decrease public health expenditures among Veterans. 
 
BACKGROUND AND SIGNIFICANCE 
Overview. As a result of sustained operations in Iraq and Afghanistan, a large and growing number of 
Veterans are suffering from posttraumatic stress disorder (PTSD). Approximately 11% of the 8 million Veterans 
receiving care at the Department of Veterans Affairs (VA) are diagnosed with PTSD21, resulting in enormous 
healthcare expenditures for our nation3. While several behavioral interventions for PTSD have demonstrated 
efficacy, there remains a scarcity of effective pharmacological treatments for PTSD and ample room to improve 
existing behavioral interventions. To address this critical need, this two-site, Phase II, randomized, placebo-
controlled trial will examine the synergistic effects of combining a novel pharmacotherapy (oxytocin) with an 
evidence-based treatment for PTSD (i.e., Prolonged Exposure therapy). We will examine the amount and rate 
of reductions in PTSD severity, treatment retention and adherence, and improvement in associated areas of 
functioning (e.g., depression, aggression, suicidality, sleep). This project may help optimize PTSD treatment, 
reduce the individual, familial, and societal burden associated with PTSD, and reduce public health 
expenditures associated with PTSD among Veterans. 
PTSD among Veterans. Compared to civilians, Veterans incur a four-fold heightened risk for PTSD22,23.  
PTSD is a highly prevalent, chronic, and debilitating psychiatric condition characterized by: (1) intrusive 
cognitions, memories, and nightmares; (2) avoidance of people, places or situations that are reminders of the 
traumatic event(s); (3) negative cognitions and mood (e.g., thoughts and feelings related to guilt and shame); 
and (4) alterations in arousal and reactivity (e.g., trouble sleeping, aggression, exaggerated startle response). 
PTSD is the most commonly diagnosed mental health condition among U.S. military and Veteran populations1, 
and it is associated with extensive health and economic burdens. If left untreated, Veterans with PTSD are at 
risk for developing other psychiatric problems (e.g., depression), suicidality, interpersonal violence, physical 
health problems, neuropsychological impairment, increased mortality, unemployment, and family/occupational 
impairment. Recent estimates suggest that the cost of treating PTSD and depression alone, solely among Iraq 
and Afghanistan war Veterans, has exceeded $900 million3. Therefore, the need to optimize PTSD treatment 
outcomes among Veterans is paramount.  
Prolonged Exposure (PE) Therapy for PTSD. PE is a manualized, cognitive-behavioral treatment 
consisting of 10 weekly, 60-90 minute individual therapy sessions24. Based on Pavlovian learning theory, the 
central therapeutic component of PE involves repeatedly presenting a conditioned stimulus (i.e., a trauma 
reminder) (1) imaginally and (2) in-vivo (in the environment) in the absence of the unconditioned stimulus (i.e., 
the traumatic event). Abundant evidence documents the efficacy of PE for the treatment of PTSD across diverse 
clinical populations including Veterans from various eras of service6,25. On average, PE demonstrates a robust 
improvement of 1-2 standard deviations in symptom severity4,25,26. PE is recognized by the VA and the 
Department of Defense as one of only four evidence-based psychotherapies with sufficient empirical evidence 
to be deemed effective in the treatment of PTSD27. Indeed, PE is a “gold standard,” first-line psychosocial 
treatment for PTSD5. VA clinicians nationwide are trained to deliver PE; thus the proposed study will leverage 
an evidence-based treatment that is already widely implemented in VA healthcare settings across the country. 
While PE consistently outperforms control and waitlist conditions in randomized clinical trials8,26, there is a critical 
need to improve retention and there is substantial room to improve outcomes. PE dropout rates are 
approximately 30%2,10,28, with the highest dropout rates observed in military and Veteran populations7. Indeed, 
many Veterans struggle with distress and avoidance during treatment, and fail to receive an adequate dose of 
PE therapy9,10,24,29. As a result, a substantial proportion of Veterans maintain clinically significant symptoms 
and/or continue to meet diagnostic criteria for PTSD following an incomplete “dose” of PE treatment2. 
Pharmacological augmentation strategies may help optimize PE treatment response, enhance treatment 
retention and adherence, and significantly improve long-term outcomes for Veterans with PTSD.  
Pharmacotherapies for PTSD. The PTSD Psychopharmacology Working Group within the VA Office 
of Research and Development recently determined that investing in the development of novel medications to 
treat PTSD is an urgent public health priority for our nation30. Findings from this group note that because 

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substantial advancements have been made in the science examining the neurobiology of PTSD, clinical trials 
examining novel medications are particularly critical to advance PTSD treatments for Veterans. While many 
medications have been investigated, only selective serotonin reuptake inhibitors (SSRIs) have received FDA 
approval to treat PTSD. However, findings show that only 20-30% of patients experience PTSD remission with 
SSRI treatment31. SSRIs have also not demonstrated improved patient tolerability or retention in psychotherapy, 
and results are mixed regarding whether augmenting PE with SSRIs is superior to PE alone32. Overall, little 
progress has been made toward developing new pharmacotherapies for PTSD.  
Neurobiological Mechanisms Underlying Oxytocin Treatment of PTSD. Dysregulation of the 
oxytocin system, which includes functional impairments in the hypothalamic-pituitary-adrenal (HPA) axis and 
corticolimbic brain regions such as the prefrontal cortex (PFC) and amygdala (AMY), are well-established 
biomarkers of PTSD pathophysiology and maintenance. Individuals with PTSD evidence lower basal oxytocin 
levels as compared to healthy controls33, although one recent study found that endogenous oxytocin levels did 
not predict PTSD development over combat exposure34. Moreover, variants in the oxytocin receptor gene have 
been linked to the brain’s responsiveness to stress. For example, recent findings from the National Health and 
Resilience in Veterans Study found that one polymorphism in the oxytocin receptor gene, in combination with 
attachment style, contributed to risk for PTSD among Veterans35.  
With regard to corticolimbic brain functioning, recent imaging studies demonstrate hypoactivation of the 
PFC and hyperactivation of the temporal lobe (including AMY and hippocampus) among individuals with PTSD36. 
Compared to healthy controls, individuals with PTSD exhibit hyperactive AMY and hypoactive medial PFC 
activity37, and significant uncoupling between the medial PFC and the AMY during symptom provocation and at 
rest38. Dysregulation of the PFC-AMY circuitry makes it difficult to modulate repetitive cognitions (e.g., intrusive 
trauma-related memories), and impairs working memory, executive decision making, ability to distinguish 
between a memory vs. reality (e.g., flashbacks), and emotional control (e.g., exaggerated startle response)39,40. 
Importantly, oxytocin attenuates AMY reactivity and increases resting state connectivity between corticolimbic 
brain regions41. A recent study by our group demonstrates that oxytocin improves working memory and mitigates 
hyperactive AMY responses to fearful faces among individuals with PTSD compared to trauma-exposed resilient 
controls19,42. Oxytocin is a promising candidate to help restore the neurobiological impairments underlying PTSD 
and enhance long-term outcomes. 
Behavioral Mechanisms Underlying Oxytocin Treatment of PTSD. Data indicate that central and 
systemic oxytocin administration exerts anxiolytic and anti-stress properties in animal models14,43, and oxytocin 
has anxiolytic and prosocial effects in individuals with PTSD, including increased trust, empathy, compassion, 
and improved social cue recognition13,44,45. Oxytocin has demonstrated the ability to reduce neurobiological 
reactivity to social stress among healthy individuals and those with PTSD using laboratory paradigms such as 
the Trier Social Stress Task46. In addition, oxytocin enhances fear extinction recall in healthy individuals, 
suggesting that oxytocin has potential as an adjunct therapy for extinction-based PTSD treatments such as PE 
15,18,47. A recent cross-sectional study among patients with PTSD found that a single dose of oxytocin had positive 
effects on anxiety, irritability, mood, intensity of intrusive thoughts, and desire for social interaction48. Our team 
recently found that pairing PE with weekly doses of oxytocin, as compared to placebo, resulted in lower self-
reported PTSD and depression symptoms at end of treatment47. Dr. Miranda Olff (Consultant) and others have 
shown that oxytocin may synergistically mitigate some of the most salient behavioral, physiological, and social 
underpinnings of PTSD, thereby facilitating therapeutic alliance, adherence, and engagement, all of which are 
critical for positive outcomes in PTSD treatment49.  
Summary. PTSD is a chronic, debilitating and common mental health disorder among Veterans. 
Prolonged Exposure (PE) therapy is an evidence-based treatment for PTSD that is widely used in VA clinics 
nationwide4,6,7. However, there is significant room for improvement with regard to PE retention and treatment 
response2,28. Oxytocin is a promising candidate pharmacotherapy to enhance PE treatment outcomes and 
retention in Veterans with PTSD. Oxytocin has well-documented positive effects on interpersonal behavior and 
cognition, as well as fear extinction and neurobiological underpinnings of PTSD in human and animal studies13,15. 
The proposed project will examine the efficacy of combining PE with oxytocin to enhance treatment outcomes 
and retention in Veterans with PTSD.  
 
