Clinical trial NCT03176953
Conditions: PTSD and Alcohol Use Disorder
Keywords: PTSD alcohol use disorder Veterans
Sponsor: VA Office of Research and Development
Start date: 2017-11-01; Completion date: 2023-09-30
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) frequently co-occur, and having both disorders is associated with greater psychological and functional impairment than having either disorder alone. The most effective PTSD treatment, prolonged exposure (PE) is sometimes less effective when individuals also have AUD. Anti-relapse medication appears promising to improve the effectiveness of PE to help individuals reduce alcohol use and PTSD symptoms and improve functioning. This study compares PE with and without topiramate, a medication shown to both reduce drinking and PTSD symptoms, with the hypothesis that combined PE and topiramate will be more effective than PE and placebo. The aim of this grant is to improve treatment outcomes for Veterans with AUD and PTSD.

Detailed description:
Objectives. Alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) frequently co-occur, and having one condition worsens the course of the other. Individuals with both disorders exhibit worse functioning across a number of domains than individuals with either disorder alone. Prolonged exposure therapy (PE) is among the most effective treatments for PTSD. PE has been rated as a frontline treatment by multiple guidelines and reviews including the VA/DoD Clinical Practice Guidelines for the treatment of PTSD. However, in studies of individuals with PTSD and AUD, changes in alcohol use are only slightly better than in control or standard care conditions, reductions in PTSD symptoms are sometimes modest relative to studies of PE in PTSD patients without AUD, and rates of drop out from treatment are high. Combining PE with medication to curb drinking shows promise to improve upon the effectiveness of PE for individuals with comorbid AUD and PTSD, although thus far few studies have examined combining psychotherapy and medication. Topiramate is the single medication that has shown effectiveness for both AUD and PTSD and shows promise for reducing drinking among individuals with AUD and PTSD. However, the effect of adding topiramate to PE to treat comorbid AUD/PTSD has yet to be examined. The critical next step is to test a best practice PTSD treatment, PE, together with a promising pharmacological agent, topiramate, which has been found to be effective for both AUD and PTSD. Innovation: This application seeks to shift current clinical practice paradigms. A refinement to existing interventions is proposed through integration of two evidence based treatments.

Methodology. The investigators propose to use a randomized, controlled, double blind study design to examine the effect of adding topiramate (TOP) to a best practice treatment for PTSD, PE. Participants will be 120 male and female Veterans from all services with AUD and PTSD. The investigators' primary aims are to determine the relative efficacy of PE+topiramate, as compared to PE+placebo, in reducing problematic drinking, reducing PTSD symptoms, and improving functioning and quality of life among Veterans with comorbid AUD/PTSD at post-treatment and 3- and 6-month post-treatment follow-up. The investigators will explore the extent to which decreases in drinking and PTSD symptoms lead to improvement in functioning.

The proposed study has the potential to improve functional and psychological recovery for a highly prevalent and highly impaired population of Veterans. This study will test a novel and innovative combination of psychotherapy and medication with the goal of improving the care of Veterans. The successful completion of this project will help change the practices that drive treatment for Veterans who have both AUD and PTSD. The fundamental rationale for this study is to improve the evidence base that informs how patients with AUD and PTSD can attain sustained recovery from both of these disorders. The investigators will also explore whether changes in PTSD symptoms in the PE+TOP condition are partially explained by reductions in alcohol cravings.

Arms: arm 1: psychotherapy plus active medication arm 2: psychotherapy plus placebo medication
Interventions: intervention 1: topiramate intervention 2: prolonged exposure intervention 3: placebo
Intervention descriptions: intervention 1: active medication intervention 2: psychotherapy intervention 3: non-active medication

Protocol documents:
Prot_SAP_000.pdf: 
Topiramate and Prolonged Exposure 
NCT03176953 
Last Approved/Updated 10/04/2023 


Human Protocol (Version 1.49)
General Information
*Please enter the full title of your study::
Combining Topiramate and Prolonged Exposure for PTSD and Alcohol Use Disorder
*Please enter the Study Number you would like to use to reference the study:
TOP Study
* This field allows you to enter an abbreviated version of the Study Title to quickly identify this
study.
Add departments
and Specify Research Location:
Is 
Primary? Department Name
VASDHS - VASDHS
Assign key study personnel(KSP) access to the study
*Please add a Principal Investigator for the study:
Norman, Sonya B., PhD
3.1 If applicable, please select the Research Staff personnel
A) Additional Investigators
Angkaw, Abigail Candare, PhD 
Co-Investigator
Brody, Arthur L., MD 
Co-Investigator
Davis, Brittany C 
Co-Investigator
Lacefield, Katharine I., PhD 
Co-Investigator
Martis, Brian, MD 
Co-Investigator
Matthews, Scott Christian, MD 
Co-Investigator
Pitts, Michelle, PhD 
Co-Investigator
Risbrough, Victoria B., PhD 
Co-Investigator
N


Stein, Murray B., MD 
 Co-Investigator
Townsend, Andrea Spadoni, PhD 
 Co-Investigator
B) Research Support Staff
Higdon, Alexandra O., PsyD 
 Research Associate
Holcomb, Julie M. 
 Clinical Research Associate
Katawazi, Julia G. 
 Clinical Research Associate
Klein, Alexandra, PhD 
 Post-Doc
Kline, Alexander C., PhD 
 Post-Doc
Luciano, Matthew T., PhD 
 Research Associate
Lyons, Robert C., PhD 
 Student
Marvin, Morgan E., BA 
 Research Associate
Miller, Ruth Klaming, PhD 
 Research Associate
Panza, Kaitlyn E., PhD 
 Study Coordinator
Park, Jae Eun 
 Research Associate
*Please add a Study Contact
 
Norman, Sonya B., PhD 
Panza, Kaitlyn E., PhD 
The Study Contact(s) will receive all important system notifications along with the Principal 
Investigator. (e.g. The project contact(s) are typically either the Study Coordinator or the Principal 
Investigator themselves).
 
VASDHS - IRB Protocol
v20150312
 - Preliminaries
Section 1
Principal Investigator:
Sonya B. Norman, PhD
Protocol Title:
Combining Topiramate and Prolonged Exposure for PTSD and Alcohol Use Disorder
IRB Protocol Number:
H170056
Protocol Nickname:


TOP Study
Form Template Version:
v20150115
Date Prepared:
10/04/2023
 Is this study considered human research?
1a)
 Yes  
 No
 Is this a request for a determination of exemption from IRB review?
1b)
  Yes  
  No
 Is this a request for an expedited IRB review?
1c)
  Yes  
  No
 
New Protocol or Transfer/Renewal of Prior Protocol
1.3 
Section 
 Select the type of protocol application:
1.3)
Is this a new protocol?  (if transfer to VA IRB, select 
)
1.3a) 
No
 Yes  
 No
 Is this a resubmission of a VASDHS IRB protocol?
1.3b)
  Yes  
  No
 Is this a transfer of a protocol to the VASDHS IRB?
1.3c)
  Yes  
  No
 
 - Research Subjects
Section 2
 What is the total planned number of VASDHS-consented subjects needed?
2a)
(Include even if using a waiver of documented consent, e.g. oral consents)
120
 What is the total number of VASDHS subjects needed that WILL NOT be consented (e.g., 
2b)
retrospective reviews) ?
0
 
Consented Subject Groups
2.1 
Section 
 For each of the subject categories listed below, indicate whether or not these subjects will be 
2.1)
enrolled (consented) in the study: (exclude cases of data or specimens only)
 Children under age 18
2.1a)