 
 

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RESEARCH DESIGN AND METHODS 
Overview. The proposed study is a 10-week, Phase II, double-blind RCT examining the efficacy of 
combining Prolonged Exposure (PE) with intranasal oxytocin for the treatment of PTSD among Veterans. A 
repeated measures design with two intervention arms will be used: PE + oxytocin vs. PE + placebo (see Figure 
3). 
 
Figure 3. Overview of Study Design 
 
 
 
 
 
 
Participants. Participants will be 210 VAMC Veterans (specifically regarding the Charleston site, n=105 
Veterans must be enrolled at RHJ VAMC or eligible for care) with current PTSD. Inclusion criteria are: (1) male 
or female; any race or ethnicity; aged ≥ 18 years, (2) English fluency and intellectual functioning sufficient to 
provide informed consent and complete assessments (as assessed by a criterion of ≥ 26 on the Mini-Mental 
Status Exam [MMSE]50), (3) meet DSM-5 criteria for current PTSD (assessed via the CAPS-5), and (4) 
participants taking psychotropic medications will be required to be maintained on a stable dose for at least one 
month before study initiation. This is because initiation or change of psychotropic medications during the study 
may interfere with interpretation of results. In the event of telehealth, the MMSE will only be administered if 
deemed necessary. Exclusion criteria include: (1) meeting DSM-5 criteria for psychotic, bipolar or substance use 
disorders (those participants will be referred clinically), (2) participants who present a serious suicide or homicide 
risk or are likely to require hospitalization during the study, (3) participants on maintenance psychotropic 
medications initiated during the past month, and (4) pregnancy or breastfeeding for women. See Human Subjects 
section for additional exclusion criteria. 
Recruitment. The primary recruitment sites will be the outpatient PTSD Treatment Clinics (PCT) at the 
Ralph H. Johnson VAMC (directed by Dr. Bethany Wangelin, Co-I) and the San Francisco VAMC (directed by 
Dr. William Wolfe (Co-I). Participant referrals will also be received from clinicians at affiliated VAMCs and 
community-based outpatient clinics (CBOC), as well as referrals from other studies operating at the Medical 
University of South Carolina (MUSC) and the University of California, San Francisco (UCSF). Participants will 
also be recruited through IRB-approved flyers in (a) VAMC Women’s Health Clinics, Primary Care Clinics, 
Emergency Departments, and throughout the VAMC common areas and additional treatment clinics; (b) in 
affiliated CBOCs; (c) in MUSC and UCSF treatment clinics; and (d) via direct mailing. Finally, we will place 
advertisements on social networking sites (e.g., Craigslist, Facebook) and in local newspapers. Our research 
teams have used these methods successfully in previous RCTs among Veterans with PTSD. To maximize 
retention, participants will be asked to list the names and contact information of two family members or close 
contacts.  
Screening, Eligibility, and Informed Consent. Initial eligibility will be conducted by the PI, Co-Is, 
Coordinator, or a trained Research Assistant by telephone or in person. Following phone screening for 
preliminary eligibility, participants will be given a full description of the study procedures and asked to read and 
sign an IRB- and VA R&D-approved informed consent form before any study procedures are conducted. Consent 
will take place in a private office or via telemedicine and will be conducted by trained staff, including the PIs, Co-
Is, or Study Coordinators. Ineligible participants will be referred clinically for treatment. Individuals who meet 
inclusion/exclusion criteria will be invited to come into the office or will schedule a telemedicine appointment for 
a baseline assessment.  
VA eConsent: In the case of VA eConsent, study staff will send the paper consent document to the 
study participant via email or snail mail prior to the consent and baseline appointment. Study staff will arrange 
to have a call with the study participant where the study participant will sign the physical consent form and/or 
sign electronically via Docusign. This electronic signature would then be saved by the study staff as 
documentation.  
Randomization 
Oxytocin n= 105 
Placebo n= 105 
 
Informed 
Consent & 
Baseline 
Assessment  
Follow-Up 
at 3 & 6 
Months 
 
Treatment Phase Weeks 1 - 10 
Weekly Prolonged Exposure Therapy and AE monitoring  
Oxytocin (40 IU) or placebo prior to each session 
 

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General Procedures. All procedures will be conducted at the Ralph H. Johnson VA Medical Center 
(RHJVAMC) or through VA approved telemedicine interface (consent, baseline appointment, weekly 
assessments, prolonged exposure therapy via VVC, MUSC DoxyME, Microsoft Teams, Zoom OR WebEX). 
Participants will be consented via telemedicine only if and when consent via telemedicine is approved at VA. 
Following phone screening for preliminary eligibility and informed consent, participants will complete a baseline 
assessment. During the baseline visit, participants will complete a pregnancy test (for women of childbearing 
potential), a history and physical (H&P) exam, and a battery of standardized self-report and interview measures 
(Table 2). H&P exams will include a physical and neurological examination; orthostatic blood pressure and pulse 
measurements; and weight and body mass index calculation (BMI). In the case of telemedicine, female 
participants will be shipped pregnancy tests and will be asked to take the pregnancy test at home (as opposed 
to in the office) and confirm a negative result prior to enrollment in this study. Basic information such as blood 
pressure, pulse, weight and BMI will be obtained by CPRS record, self-report from the participant, or provided 
from a recent medical appointment (past 3 months). This information will be reviewed by trained medical staff 
during the H&P exam.  An IRB-approved clinician and Co-I on the SFVAMC team will direct the PTSD 
assessment core for the proposed project via telemedicine, described below.  
Provided full eligibility criteria are met, participants will enter the treatment phase, which is a 10-week, 
double-blind, placebo controlled RCT during which they will receive weekly PE therapy sessions in combination 
with intranasal oxytocin or placebo. Following completion of the week 10 therapy visit, participants will also 
complete 3- and 6-month follow-up visits. PTSD symptoms, treatment adherence, and functioning in associated 
areas (e.g., depression, aggression, sleep) will be assessed weekly. Women of childbearing potential will 
complete weekly pregnancy tests prior to receiving the medication. Participants’ heart rate and skin conductance 
will be measured continuously throughout each PE session. All procedures that take place via telemedicine will 
be performed and completed as though they were in-person/in-office. Data will be collected and entered 
electronically using the MUSC or UCSF REDCap database allowing for study participants to complete 
assessments via survey links. A copy of all data will be stored on the VA server. Data will be securely stored 
using MUSC or UCSF REDCap and will not leave the VA.  
Primary Outcome Measures. Primary outcomes include (1) clinician-rated PTSD diagnosis and 
symptom severity (CAPS-551) and (2) self-reported PTSD symptom severity (PCL-552).  In order to ensure that 
CAPS-5 assessment is conducted in a standardized manner across sites by reliable interviewers, all clinical 
assessors will have completed the accredited VA Employee Education System CAPS-5 training program (VA 
TMS 31134). Assessors who demonstrate reliability with at least two pilot cases will then conduct assessments 
with participants through VAMC approved telemedicine program. Assessment supervision will occur bi-weekly 
or more as needed, and cases will be discussed and adjudicated as necessary in collaboration with PIs. 
Additional proposed assessment measures have strong psychometric properties and have been used 
successfully in our group’s previous and ongoing research among Veterans with PTSD. 
 
Telemedicine. Participants in this research study may choose to complete this study via telemedicine 
home-based telemedicine (HBT) care (i.e., service delivery to patients in their homes using consumer friendly, 
video-conferencing technology) which may likely enhance retention by directly circumventing financial and 
transportation barriers associated with traveling to RHJVAMC for in-person sessions. HBT sessions will be 
delivered via standard desk, laptop computer, tablet, or smartphone running VA approved applications. In the 
case of telemedicine, assessments will be administered via telemedicine by trained, IRB approved facilitators 
located at the SFVA or RHJVAMC. All telemedicine procedures will be completed as though they were being 
performed in person. Study participants who participate via telehealth will complete assessments utilizing 
password protected, individualized MUSC REDCap surveys.  
 
 

V17 8/19/24 
 
Table 2. Assessment Instruments and Timeline 
Instrument 
Purpose 
BSL 
WK   
1-10 
WK 
5 
WK 
10 
3M 
F/U 
6M 
F/U 
Online/Phone Screener 
Assess initial eligibility 
X 
 
 
 
 
 
Locator Form 
Comprehensive patient locator 
X 
 
 
 
 
 
History & Physical (H&P) 
Assess health and medical history 
X 
 
 
 
 
 
Birth Control Form 
Ensure participant safety 
X 
 
 
 
 
 
Pregnancy Testing 
Assess pregnancy for women 
X 
X 
X 
X 
 
 
Concomitant Medications Form 
Assess concomitant medications 
X 
X 
X 
X 
X 
X 
Demographics Form 
Characterize sample 
X 
 
 
 
 
 
Military Service Demographics 
Assess military service information 
X 
 
 
 
 
 
Mini-Mental Status Exam [MMSE]50 
Screen for cognitive impairment 
X 
 
 
 
 
 
Quick Structured Clinical Interview for DSM-5 Disorders 
(QuickSCID-5)55 
Assess DSM-5 psychiatric disorders 
X 
 
 
 
 
 
Life Events Checklist for DSM-5 (LEC-5)53 
Assess lifetime trauma exposure 
X 
 
 
 
 
 
Clinician Administered PTSD Scale (CAPS-5)51 
Primary Outcome: PTSD 
X 
 
X 
X 
X 
X 
PTSD Checklist (PCL-5)52 
Primary Outcome: PTSD 
X 
X 
X 
X 
X 
X 
Patient Health Questionnaire (PHQ-9)56 
Assess depression symptoms 
X 
X 
X 
X 
X 
X 
Columbia-Suicide Severity Rating Scale (C-SSRS)57 
Assess suicidality 
X 
 
X 
X 
X 
X 
Insomnia Severity Index (ISI)58 
Assess sleep functioning  
X 
 
X 
X 
X 
X 
Buss Perry Aggression Questionnaire (BPAQ)59 
Assess severity of aggression 
X 
 
X 
X 
X 
X 
State-Trait Anxiety Inventory (STAI)86 
Assess anxiety 
X 
 
 
X 
 
 
Timeline Follow Back (TLFB)80 
Alcohol, tobacco, and drug use 
X 
 
 
 
 
 
Alcohol Use Disorders Identification Test (AUDIT)78 
Assess alcohol use 
X 
 
 
 
 
 
Drug Abuse Screening Test (DAST-10)79 
Assess drug use 
X 
 
 
 
 
 
Fagerstrom Test for Nicotine Dependence87 
Assess nicotine use 
X 
 
 
 
 
 
Adverse Childhood Experiences (ACE) Questionnaire81 
Assess childhood trauma 
X 
 
 
 
 
 
Combat Exposure Scale (CES)82 
Assess wartime stressors 
X 
 
 
 
 
 
(Revised) Conflict Tactics Scale (CTS2)83 
Assess intimate partner violence 
X 
 
 
 
 
 
Dyadic Adjustment Scale (DAS-7)84 
Relationship functioning 
X 
 
 
 
 
 
Experiences in Close Relationship Scale (ECR-S)85 
Assess adult attachment 
X 
 
 
 
 
 
 Moral Injury Events Scale89 
Assess morality 
X 
 
 
 
 
 
 Psychological Stress Associated with COVID1988 
Assess stress associated with COVID19 
X 
 
 
 
 
 
Adverse Events Form 
Assess adverse events 
 
X 
X 
X 
X 
X 
Treatment Services Review 
Monitor service utilization 
 
X 
X 
X 
X 
X 
Treatment Adherence 
Primary Outcome: Homework compliance 
 
X 
X 
X 
 
 
Utility of Techniques Inventory (UTI)54 
Assess treatment adherence 
 
X 
X 
X 
 
 
Visual Analogue Scale61(VAS) 
Assess subjective reactivity 
 
X 
X 
X 
 
 
Physiological measures (Heart Rate, Skin Conductance) 
Assess physiological reactivity 
 
X 
X 
X 
 
 
Helping Alliance Questionnaire, Therapist and Client Version62 
Primary Outcome: Therapeutic Alliance 
 
 
X 
X 
 
 
Penetration of the Blind Assessment 
Assess participant/clinician blinding 
 
 
 
X 
 
 
Charleston Psychiatric Outpatient Satisfaction Scale63 
Assess patient treatment satisfaction 
 
 
 
X 
X 
X 
BSL = Baseline. WK = Week. F/U = Follow-Up. 

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PTSD Diagnosis and Symptom Severity 
• Clinician Administered PTSD Scale (CAPS-5)51 is a structured diagnostic interview with excellent psychometric 
properties and diagnostic efficiency. The CAPS-5 will be administered via telemedicine by trained study team 
members. 
• Life Events Checklist for DSM-5 (LEC-5)53 assesses lifetime exposure to trauma including two items screening 
for military sexual trauma and a category involving occupational exposure (e.g., military, paramedic, police, or 
other first responder).  
• PTSD Checklist (PCL-5)52 is a 20-item self-report measure based on the DSM-5, which has excellent 
psychometric characteristics for screening and used as a secondary indicator of PTSD symptom severity. 
 
Treatment Adherence and Retention 
• Treatment Services Review. This self-report survey will be used to monitor service utilization. 
• Treatment Adherence. Homework sessions are assigned as one per type each day (one imaginal assignment 
and one in-vivo assignment) for the days between each treatment session (for sessions 2-10). The number 
and percent of completed in vivo and imaginal homework assignments will be monitored weekly and computed 
as indicators of treatment adherence.  
• The Utility of Techniques Inventory (UTI)54. The UTI is a self-report measure that will also be used to examine 
treatment adherence between PE sessions consistent with the PE manual. 
• Session Attendance and Study Attrition. We will record session attendance and study attrition. A treatment 
dropout will be defined as a participant who does not complete at least 7/10 PE sessions or who fails to attend 
four consecutive therapy sessions despite attempts by phone and mail to engage the participant in treatment. 
 
Associated Areas of Functioning 
• Patient Health Questionnaire (PHQ-9)56 The PHQ-9 is a self-administered depression diagnostic instrument 
which scores each of the 9 DSM-IV criteria as “0” (not at all) to “3” (nearly every day). 
• Columbia-Suicide Severity Rating Scale (C-SSRS)57 The C-SSRS will be used to assess past/lifetime suicide 
ideation. Participants who endorse 2 or more attempts will be considered multiple attempters. 
• Insomnia Severity Index (ISI)58 The ISI is a 7-item self-report measure that assesses perceived severity of 
insomnia. The ISI has an internal consistency alpha coefficient of 0.74 and has shown convergent validity 
with other measures such as the Pittsburgh Sleep Quality Index (r = 0.67), the Dysfunctional Beliefs and 
Attitudes about Sleep (r = 0.55), and sleep diaries (r ranges from 0.32-0.91). 
• Buss Perry Aggression Questionnaire (BPAQ)59 The BPAQ assesses aggression severity via 4 subscales:  
Physical Aggression, Verbal Aggression, Anger, and Hostility, demonstrating strong internal consistency 
(alpha coefficient of 0.89) and strong test-retest reliability (alpha coefficient of 0.80). 
• Mini-Mental State Examination (MMSE)50 The MMSE is a widely used tool for detecting cognitive impairment, 
assessing severity, and monitoring cognitive changes over time. 
• Quick Structured Clinical Interview for Dsm-5 Disorders (QuickSCID-5)55 The QuickSCID-5 is used to assess 
the 17 most common psychiatric disorders in DSM-III-R, DSM-IV and DSM-5 and ICD-10. 
• Alcohol Use Disorders Identification Test (AUDIT)78 The AUDIT is a 10-item screening tool developed by the 
World Health Organization (WHO) to assess alcohol consumption, drinking behaviors, and alcohol-related 
problems. 
• Drug Abuse Screening Test (DAST-10)79 The DAST-10 is a 10-item self-report instrument that assesses drug 
abuse and is used for population screening, clinical case finding and treatment evaluation research. 
• Timeline Follow Back (TLFB)80 TLFB is a method that can be used as a clinical and research tool to obtain a 
variety of quantitative estimates of marijuana, cigarette, and other drug use. 
• Adverse Childhood Experiences (ACE)81 The ACE Assessment is a 10-question assessment that predicts 
health outcomes based on the frequency of answers to questions. 
• Combat Exposure Scale (CES)82 The CES is a 7-item self-report measure that assesses wartime stressors 
experienced by combatants. 
• (Revised) Conflict Tactics Scale (CTS2)83 The (revised) Conflict Tactics Scale is a 20-item self-report that 
explores conflict and violence within a relationship. 
• Dyadic Adjustment Scale (DAS-7)84 The DAS-7 is a self-report measure assess relationship functioning and is 
a psychometrically sound short form for assessing marital adjustment. 

V17 8/19/24 
• Experiences in Close Relationship Scale (ECR-S)85 ECR is 12-item self-report questionnaires on adult 
romantic attachment style, comprising two scales assessing attachment anxiety and avoidance. 
• State-Trait Anxiety Inventory (STAI)86 STAI is a commonly used measure of trait and state anxiety that can be 
used in clinical settings to diagnose anxiety and to distinguish it from depressive syndromes. 
• Fagerstrom87 The Fagerström Test for Nicotine Dependence is a standard instrument for assessing the 
intensity of physical addiction to nicotine. 
 
Therapy Process 
• Helping Alliance Questionnaire (HAQ-II)62 Therapeutic alliance has proven to be a promising variable for 
predicting psychotherapy treatment outcomes. The revised HAQ-II is a well-validated measure of this 
construct which will be completed at midpoint and end of treatment (i.e., sessions five and ten). 
• Charleston Psychiatric Outpatient Satisfaction Scale (CPOSS-VA)63. The CPOSS-VA uses a 16-item Likert 
scale response format to assess treatment satisfaction among Veterans seeking PTSD specialty care. Data 
show excellent reliability and convergent validity (α = .96)63. This assessment will be completed at end of 
treatment and 3 and 6-month follow-up visits. 
 