  Yes  
  No
 Women of child-bearing potential
2.1b)
 Yes  
 No
 Pregnant women
2.1c)
  Yes  
  No
 Individuals with cognitive/decisional impairment
2.1d)
  Yes  
  No
 Non-English speaking individuals
2.1e)
  Yes  
  No
 Prisoners of War [explicitly targeting this group]
2.1f)
  Yes  
  No
 Non-Veterans (Note: A justification will be required below)
2.1g)
  Yes  
  No
 Incarcerated individuals (Note:  VA CRADO approval will be required)
2.1h)
  Yes  
  No
 VA employees (or WOCs)
2.1i)
  Yes  
  No
 Students
2.1j)
  Yes  
  No
 Patients with cancer (or high cancer risk) [explicitly targeting this group]
2.1k)
  Yes  
  No
 
 - Study Features
Section 3
       (these items default to "No" for convenience)
This section consists of several Yes/No questions addressing protocol characteristics.    
3) 
   Click on Save 
.
and Continue
 
Protocol Basics
3.1 
Section 
Indicate whether or not each of the following applies to this protocol
 The research 
 the participant
3.1a)
intends to change
 Yes  
 No
 with living participants to collect data or specimens with no intent to change 
3.1b) Interactions
them.
 Yes  
 No
This is a study that 
 has any 
 (e.g., de-
3.1c) 
never
subject contact or subject identifiers
identified tissue only).
  Yes  
  No


 This is a 
 study (multiple IRB's involved) and 
 is the 
 or a 
3.1d)
multi-site
VASDHS
main
coordinating site
  Yes  
  No
This is a 
study (multiple IRB's involved) and VASDHS is NOT the main or a 
3.1e) 
multi-site 
coordinating site
  Yes  
  No
There is an 
 component to this research
3.1f) 
international
  Yes  
  No
Any study activity occurs at 
(not including VHASDC leased space 
3.1g) 
non-VASDHS locations 
or clinics) under the VASDHS IRB protocol.
  Yes  
  No
VASDHS subjects 
 in whole or in part 
 (not including 
3.1h) 
participate
at other locations
VHASDC leased space or clinics) under this VASDHS IRB protocol.
  Yes  
  No
 
Specimen Use and Data Repository
3.2 
Section 
Indicate whether or not each of the following applies to this protocol
Involves specimens that are left over from pathological or diagnostic testing (
3.2a) 
non-
)
research specimens
  Yes  
  No
Involves 
 purposes 
3.2b) 
specimens collected for research
only
 Yes  
 No
This study includes 
 (specimens are retained for use outside of the 
3.2c) 
specimen banking
purposes of this protocol)
 Yes  
 No
The study involves 
genotyping or other 
3.2d) 
DNA 
genetic analysis
 Yes  
 No
A Biological 
Agreement is required.
3.2e) 
Materials Transfer 
 Yes  
 No
A 
 is maintained (data are retained after completion of the protocol for 
3.2f) 
data repository
other uses, 
 see  before checking "yes")
IMPORTANT
?
 Yes  
 No
 
Treatment and Clinical Trials
3.3 
Section 
Indicate whether or not each of the following applies to this protocol
Includes a 
 component 
3.3a) 
treatment
(a research treatment)
 Yes  
 No


Study is a 
3.3b) 
clinical trial
 Yes  
 No
Has a data safety monitoring board (
or data safety monitoring committee
3.3c) 
DSMB) 
  Yes  
  No
 Has a 
 (but not a DSMB) 
3.3d)
data safety monitoring plan
(this is not the data security plan, 
it is a safety plan)
 Yes  
 No
 
Drugs and Devices
3.4 
Section 
Indicate whether or not each of the following applies to this protocol
 that require 
 action such as an Investigational New Drug (IND) approval or 
3.4a) Drugs
FDA
exemption or 510(k) approval.
  Yes  
  No
Other drugs that
action for inclusion in the study
3.4b) 
 do not require FDA 
 Yes  
 No
 Medical 
 IDE approval or waiver
3.4c)
devices requiring FDA
  Yes  
  No
 medical 
3.4d) Other
devices
  Yes  
  No
 