Within-Session Reactivity 
• Subjective Reactivity. In addition to measuring Subjective Units of Distress (SUDS) as indicated by the PE 
manual, we will monitor subjective reactivity (e.g., anger, fear) using a modified Visual Analogue Scale (VAS) 
at pre- and post-session. 
• Physiological Reactivity. Consistent with the procedures used in Dr. Wangelin’s completed and ongoing work, 
skin conductance (SC) and heart rate (HR) will be recorded using an eight-channel, multi-modality encoder 
commonly used by Drs. Flanagan and Wangelin (ProComp Infiniti; Thought Technology, Ltd.). HR and SC will 
be measured continuously throughout each PE session using non-invasive fingertip blood-volume-pulse and 
finger-cuff sensors attached to the participant’s non-dominant hand. The raw electrocardiogram will be 
sampled at 256 Hz and will be examined by the interbeat interval (IBI, the amount of time between heart beats). 
SC will be measured in microsiemens and continuously recorded at 256 Hz. Video recording will take place 
during the therapy sessions to observe reactivity through telehealth procedures. 
 
STUDY INTERVENTIONS AND PROCEDURES 
Study Medication, Dosage, and Administration. A 40 IU dose of oxytocin or placebo (saline) will be 
self-administered intranasally 30 minutes prior to the start of each weekly PE session. The dose and timing of 
medication administration is based on past research in our group and others47,64,65 and determined in 
consultation with a leading oxytocin researcher in the area of PTSD, Dr. Miranda Olff (Consultant). The study 
prescribers will conduct H&P exams, provide prescriptions for oxytocin, and assist with weekly assessment of 
adverse events. Oxytocin will be compounded, refrigerated and shipped to the VA Pharmacy. PI will consult 
with VA Research Pharmacy and oxytocin will be dispensed through VA pharmacy. If participant elects to 
telemedicine, medication will be shipped directly to the participant’s home with administration and refrigerated 
storage instructions. Research staff will instruct participants on the correct method of administration to achieve 
the 40 IU dose and will observe participants’ self-administration. Participants will blow their nose, exhale 
through their nose, then spray into one nostril while inhaling, alternating nostrils until the 40 IU dose is achieved. 
A 40 IU dose has demonstrated extensive safety and efficacy, is within the normal dosing range, and is one of 
the most common concentrations utilized in human research, including the pilot study conducted by the 
investigative team47,65. Side effects and adverse events will be evaluated weekly. Treatment assignment will 
follow a pre-arranged randomization scheme and will be carried out by personnel not involved in clinical 
management of participants in order to preserve the double-blind design. 
Behavioral Intervention: Prolonged Exposure (PE) Therapy. All participants will receive 10 
individual, weekly sessions of PE therapy according to the treatment manual published by Foa and 
colleagues24. Each session will last approximately 60-90 minutes. All PE therapy sessions will be recorded for 
fidelity monitoring, for patients to listen to between the therapy sessions as homework and for 
psychophysiological processes and monitoring. Homework engagement and between-session habituation are 
especially important for treatment success66. Within and between sessions, participants will report pre, peak, 
and post subjective units of distress during exposure. 

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Therapist Training, Supervision, and Fidelity Monitoring. Study therapists will be Masters- or 
Doctoral- level VA clinicians with extensive training and experience delivering PE in VA treatment clinics. IRB-
approved clinical supervisors from the Charleston team (PI or Co-I) will provide weekly supervision to study 
therapists at both study sites. Weekly supervision will focus on adherence to treatment and clinical concerns 
about particular participants. Supervisors will provide feedback to reduce therapist departure from the treatment 
protocol and to assist therapists in identifying issues to be addressed in subsequent sessions. If it is determined 
that a therapist is not competent or does not adhere sufficiently to the manual, the therapist will be replaced. 
This decision will be made collaboratively by Drs. Flanagan and Mitchell. To assure that PE is delivered in a 
manner consistent with manual guidelines, therapy sessions will be discussed during weekly therapy supervision 
and will be evaluated using the Yale Adherence and Competence Scale67. Interrater reliability on adherence and 
competence measures and intraclass correlation coefficients will be calculated. 
Participant Compensation. Participants will receive $50 for the baseline assessment visit. Participants 
will receive $25 for each weekly PE session and study assessment. Participants will also receive $100 for each 
follow-up visit. Thus, participants who complete all study components may receive up to $600 total ($50 for the 
baseline assessment, $350 for 10 weekly PE therapy visits (including additional compensation for week 5 and 
week 10 sessions), and $200 for follow-up visits). The VA will either directly deposit the compensation into the 
participant’s bank account, or if they do not have a bank account, a direct deposit Debit Mastercard will be issued. 
Ink signatures from participants are required for both options prior to payment submission or be signed/submitted 
via MyHealthEVet. Direct deposit will be available within 3-5 days of submission. Funds for the Debit Mastercard 
will be available within 10 business days of submission. 
 
STATISTICAL METHODS.  
Power and Sample Size. This study is powered to estimate the effects of oxytocin on significant 
reduction in both self-reported and clinician administered PTSD symptom severity at the end of treatment 
(Session 10; Aim 1) and an increased rate of early reduction in self-reported PTSD symptoms (Aim 2).  
Specific Aim 1: Prior work has shown that PE therapy alone is efficacious in the reduction of both 
clinician administered (CAPS reductions of 35-55%)47,68,69 and participant-rated PTSD symptom scores 
(reductions of 29-44%)25,47,68,70. In our pilot study, the addition of oxytocin to PE resulted in a 67% decrease in 
CAPS-5 scores following 10 weeks of treatment (mean ± SD: Baseline 39.0 ± 6.3 vs. end of treatment 13.0 ± 
14.7) and a 61% decrease in PCL-5 scores (mean ± SD: Baseline 52.2 ± 12.0 vs. end of treatment 20.5 ± 22.5). 
Assuming a conservative estimate of the effect of PE-only on both the CAPS-5 (45% reduction from baseline) 
and the PCL-5 (35% reduction from baseline) and a similarly robust reduction in the oxytocin augmented PE 
group (CAPS-5: 65% reduction from baseline and PCL-5: 60% reduction) along with conservative estimates of 
variance from our pilot data (end of treatment differences); we anticipate end of treatment between group effect 
sizes of Cohen’s d=0.55 (CAPS-5 Δ=7.8, SD=14.7) and Cohen’s d=0.58 (PCL-5 Δ=13.1, SD=22.5). To achieve 
80% power with a multiplicity corrected type 1 error rate of 2.5% to assess specific aim 1, 65 participants will be 
randomized per treatment arm (n=130). Additionally, analysis of multi-center trial data must account for possible 
center heterogeneity and unequal participant allocation across study sites71,72. Assuming no more than 10% of 
model variance is due to site differences (ρ=.10) and the randomization balance across sites is 55%: 45% or 
better, 75 participants per treatment arm will be necessary to guarantee adequate power (n=150 total 
participants). We also anticipate up to 20% attrition between study randomization and the end of treatment 
CAPS-5 and PCL-5 measurements, inflating the necessary randomized sample size to 210 total participants 
(n=-105 per treatment arm). If imbalance in these characteristics is curtailed, statistical power may exceed 80%. 
Specific Aim 2: Our pilot data showed between group changes during the first 5 weeks of PE treatment 
favoring PE + oxytocin over PE + placebo in both self-reported (PCL: Δ=13.7, SD=19.8, Cohen’s d=0.69) and 
clinician administered PTSD symptoms (CAPS-5:, Δ=7.6, SD=11.8, Cohen’s d=0.64). In order to detect the least 
of the two effect sizes at the session 5 visit (Cohen’s d>0.6), 56 participants will be necessary per treatment arm 
to achieve 80% power with a type 1 error rate of 2.5% (n=112). To account for up to 20% attrition, possible 
moderate center heterogeneity and a slight imbalance across study sites, 134 total participants (n=67 per 
treatment arm) will be necessary to maintain adequate statistical power to detect early differences in PTSD 
symptom changes between groups.  

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Specific Aim 3: There is little available information on the benefit of augmenting PE with oxytocin on 
secondary study outcomes such as treatment retention and adherence. However, using the sample size 
necessary to adequately address specific aims 1 and 2, and an estimated session attendance rate of 60% in the 
PE + placebo group, we will have sufficient power (80%) to detect a session attendance rate of 77% or better in 
the participants randomized to the PE + oxytocin group.   
Statistical Analysis. A univariate approach will be used to examine differences between treatment 
groups on baseline clinical and demographic characteristics. Characteristics will be examined and compared 
between treatment groups using chi-square tests, Fisher’s exact tests, or Wilcoxon rank sum tests, as 
appropriate. Additionally, baseline clinical and demographic characteristics will be assessed for univariate 
associations with study outcomes. Sex will be examined as a covariate, and estimates will be examined across 
sex. If other baseline characteristics are significantly associated with an outcome, the corresponding variables 
will be used as initial covariates in the model analyses. Secondarily, possible covariates will be tested for 
confounding effects on treatment and when present, they will be included in the final adjusted model. For 
Gaussian distribution assumptions, residual normality will be assessed using QQ plots and when deviations from 
normality occur, appropriate transformations will be made. All randomized participants will be included in the 
primary analysis (intent-to-treat; ITT) and all statistical models will be implemented using SAS v. 9.4.   
Hypothesis 1: Veterans randomized to the PE + oxytocin group will demonstrate significantly greater 
reduction in PTSD symptoms on the CAPS-5 and PCL-5 from baseline to end of treatment compared to Veterans 
randomized to the PE + placebo group. To assess the efficacy of oxytocin added to PE as compared to PE 
combined with placebo, generalized linear mixed effects models will be developed. The primary outcomes for 
specific aim 1 is the end of treatment response in both the CAPS-5 as well as the PCL adjusted for baseline 
scores. Both design-adjusted and full covariate adjusted models will be assessed. Design adjusted models will 
include study treatment assignment, study site, sex, and baseline CAPS-5/PCL-5 scores while covariate 
adjusted models will additionally adjust for characteristics determined to be associated with either outcome 
progression in the univariate analysis as well as known confounders. Possible moderating effects of study site 
on treatment assignment will be investigated through model interactions. We will make every effort to prevent 
study attrition. However, appropriate analysis methods will be employed to accommodate missing data. Mixed-
effects models yield valid inferences assuming ignorable attrition (i.e., attrition is accounted for by covariates or 
the dependent variable measured prior to dropout). We propose a sensitivity strategy to examine and compare 
treatment efficacy parameter estimates between primary methods noted above and those obtained using 
methods of multiple imputation (MI). MI will be implemented using 10 imputation sets and the expectation-
maximization (EM) algorithm. Hypothesis 1 results will be estimated independently for the CAPS-5 and the PCL-
5 using α=0.025 as the threshold for statistical significance. 
Hypothesis 2: Veterans randomized to the PE + oxytocin group will demonstrate a significantly faster 
rate of improvement in participant rated PTSD symptoms as measured by the PCL-5 compared to Veterans 
randomized to the PE + placebo group. The PCL-5 will be administered weekly. To assess the differential rate 
of early decline in PTSD symptoms between groups, models utilizing treatment measured time points from 
baseline to PE session 5 will be assessed using generalized linear mixed effects models. To determine 
differential treatment improvement over time, a treatment x time interaction and a quadratic time term will be 
included in the model (removed when insignificant). A significant interaction effect will indicate that the relative 
change in PTSD symptoms over time were greater in one group as compared to another. Following a significant 
interaction, assessment of pairwise comparisons at meaningful time points will be conducted to determine the 
earliest study visit at which the two treatment assignments deviate in PTSD symptoms. The CAPS-5 will be 
administered at visit 5 and the differential effect of groups will be assessed using generalized linear mixed effects 
models.  Design adjusted models will include study treatment assignment, study site, sex, and baseline CAPS-
5/PCL-5 scores while covariate adjusted models will additionally adjust for characteristics determined to be 
associated in Study Aim 1. Hypothesis 2 results will be estimated independently for the CAPS-5 and the PCL-5 
using α=0.025 as the threshold for statistical significance. 
Hypothesis 3: Veterans randomized to the PE + oxytocin group will demonstrate a significantly greater 
number of sessions attended and homework assignments completed compared to Veterans randomized to the 
PE + placebo group. Session attendance and homework completion count will be tabulated for all randomized 
participants and compared across treatment assignments. To assess differences in the number of sessions 
attended, general linear mixed effects models employing a log-linear framework (i.e., Poisson or negative 

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binomial regression with a log link) will be used to assess differences in the number of attended treatment 
sessions as a function of treatment group. Treatment assignment will be the primary independent variable of 
interest and any baseline variables found to be associated with study outcomes will be considered as covariates.  
Because it is possible that the number of attended sessions between groups could be similar at study closeout 
with differing profiles over time (i.e., early vs. late dropout), we will also examine longitudinal patterns in session 
attendance (using GLMM) as well as time to study dropout between groups (using Cox Proportional Hazards 
regression models). In the longitudinal models, we will assess the treatment x time interaction in an effort to 
detect differential patterns of attendance over time between treatment groups. The number of homework 
assignments completed between each session will also be compared between groups over time. Secondarily, 
we hypothesize that a reduction in homework completion will inform failure to complete the study protocol at 
upcoming visits. These models will use the time varying effects of homework completion as the primary 
independent variable with study attrition status as the dependent variable. All analysis for hypothesis 3 will be 
examined using α=0.05 as the threshold for statistical significance.  
Secondary Data Analyses. In addition to the primary study outcomes, we will examine the effects of 
treatment condition on time to PTSD remission as measured by the CAPS-5 and changes in physiological 
reactivity (e.g., heart rate and skin conductance). To assess early or incremental benefit on remission of 
symptoms, time to PTSD remission will be assessed using a Cox Proportional Hazards regression model. 
Although the existing literature examining the effects of PE therapy on physiological reactivity is preliminary, data 
suggests that heart rate and skin conductance may decrease during the course of exposure therapy for PTSD73, 
providing an additional objective, non-invasive measure of treatment outcome. We hypothesize that Veterans 
randomized to the oxytocin condition will demonstrate greater within-session reductions in heart rate and skin 
conductance compared to Veterans randomized to the placebo condition. Physiological data will be 
downsampled to 8 Hz for analysis. Interbeat interval (IBI) and SC will be assessed using generalized linear mixed 
effects models that will assess within session and between session changes during study treatment. We will also 
examine associations between IBI and SC measurements and changes in CAPS-5 and PCL-5 scores throughout 
treatment. Generalized linear mixed effects models will be developed to assess physiological reactivity between 
study groups over time. Finally, we will also examine treatment group differences on outcomes commonly 
associated with PTSD symptom severity such as depression, aggression, and sleep. In addition, the durability 
of all primary and secondary outcome models will be assessed at 3 and 6 month follow up visits using appropriate 
outcome specific models. Secondary analysis will be examined using α=0.05 as the threshold for statistical 
significance. 
Missing Data. Missing data are common in PTSD trials where end of treatment symptom severity is the 
primary outcome of interest. The primary cause attributed to such missing data is participant attrition. Attrition 
can introduce bias into the parameter estimate and reduce study power, estimate precision and generalizability. 
In order to minimize missing data and study attrition, study simplification and enhanced communication between 
study coordinators and participants will be emphasized. We will make every effort to prevent attrition, e.g., 
phone/text/email reminders prior to visits, compensation for participation, meeting with participants in community 
if needed, and reinforcing adherence at each visit. However, these methods do not ensure that all data will be 
collected and appropriate analysis methods will be employed to accommodate missing data e.g., (multiple 
imputation). In keeping with the Intent to Treat principle, we will make every effort to continue assessments for 
the entire course of randomized treatment, even among those who fail to adhere to randomized assignment or 
stop participating in the study assigned intervention. Additionally, we will perform analyses to determine whether 
Veterans who complete treatment and those who drop out differ on key variables (e.g., PTSD symptom severity, 
trauma type) and whether variables on which they differ interact with treatment to affect outcome measures. 
Furthermore, in general, less than 10% missing data have little impact upon study power and do not introduce 
bias, regardless of the missing data mechanism74.   
Randomization. Participants will be randomized in a one-to-one manner across study site using a 
stratified permuted block design (block sizes of 2 and 4). In order to ensure that the treatment groups are 
balanced with respect to PTSD symptom severity, groups will be stratified based on self-reported sex and a 
baseline PCL-5 score of 47 (based on our teams prior and ongoing RCTs among Veterans with PTSD75,76). To 
the extent that the stratification variable is predictive, stratifying on it may enhance statistical power to identify 
treatment effects77. Block randomization has the advantage of treatment balance at the completion of each block. 
Using smaller randomly assigned block sizes of 2 and 4 further minimizes the possibility of treatment allocation 

V17 8/19/24 
imbalance.  The randomization schedule will be completed by the study biostatistician and study allocation will 
be completed by the VA Research Pharmacist through the VA pharmacy. The randomization allocation will be 
audited quarterly by the research pharmacy and study biostatistician.   
 
HUMAN SUBJECTS RESEARCH 
1. Risks to Subjects 
 
Drs. Flanagan (PI), Back (Co-I), and Wangelin (Co-I) are licensed clinical psychologists with VAMC clinical 
appointments and Dr. Brady is a VA Staff Psychiatrist with ample training and experience in conducting clinical 
trials research among Veterans with PTSD. Dr. Jones is a psychiatrist and primary care physician with a WOC 
appointment at VA. The investigative team also has extensive experience in human subjects’ research. All 
investigators as well as the Project Therapists and Study Coordinators have all completed the University of Miami 
computer-based CITI Human Subjects Research Education Course. All research activity, informed consents, 
and continuing reviews will be reviewed by the Office of Research and Development (R&D) at the Ralph H. 
Johnson VAMC, San Francisco VAMC, as well as MUSC’s and UCSF’s IRB in compliance with 45CFR46 before 
the research is started. Continuing review will occur annually. Study staff will ensure that all information needed 
for the continuing review is consistent with R&D requirements. 
 