 Risk and Hazards
3.5
Section 
Indicate whether or not each of the following applies to this protocol
 Study places subjects at 
3.5a)
greater than minimal risk (do not include risks that are due to 
standard care)
 Yes  
 No
 Human subjects are exposed to 
 (do not include standard care)
3.5b)
radioisotopes
  Yes  
  No
 Subjects have other 
 (e.g., x-rays) (do not include standard clinical 
3.5c)
radiation exposure
use)
  Yes  
  No
Target population has psychiatric diagnosis or behavioral complaint.
3.5d) 
 Yes  
 No
 
Clinical Facilities and Standard Care
3.6 
Section 
Indicate whether or not each of the following applies to this protocol
 Study 
 (e.g., adds required tests run in the VA lab for study 
3.6a)
uses VA clinical services
purposes)


 Yes  
 No
 Includes procedures or drugs that will be considered 
3.6b)
part of standard care
 Yes  
 No
Involves 
purposes
3.6c) 
lab tests done for research 
 Yes  
 No
 
Subject Expenses and Compensation
3.7 
Section 
Indicate whether or not each of the following applies to this protocol
There may be expense or added 
or the subject's insurance.
3.7a) 
costs to the subject 
  Yes  
  No
 This is a 
 and subjects may be billed for study drugs or 
3.7b)
qualifying cancer treatment trial
procedures.
  Yes  
  No
This is a cancer treatment trial but 
 for study drugs or 
3.7c) 
subjects will not be billed
procedures.
  Yes  
  No
 Subjects will be
(either in cash or other means such as a gift certificate)?
3.7d)
 compensated 
 Yes  
 No
 
Subject Activities
3.8 
Section 
Indicate whether or not each of the following applies to this protocol
 Involves 
 completed by subjects
3.8a)
surveys or questionnaires
 Yes  
 No
 Includes the use of 
 such as flyers, advertisements, or letters
3.8b)
recruitment materials
 Yes  
 No
 Involves facial 
 or audio or video 
of 
3.8c)
photographs
recordings 
patients
 Yes  
 No
 
Sponsors and Collaboration
3.9 
Section 
Indicate whether or not each of the following applies to this protocol
This research has a 
3.9a) 
commercial (industry) sponsor.
  Yes  
  No
Other 
is provided (e.g., drugs or 
3.9b) 
commercial (industry) non-financial support 
supplies).
  Yes  
  No


The PI or other study staff member has a financial interest or other
3.9c) 
 real or potential 
related to this study.
conflict 
  Yes  
  No
The protocol has 
 involvement (e.g., subjects or funding).
3.9d) 
Department of Defense
  Yes  
  No
(either researchers or entities, not VA WOCs, can 
3.9e) Non-VASDHS Research collaborators 
be VA Other service also) are involved in this VASDHS IRB protocol. (Generally they cannot have 
access to sensitive information)
 Yes  
 No
 
 - Estimated Duration
Section 4
What is the estimated duration of the entire study?  
4) 
(From IRB approval to IRB closure)
4 years
 
 - Lay Language Summary
Section 5
Provide a summary or synopsis of the proposed study using non-technical language 
5) 
(not more than 1 
paragraph)
The present study was designed to find out more about how to effectively treat people who are 
experiencing symptoms related to alcohol disorder (AUD) and posttraumatic stress disorder 
(PTSD). This study will compare Topiramate vs. placebo (sugar pill) among Veterans who will 
also concurrently receive prolonged exposure therapy (PE), an evidence based psychotherapy for 
PTSD.
 