A. Human Subjects Involvement, Characteristics, and Design 
A total of 210 participants comprised of adults at least 18 years of age or older will be recruited over a 5 year 
period. Only VAMC Veterans will be enrolled in this study. Specifically, for the Charleston site, participants 
must be RHJ VAMC Veterans (enrolled at RHJ VAMC or eligible for care and with required verification). 
Women and members of minority groups will be eligible for participation. Study inclusion/exclusion criteria 
are as follows: 
Inclusion criteria  
1. Male or female VAMC Veteran; any race or ethnicity; aged ≥18 years. Specifically, for the Charleston 
site, participants must be RHJ VAMC Veterans (enrolled at RHJ VAMC or eligible for care and with 
required verification). 
2. Able to provide informed consent and function at an intellectual level sufficient to allow accurate 
completion of the assessment instruments (> 26 on the Mini Mental Status Exam). 
3. Meet DSM-5 diagnostic criteria for current (i.e., past 6 months) PTSD (assessed via the CAPS-5). 
Participants may also meet criteria for a mood disorder (except bipolar affective disorder, see 
Exclusion Criteria) or anxiety disorders (e.g. panic disorder, agoraphobia, social phobia, generalized 
anxiety disorder, or obsessive compulsive disorder). The inclusion of participants with affective and 
anxiety disorders is essential because of the marked frequency of the co-existence of mood and 
anxiety disorders among patients with PTSD.  
4. Participants taking psychotropic medications will be required to be maintained on a stable dose for at 
least four weeks before study initiation. This is because initiation or change of psychotropic 
medications during the course of the trial may interfere with interpretation of results. 
Exclusion criteria 
1. Meeting DSM-5 criteria for a history of or current psychotic, bipolar or substance use disorders, or 
with current suicidal or homicidal ideation and intent. Those participants will be referred clinically. 
2. Participants who present a serious suicide risk or are likely to require hospitalization during the study. 
3. Participants on maintenance anxiolytic, antidepressant, or mood stabilizing medications, which have 
been initiated during the past 4 weeks.  
4. Pregnancy or breastfeeding for women. 
 
B. Sources of Materials 
Research materials obtained from participants include self-report surveys, structured clinical interviews, and 
physiological measurements (e.g., heart rate and skin conductance).  
 

V17 8/19/24 
 
 
C. Potential Risks  
Oxytocin Safety. Oxytocin is a neuropeptide commonly administered intravenously among women 
during childbirth. Risks associated with oxytocin administration have been noted among women given 
intravenous, but not intranasal, oxytocin for its FDA-approved purpose to induce labor and facilitate 
lactation135,136. These risks include seizures, mental disturbances, nausea, vomiting, irregular heartbeat, high 
blood pressure, and unexpected bleeding or contraction of the uterus and have been observed in a small 
number of women99. However, preliminary studies conducted by our group and others indicate that risks of 
intranasal oxytocin administration at the planned dose of 40 IU is minimal and manageable through the 
proposed human participants protection methods. Our teams have administered intranasal oxytocin at this 
dose to over 900 research participants to date, including Veterans with PTSD and complex psychiatric 
comorbidities, without a single related adverse event reported. Participants will be informed about the 
potential side effects of oxytocin and will be closely monitored by the research team. Oxytocin self-
administration will occur in a fully-staffed clinical environment equipped with ready access to clinicians 
and emergency care if necessary. 
Risks of Pregnancy. Because this study involves a 50% chance of a participant receiving active 
medication (i.e., intranasal oxytocin) and the effects of oxytocin on pregnancy outcome are well known, 
pregnant and lactating females will be excluded from the trial. We will instruct female participants to use 
appropriate forms of contraception, and we will perform urine pregnancy tests at baseline and weekly during 
treatment. 
Confidentiality. All possible efforts to protect participants’ privacy and confidentially will be made 
throughout the course of the study. Consistent with VA policy, all data and results generated during the 
course of this study will be kept on password-protected Research Sharing Drive at the Ralph H. Johnson 
VAMC or the San Francisco VA Medical Center, with deidentified data stored on a VA and IRB approved 
data management system such as REDCap. The data will be kept on a password-protected Research 
Sharing Drive where study therapists and staff will have access from the RHJVAMC and/or SFVAMC. 
Participants will be provided with a written informed consent document which specifies the risks and 
confidentiality protections and limits of study procedures. All participants will review the R&D and IRB-
approved informed consent document with research staff in a private room. Through this process, research 
staff will inform all research participants of the risks of participation, including emotional distress. In the event 
that a participant experiences substantial distress or reports risk of harm to oneself or others, they will be 
asked to complete a safety plan. Recent safety plans completed by VA providers will be reviewed and an 
updated safety plan will be developed. Urgent care services at the RHJVAMC, the SFVAMC, or VA clinics 
local to participants are available to study staff and research participants. Risks of participation will be 
outlined in the informed consent and reviewed during the informed consent procedure. In similar past and 
ongoing studies, these resources have been sufficient to manage problems or distress related to 
participation. Please see Data Management and Access Plan for more information on participant 
confidentiality. 
Emotional Distress. Some participants may experience distress in response to self-report and 
interview measures pertaining to PTSD symptoms or associated areas of functioning such as depression 
and aggression. Participants may also experience physical or psychological discomfort during the medication 
self-administration. However, based on the research team’s past experience and available literature, the 
risks involved in the proposed project are minimal and manageable. Nevertheless, we have a specific 
protocol in place to manage participant distress in the event that it arises. This protocol is discussed in more 
detail below. 
Randomization Risk. Participants will be randomized to receive either the Investigational Drug 
(oxytocin) or inactive placebo. Since there is a 50:50 chance of receiving an inactive placebo, there is a risk 
that half of the participants will not receive any medication to treat their condition. Even though a portion of 
the participants will not receive any active medication, all participants will receive an evidence-based 
treatment (PE) to treat their condition (PTSD).  
 
2. Protection against Risks 

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Recruitment and Informed Consent Procedures. All personnel will be trained in the responsible conduct 
of research. Participants will be recruited from VAMC treatment clinics, community settings, community-based 
outpatient clinics (CBOC), direct mailing and ads placed on Craigslist/Facebook. The screening measure 
contains questions directly pertaining to the study’s inclusion and exclusion criteria. Participants who meet 
eligibility criteria will be scheduled with research staff for a baseline assessment session. In a private room, 
participants will be provided with a description of the nature and requirements of study participation and asked 
to read and sign an IRB-approved consent form prior to beginning any study procedures. Informed consent 
will be collected by a Study Coordinator, trained research assistant, PI, or Co-Is. The PIs and Co-Is are all PhD 
or MD level clinicians. All study personnel will read and attend training sessions in the study protocol conducted 
by the PI and in coordination with the Co-Is. These trainings will include the essential elements of ethical 
conduct of research so that each member of the research staff is well-equipped to provide participants with 
adequate information prior to their agreeing to participate in the study.  
Participants will also be informed that they are not required to make a decision about whether or not 
they choose to participate on that day. All participants will have the opportunity to consider and discuss 
participation with their provider or family members prior to providing informed consent. Participants who are 
eligible to participate and choose to do so will be encouraged to ask any questions they might have about the 
study. Both the participant and research staff member will sign the form.  
The informed consent document will outline 1) the sponsorship of the study; 2) the nature, purpose and 
procedures of the research study; 3) the voluntary nature of participation (i.e., participation is not required and 
can be discontinued at any time; 4) duration of the study; 5) potential risks and discomforts and potential benefits 
of participating; 6) that all information will be kept confidential subject to the provisions of state and federal law; 7) 
compensation; and 8) alternative treatments. Participants will be informed that they can discontinue participation 
in the study at any time and that this decision will not influence the care they receive at any VAMC or MUSC clinic. 
Emotional Distress. Some participants may experience distress in response to self-report and interview 
measures pertaining to PTSD symptoms or associated areas of functioning such as depression and aggression. 
Participants may also experience physical or psychological discomfort during the medication self-administration. 
However, based on the research team’s past experience and available literature, the risks involved in the 
proposed project are minimal and manageable. Nevertheless, we have a specific protocol in place to manage 
participant distress in the event that it arises. This protocol is discussed in more detail below. Additionally, all 
participants will receive an evidence-based behavioral intervention (Prolonged Exposure) that includes 
techniques to help reduce distress and anxiety, and improve mood (e.g., breathing retraining, sleep hygiene, 
cognitive restructuring). We will also inform participants during the informed consent process that they may 
terminate any assessments, study procedures, or therapy sessions at any point. Our past and ongoing research 
with Veterans suggests that the measures and methods proposed in this study can be implemented without 
undue psychological distress or exacerbation of symptoms. This experience includes numerous federally-funded 
projects among Veterans with PTSD. 
In the event that a participant becomes distressed secondary to participation, they will be encouraged to 
contact the Principal Investigator (PI). In addition, they will have access to urgent care services at VAMC, MUSC, 
and UCSF treatment clinics. Any adverse effects noted by any project personnel will be immediately reported to 
the PIs, who will then report these adverse effects in writing to the IRB and the VA R&D Committee per protocol 
(see the Data and Safety Monitoring Plan at the end of this section for more details). This also includes 
telemedicine procedures that are performed at the SFVA. The research team includes several licensed clinical 
psychologists and psychiatrists who are equipped to help participants manage distress and to evaluate 
conditions in which participants need additional assistance. In the event that a participant becomes significantly 
distressed, the PI will contact the participant later that day and the following day to check-in to ensure they have 
received necessary resources, and to assess their safety and welfare. If called by participants, the PI will attempt 
to address all participant concerns and set up an alternate referral for counseling for those who desire it from 
outside the project. Every attempt will be made to engage participants for the entirety of the 10-session treatment 
phase. Participants will be considered drop-outs from treatment if they do not complete at least 7/10 PE sessions 
or fail to attend four consecutive therapy sessions despite attempts by phone and mail to engage the participant 
in treatment. A Participant Locator Form will be used at the start of each telemedicine appointment. This will 
provide the location of the participant and contact information for non-emergency police line, should the study 
team need to send help to the participant’s location. All other safety procedures will be followed.  

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Study Physician. Kathleen Brady, M.D., Ph.D. and Jennifer Jones, M.D. will serve as the Study 
Physicians on this project at the Charleston site and William Wolfe, M.D. and Thomas Neylan, M.D. will serve 
as Study Physicians at the San Francisco site. Drs. Brady, Jones, Wolfe, and Neylan all have extensive 
experience with VA, DoD, and NIH-sponsored clinical trials involving individuals with PTSD and comorbid 
psychiatric conditions. They have ample experience monitoring and treating individuals with PTSD in the context 
of clinical practice and randomized controlled trials. Study physicians will review all adverse events, 
unanticipated problems involving risk to participants or others, serious adverse events, and any participant 
deaths associated with the protocol and provide an unbiased written report of the event within 10 calendar days. 
In addition, the investigative team includes psychologists with ample PTSD expertise (Drs. Flanagan, Back, 
Wangelin) who will closely monitor study participants. If at any point a participant necessitates medical 
management, psychiatric consultation or psychiatric hospitalization, they will be evaluated and referral to 
treatment will be provided accordingly. If a participant becomes suicidal, emergency psychiatric assessment will 
be arranged. The participant will be closely monitored until they are no longer suicidal or an appropriate care 
plan is in place. 
Study Prescribers. Anjinetta Johnson, P.A., who has a without compensation (WOC) appointment at the 
Ralph H. Johnson VAMC, will serve as the Study Prescriber at the Charleston site and Dr. Neylan (study 
physician) will serve as prescriber for the San Francisco site. Dr. Jones (Study Physician) will serve as a backup 
prescriber. Ms. Johnson has extensive experience with federally-funded clinical trials involving Veterans with 
PTSD. Providers also have the ability to provide study coverage via telemedicine if necessary. Ms. Johnson 
along with the PIs, will conduct H&P exams, review all adverse events, unanticipated problems involving risk 
to participants or others, serious adverse events, and any participant deaths associated with the protocol and 
provide an unbiased written report of the event within 10 calendar days. PI will consult with VA Research 
Pharmacist as needed.  Oxytocin/placebo will be dispensed through the VA pharmacy, and shipped to 
participants as needed for telemedicine. 
Military Personnel. Because some participants may be U.S. military personnel, absolute confidentiality of 
research records cannot be guaranteed. However, all possible efforts will be made to protect the confidentiality 
of participants’ data, except in the event of imminent risk to self or others, or in the event of disclosure of child or 
elder abuse. In the event that confidentiality must be broken to protect the safety of participants or others, only 
the data essential to make an adequate report to authorities will be disclosed.  
Safety and Monitoring Plan. A procedure for clinical deterioration has been established based upon our 
experience with previous and ongoing federally-funded clinical trials. Therapists (who are trained Master’s or 
Doctoral level clinicians) will be instructed to use their best clinical judgment regarding emergencies and inform 
the PI as soon as possible. In addition to relying on clinical judgment on the part of the treating therapists who 
are experienced with this population, we will also monitor the following symptoms and behaviors weekly: PTSD, 
depression, and suicidality, using standardized measures (PCL, PHQ-9) in order to detect any symptom 
worsening requiring further evaluation. Additionally, participants will be advised to observe any signs of 
worsening mental health symptoms and to discuss these challenges with their therapist. 
Participants will be withdrawn from the study and referred for more intensive treatment if: (1) there are 
increases in mental health symptoms leading to the need for a more intensive level of care (i.e., inpatient or 
partial hospitalization); (2) there is active suicidal or homicidal ideation and/or intent; (3) there is an inability to 
manage the participant psychiatrically within the inclusion/exclusion criteria of the study (i.e., need for the 
initiation of psychotropic medications; development of psychosis); or (4) there is an inability to complete PE 
therapy appointments due to incarceration or hospitalization. 
There is a well-established protocol at the Charleston and San Francisco VAMCs for emergency 
psychiatric evaluation, crisis intervention and/or psychiatric hospitalization, including telemedicine, for suicidal, 
homicidal, psychotic or other acutely distressed participants. Immediately on detection of these needs, the 
assessor/therapist will page a psychiatrist to review the participant's situation. If appropriate, the psychiatrist will 
personally evaluate the participant. Alternatively, during weekdays, the participant will be escorted by a study 
staff member to the psychiatric walk-in clinic or emergency room. Psychiatric hospitalization is available for 
emergencies. 
Participants will be informed during informed consent procedures of the standard limitations of 
confidentiality such as imminent risk of harm to self or others, or child or elder abuse. Participants will be informed 
that they can decide not to answer any questions and, should they become distressed or are uncomfortable with 

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continuing to participate, they may discontinue participation at any time without penalty. The compensation 
schedule will be stated verbally and in writing in the initial study description and the informed consent procedure. 
The participant’s copy of the consent form will provide contact phone numbers and email for the PI should a 
participant have any questions, comments, or concerns about their participation. Participants will have the 
opportunity to have a copy of the consent form mailed to them at any time. 
Suicide Specific Risk Identification and Response Plan. Specific precautions will be taken to prevent 
harm to participants. Project therapists will be trained Masters or Doctorate level clinicians and will be supervised 
by Drs. Flanagan (PI) and Back (Co-I). All project therapists and staff will be specifically trained to assess suicide 
risk, including ideation, plan, and intent as well as history of ideation or attempts, and they will be trained to 
develop a safety contract with participants. In initial screening procedures, participants identified by clinical 
interview with both suicidal ideation and acute intent will be excluded from the study but will be offered emergency 
psychiatric care immediately. This care is available 24 hours per day at the Charleston VAMC and MUSC as 
indicated above. Moreover, during the course of the study, any participant scoring a 1 or above on the PHQ-9 
question 9 (administered weekly) or a 4 or 5 on the C-SSRS (administered at BSL, WK5, WK10 and at 3- and 
6-month follow-up) will be specifically queried about suicidal ideation and intent. In any instance where ideation 
or intent is identified, the PI will be immediately notified and will contact the participant for further evaluation. If 
both ideation and intent are present, the aforementioned hospital intervention will be provided. Thus, all 
assessment points represent suicide risk identification, assessment, and intervention opportunities. Study 
therapists and staff will be specifically trained regarding the increased risk of suicide in Veterans with PTSD, and 
will receive specific instruction of suicide risk assessment during the initial training workshop. 
 
Study Implementation and Data Security. We will take careful precautions to maintain confidentiality for 
all participants, using procedures we have used with similar previous studies. Consistent with VA policy, raw 
data generated during the course of this study will be kept on a password-protected Research Sharing Drive at 
the RHJVAMC and the SFVAMC. De-Identified data for study analyses from both sites will be entered into a VA 
approved-data storage program such as REDCap. All research personnel will attend a required in-service 
training conducted by PI where the screening, informed consent, and assessment protocols will be described. 
All members of the research team will sign a confidentiality agreement that no identifying information of specific 
individuals will appear in any external documents (e.g., peer-reviewed publications, presentations) or in any 
internal reports.  
All study data related to psychological outcomes (i.e., the participant responses to questionnaires) and 
demographics will not have any unique identifying data attached in any way. Access to study data will be 
controlled through the use of standard access controls such as usernames and passwords consistent with VAMC 
policies. All participants will be assigned a numerical study identifier to minimize the potential to link identifying 
information with study data. One master list of study participants will be kept separate from all other study data  
and will be available only to the PIs, Study Coordinators, and RAs. To protect participant confidentiality, all data 
will be maintained in a manner consistent with VA R&D-approved protocol. Data will be stored in locked filing 
cabinets within a locked office and on VA encrypted computers and data servers. Access to de-identified study 
data will be limited to named project investigators, the Study Coordinators, VAMC Office of Research & 
Development (R&D) personnel, and MUSC IRB audit personnel. Data will be maintained per an R&D and IRB-
approved protocol. 
The study protocol and safety plan will be printed and kept in a central location within the research space 
for easy access for all research staff. Standard operating procedures (SOPs) for the management of any 
participant or study-related emergency will be established and research staff will be trained on these protocols. 
All participant assessments will be scheduled during normal working hours on the VA campus or through VA 
approved telemedicine to ensure the presence of clinical staff and the safety of participants and research staff.  
All research staff have completed or will complete the University of Miami CITI training course in the responsible 
conduct of research. Necessary certifications in the responsible conduct of research and the protection of human 
research participants will be completed on an annual basis, in compliance with VAMC, MUSC, and UCSF 
institutional regulations. 
 