 - Specific Aims
Section 6
Provide a statement of specific aims and 
 that serve as the basis for this 
6) 
hypotheses
protocol.  Emphasize those aspects that justify the use of human subjects.
Alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) frequently co-occur, and 
having one condition worsens the course of the other [15, 16]. Individuals with both disorders 
exhibit worse functioning across a number of domains than individuals with either disorder alone 
[e.g., 17, 18]. Prolonged exposure therapy [PE; 19] is among the most effective treatments for 
PTSD [3]. PE has been rated as a frontline treatment by multiple guidelines and reviews 
including the VA/DoD Clinical Practice Guidelines for the treatment of PTSD [20]. However, 
among samples with PTSD and AUD, changes in alcohol use following PE are only slightly better 
than in control or standard care conditions, reductions in PTSD symptoms are modest relative to 
studies of PE in PTSD patients without AUD, and rates of drop out from treatment are high [8]. 
Thus, studies of adjunctive treatments, such as medication, are critical to improve the benefits of 
PE for individuals who have AUD in addition to PTSD [4]; however, few studies have examined 
combining psychotherapy and medication [4] and none have examined Topiramate (TOP). TOP is 
the single medication that has shown effectiveness for both AUD and PTSD [3, 5] and shows 
promise for reducing drinking among individuals with AUD and PTSD [10]. The key next step is 
to test a best practice PTSD treatment, PE, together with a uniquely promising pharmacological 
agent, TOP.
The proposed study is designed to extend our prior research to identify effective treatments for 
comorbid AUD and PTSD with the goals of reducing problematic alcohol use and PTSD symptoms 
and improving functioning. We propose to use a randomized, controlled, double blind study 
design to examine the effect of adding TOP to a best practice treatment for PTSD, PE. 
Participants will be 120 male and female Veterans from all service eras with AUD and PTSD. Our 
central hypothesis is that PE+TOP will reduce alcohol use, ameliorate PTSD symptoms, and 
improve functioning and quality of life more than will PE+Placebo (PLA). Thus, there are three 


specific aims and additional exploratory aims:
Aim 1: To determine the relative efficacy of PE+TOP, as compared to PE+PLA, in reducing heavy 
drinking among Veterans with comorbid AUD/PTSD at post-treatment and 3- and 6-month follow-
up.
Hypothesis 1. We hypothesize that AUD/PTSD Veterans receiving PE+TOP will have fewer heavy 
drinking days at post-treatment and 3- and 6-month follow-up after active treatment compared 
with participants receiving PE+PLA.
Aim 2: To determine the relative efficacy of PE+TOP, as compared to PE+PLA, in reducing PTSD 
and depression symptoms in Veterans with comorbid AUD/PTSD at post-treatment and 3- and 6-
month follow-up.
Hypothesis 2. We hypothesize that those receiving PE+TOP will show greater improvements in 
PTSD and depression symptoms at post-treatment and 3- and 6-month follow-up compared with 
participants receiving PE+PLA.
Aim 3: To determine the relative efficacy of PE+TOP, as compared to PE+PLA, in improving 
functioning and quality of life among Veterans with comorbid AUD/PTSD at post-treatment and 
3- and 6-month follow-up.
Hypothesis 3. We hypothesize that AUD/PTSD Veterans receiving PE+TOP will show greater 
improvements in functional impairment and quality of life at post-treatment and 3- and 6-month 
follow-up compared with participants receiving PE+PLA.
Exploratory Aims: We will explore 1) the extent to which decreases in drinking and PTSD 
symptoms are associated with improvements in functioning; 2) whether PE completion and 
reductions in heavy drinking at post-treatment and follow-up in the PE+TOP condition are 
partially mediated by reduction in alcohol cravings and PTSD symptoms during the first half of 
treatment, and 3) whether reductions in cognitive functioning between baseline and mid-
treatment will be associated with less PTSD symptom reduction and less reduction in subjective 
units of distress (SUDs) during imaginal exposure across PE sessions. Additionally, we will look 
for genetic associations with treatment response.
The proposed study is highly relevant to the goals of RR&D and the VA. It has the potential to 
improve functional and psychological recovery for a highly prevalent and highly impaired 
population of Veterans. This efficacy trial will test a novel and innovative combination of 
psychotherapy and medication with the goal of improving the care of Veterans. The successful 
completion of this project will help change the practices that drive treatment for Veterans with 
comorbid AUD and PTSD. The fundamental rationale for this study is to improve the evidence 
base that informs how patients with AUD and PTSD can attain sustained recovery from both of 
these disorders.
 