3. Potential Benefits of the Proposed Research to the Participants and Others 

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While there is no guarantee of specific benefit to participants in this study, the potential benefits include 
a thorough psychological assessment, referral to appropriate treatment services and community resources, and 
remuneration. Participants may also benefit from receiving access to an evidence-based behavioral treatment 
which may result in a reduction in aversive PTSD symptom severity, improvement in symptoms of other mental 
health problems (e.g., depression) and improvements in other areas of functioning (e.g., sleep, quality of life). 
Other study benefits include regular contact with research staff, access to assessment information pertaining to 
mental health and referral to treatments for associated problems such as smoking. While these benefits may be 
considered minimal, we believe that they outweigh the minimal risk and burden incurred by participants. 
Participants will also enroll in a study that has the potential to enhance treatment for other Veterans. 
 
4. Importance of Knowledge to be Gained 
There is considerable knowledge to be gained from the proposed study. Veterans incur PTSD at uniquely 
high rates, resulting in a tremendous health burden in the United States. The extant literature strongly indicates 
the need to (1) develop strategies to improve retention and outcomes in evidence-based PTSD treatments such 
as Prolonged Exposure, (2) develop novel, effective pharmacotherapies for PTSD, and (3) elucidate 
physiological mechanisms associated with PTSD and response to treatment. Preclinical and human data 
suggest that oxytocin has potential to influence treatment in the field of PTSD. Thus, the proposed study has the 
potential to advance science and patient care in this area by applying intranasal oxytocin during weekly 
behavioral intervention (PE) sessions designed to treat PTSD. Results from this study may improve clinical 
delivery of PE by enhancing treatment outcomes, adherence, and retention. The proposed study will also help 
elucidate the neurobiological mechanisms underlying oxytocin response and improved PE outcomes. 
 
Data and Safety Monitoring Plan 
This section is based on the recommendations in NIH’s “Guidelines for Developing a Data and Safety Monitoring 
Plan” to assure the appropriate clinical safety monitoring of study participants. Recruitment and safety data are 
monitored according to the schedule established by the monitoring board. Quality control and assurance of data 
entered into the database is discussed above as part of Protections Against Risk. Missing data will be considered 
as part of the plan for statistical analysis.   
Summary of the Protocol. The proposed study aims to examine the ability of intranasal oxytocin to reduce 
symptoms of PTSD among Veterans. The primary outcome in this study includes a reduction in PTSD symptom 
severity and improvements in PE adherence and retention. 
Trial Management. The study will be managed from the Ralph H. Johnson VAMC. 
Data Management and Analysis. A data analytic plan is outlined in the Data Analysis section. Because this study 
is a preliminary test of a new medication, we are interested in examining a broad range of outcome variables. 
The main outcome variables include the severity of PTSD symptoms, PE adherence/retention, and psychosocial 
functioning in areas commonly associated with PTSD. Analyses will be guided by the specific hypotheses of the 
study. Post-hoc exploratory analyses will be conducted with two-tailed tests and more conservative statistical 
procedures which guard against Type I error (e.g., Tukey tests). All primary hypotheses will be tested at level of 
significance α=0.05. We will also estimate the effect sizes of interest and provide 95% confidence intervals for 
them. See the Statistical Analysis and Power section for more details. 
Quality Assurance. Data quality will be monitored by random inspection of the completed forms by research staff 
and any irregularities or problems detected will be discussed with the PI. Project therapists will receive 
standardized training from the PI and Co-I who have extensive experience training individuals to use the 
intervention (PE) to be utilized in the proposed study. Adherence to the manual will be monitored and reviewed 
during weekly supervision. If therapy drift is observed the therapists will be re-trained. Booster sessions will be 
held annually. 
Regulatory Issues. All unexpected Adverse Events (AEs) will be reported to Charleston VAMC R&D and MUSC 
IRB within 10 working days. AEs are reportable if the AE is unexpected AND related or possibly related AND 
serious or more prevalent than expected. The IRB definition of unexpected is that the AE is not identified in 
nature, severity or frequency in the current protocol, informed consent, investigator brochure or with other current 
risk information. The definition of related is that there is a reasonable possibility that the adverse event may have 
been caused by the drug, device or intervention. Serious AEs (SAEs) will be reported within 24-hours. Follow-

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up of all unexpected and serious AEs will also be reported to these agencies. All AEs are reviewed weekly by 
the PI, and annually by the Data Safety Monitoring Board (DSMB) and IRB. AEs and SAEs occurring during the 
course of study will be collected, documented, and reported in accordance with the protocol and R&D and IRB 
reporting requirements. All research staff involved with AE reporting will receive training including identification, 
evaluation, and documentation and reporting. All research staff will identify any potential AEs during the course 
of the study from self-report data and administration of assessments and interviews. This information will be 
provided to the PI, who will be responsible for AE/SAE assessment and evaluation including a determination of 
seriousness and study relatedness. 
Definition of AE and SAE. Adverse Events are defined as any untoward medical occurrence that may present 
itself during treatment or administration of an intervention, and which may or may not have a causal relationship 
with the treatment. Serious adverse events are defined as any medical occurrence that results in: 
1) Death 
2) A life threatening event 
3) Requires or prolongs inpatient hospitalization 
4) Persistent or significant disability/incapacity 
5) A congenital anomaly or birth defect 
 
OR 
 
6) Requires intervention to prevent one of the above outcomes. 
 
Important medical events that may not result in death, be life-threatening or require hospitalization may be 
considered a serious adverse event when, based upon appropriate medical judgment, they may jeopardize the 
participant and require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Documentation and Reporting. When a reportable SAE is identified, the research assistant will initiate an SAE 
form, and the following individuals will be notified within 24 hours of the site’s initial notification of the SAE: 
1) Study Co-Investigators. 
2) VA R&D personnel. Committee meets monthly. Communication with R&D personnel is through email, 
memos, official R&D forms, and online reporting. 
3) The MUSC Institutional Review Board (IRB).   
4) The Data Safety Monitoring Board. 
If complete information is not available when the initial 24-hour SAE report is disseminated, follow-up information 
will be gathered to enable a complete assessment and outcome of the event. This information may include 
hospital discharge records, autopsy reports, clinic records, etc. The research staff will attach copies of source 
documents to the SAE report for review by the PI and for forwarding to the VA personnel as appropriate. 
We will report adverse events to VA R&D and to the MUSC IRB as soon as possible, but no later than 10 working 
days after the investigators first learns of the event. The VAMC and MUSC IRB AE reporting requirements are 
as follows: All deaths that occur during the study or 30 days post termination from the study are required to be 
reported as adverse events even if they are expected or unrelated. Other adverse events are reportable to the 
VA R&D and MUSC IRB if the AE is unexpected AND related or possibly related AND serious or more prevalent 
than expected. All three criteria must be met for an AE to be reported to the VA R&D and MUSC IRB. The R&D 
and IRB definition of unexpected is that the AE is not identified in nature, severity or frequency in the current 
protocol, informed consent, investigator brochure or with other current risk information. The definition of related 
is that there is a reasonable possibility that the adverse event may have been caused by the drug, device or 
intervention. Reportable AEs are reviewed by the VA R&D Chair and reported to the R&D Board at the next 
meeting. 
Study Safety. The potential risks and benefits of this study and methods to minimize these risks are outlined 
above. Protocols for reported AEs and SAEs are outlined above. All unexpected AE and SAEs will be monitored 
until resolved. A detailed summary of all AEs will be prepared weekly by the research staff. At the weekly team 
meetings (or before if urgent), the research staff will report any premonitory symptoms of clinical deterioration. 
Study procedures will follow the FDA’s Good Clinical Practice Guidelines (www.fda.gov/oc/gcp). Any outside 
requests for information or any breaches in confidentiality will be reported to the PI. All requests by participant’s 
physicians and other medical providers will be referred directly to the applicant. 

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DSM Plan Administration. Dr. Flanagan will be responsible for monitoring the study. The PIs and a statistician 
(Mr. Baker) will examine the outcomes database for missing data, unexpected distributions or responses, and 
outliers. A DSMB report will be filed with R&D annually, unless greater than expected problems occur. The report 
will include participant characteristics, retention and disposition of study participants, quality assurance issues 
and reports of AEs, significant/unexpected AEs and serious AEs. We will report results at the end of the trial. 
DSM Board. We will create a DSMB to monitor overall participant safety, the rate and severity of adverse events, 
and the validity and integrity of the data. The panel includes 2 researchers with experience in treating Veterans 
with PTSD (Mark Hamner, M.D., Karen Hartwell, M.D.) and a statistician (Ms. Amy Wahlquist). The board may 
be called at any point if needed for unexpected AEs, etc. Modifications will be made in the procedures and/or 
the protocol if necessary based on the recommendations of the board. Confidentiality will be maintained during 
all phases of the study. 
 
ClinicalTrials.gov Requirements 
In accordance with Public Law 110-85, the proposed trial will be registered with ClinicalTrials.gov. Applicable 
requirements regarding results reporting will be adhered to. 

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