 - Background and Significance
Section 7
Provide a succinct discussion of relevant background information to justify performing the proposed 
7) 
study.
Co-Occurring AUD & PTSD Is Associated with Poor Psychological and Functional 
Outcomes. Comorbidity of AUD and PTSD is high. Up to 28% of women and 52% of men 
[21] with PTSD meet criteria for AUD, and rates of PTSD among patients with AUD are as 
high as 30-59% [22, 23]. Furthermore, there is evidence that AUD and PTSD can co-occur 
at even higher rates among Veterans [18, 24]. In a national sample of Operation Enduring 
Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans using VA care, 62% of those with 
AUD had a diagnosis of PTSD. Alcohol or substance use disorder was associated with a 
four-fold increase in likelihood of having a PTSD diagnosis [7].
 
Individuals with AUD/PTSD generally fare worse than those with either disorder alone [16, 
25]. While PTSD and AUD are each associated with functional impairment, individuals who 
have both disorders have poorer treatment outcomes, more additional psychiatric problems, 
and more functional problems across multiple domains, including medical, legal, financial, 
and social domains [18], than those with just one disorder [16-18, 26-29]. AUD/PTSD 
patients who receive PTSD treatment are more likely to reduce their alcohol use and less 


likely to relapse to problem drinking than are patients who receive AUD only treatment [30-
32].
 
 Prolonged Exposure (PE) therapy is a best practice treatment for PTSD. The theory behind 
prolonged exposure [PE; 19] posits that exposure to avoided stimuli and emotional 
processing of avoided trauma memories are necessary for recovery from PTSD. In this 
model, exposure works through emotional processing changes that occur in tandem with 
habituation. When applying emotional processing theory to PTSD, Foa and colleagues [19] 
proposed two dysfunctional cognitions that are related to the development and maintenance 
of PTSD: 1) The world is completely dangerous; and 2) I am incompetent (i.e., “I am crazy”). 
Through the process of repeated, prolonged confrontation of trauma-related stimuli, 
habituation of emotional responses associated with the trauma occurs. As trauma-related 
stimuli are repeatedly confronted without the occurrence of feared consequences (e.g., 
“going crazy”) and with lessening emotional activation, the patient experiences repeated 
evidence that disconfirms the dysfunctional cognitions. A stronger sense of self-competence 
and control over negative affect and stimuli may allow patients to reduce trauma-related 
avoidance, leading to even more spontaneous exposure and continued reduction of PTSD 
symptoms and functional recovery [33]. Alcohol becomes less needed to medicate the 
symptoms of PTSD or cope with associated problems, thus, alcohol treatment can be more 
effective than when PTSD is not also addressed. The efficacy of PE has been examined in 
multiple studies with a variety of populations including Veterans [34, 35]. Treatment 
guidelines such as the VA/DoD Clinical Practice Guidelines for PTSD support exposure 
therapy as a first line treatment [20, 36]. However, until recently, individuals with AUD were 
excluded from studies of PE.
 
PE helps both AUD and PTSD, but symptom reduction in comorbid individuals is modest 
and dropout is high. AUD/PTSD patients traditionally received sequential treatment with 
AUD treated first and PTSD second [26, 37, 38]. This older approach was based, in part, on 
the notion that individuals with AUD could not tolerate trauma-focused treatment and that 
such treatment would lead to an exacerbation of alcohol use or other unsafe coping 
mechanisms. However, research does not support such clinical dogma [16] and a temporal 
study of patients with AUD/PTSD found that improvements in PTSD symptoms had a 
greater association with reduced drinking than vice versa [16]. A meta-analysis [8] that 
included 14 studies of psychotherapy for comorbid PTSD and AUD or another substance 
use disorder (SUD) found that exposure therapy in combination with AUD therapy was 
effective in reducing the symptoms of PTSD and problem alcohol use. However, while 
exposure therapies were more effective than other types of therapies for co-occurring PTSD 
and AUD, effect sizes were small and dropout rates were higher than in non-exposure 
based treatments. These results highlight the need to identify ways to boost the effects of 
PE on PTSD for individuals who also have an AUD.
 
Medications may improve the efficacy of PE for AUD/PTSD. Ralevski and colleagues 
recently conducted a review of PTSD/AUD treatment studies and noted that the most 
promising but understudied treatment direction is combining evidence based psychotherapy 
and medication [4]. They noted that only one trial to date combined evidence based AUD 
medication with evidence based PTSD psychotherapy (PE). Specifically, Foa and 
colleagues [39] recently completed a randomized controlled trial (RCT) of PE and naltrexone 
for the treatment of AUD and PTSD. Participants were randomized to one of four conditions: 
PE with either naltrexone or placebo, or supportive therapy with either naltrexone or 
placebo. All four groups had reductions in PTSD symptoms and alcohol use post-treatment. 
By 6-months post-treatment, all four groups were drinking more, but the group that received 
PE and naltrexone showed the smallest increase in drinking. While naltrexone (NAL) is an 
effective and widely studied AUD medicine, for a number of reasons described below, TOP 
shows even greater promise for improving outcomes of Veterans with AUD/PTSD who 
receive PE. However, TOP has not yet been studied together with evidence based 
psychotherapy for PTSD [4].
 


TOP is the only medication effective in treating both AUD and PTSD. TOP is a sulfamate-
substituted fructopyranose derivative approved by the FDA for the treatment of epilepsy, 
prophylaxis of migraine headaches, and, in combination with phentermine, for obesity. 
Among its multiple effects, TOP dampens glutamatergic neurotransmission via its 
antagonistic effects at AMPA/kainate receptors while simultaneously enhancing GABAergic 
tone through its allosteric effects at GABA-A receptors [40]. This unique mechanism of 
action impacts dopaminergic neurotransmission in mesocorticolimbic pathways and may 
diminish the effects of alcohol, thus, rendering drinking less reinforcing. Because TOP is 
both a glutamate receptor antagonist and also inhibits dopamine release, TOP may be 
uniquely effective for comorbid AUD/PTSD patients because it acts on drinking and PTSD 
symptoms through two separate mechanisms. It received the highest recommendation level 
for the treatment of AUD in the 2015 VA/DoD substance use disorder guidelines [2] and, in 
regard to PTSD, a recent review concluded it was one of the most promising medications [3] 
in need of further study. Meta-analyses examining its effects as a treatment for alcohol use 
disorder [5, 41] and PTSD [3], respectively, have found the medication to be significantly 
more effective than placebo in treating each condition independently with effect sizes 
greater than those of other AUD (e.g., NAL) and PTSD (e.g., SSRIs) medications. There is 
also a practical reason for why it is important to study TOP further in VA. A review of the VA 
National Patient Care Database from 2009 to 2012 of the use of FDA approved and off label 
prescriptions for Veterans with AUD found that TOP was prescribed more often than known 
treatments for AUD including acamprosate, IM naltrexone, and disulfiram combined [6]. 
Given this frequent use across VA and extremely high rates of comorbidity between AUD 
and PTSD in the VA [7], it is particularly important to study TOP with PTSD treatment in the 
Veteran population.
 
 A recent pilot study [10] evaluating TOP’s ability to reduce drinking in Veterans receiving 
heterogeneous treatments for PTSD found that it decreased alcohol consumption, cravings, 
and PTSD symptom severity, especially hyperarousal symptoms. Importantly, TOP was well 
tolerated, cognitive side effects were transient, and there were no group differences in 
dropout and no dropouts due to adverse events. As noted by Petrakis and colleagues [42], 
the lack of group differences in dropout may be due to the flexible dosage schedule and 
because the benefits of the treatment may have offset any adverse effects. Therefore, in the 
proposed study, we will use a similar flexible dosage schedule with similar slow upward 
titration.
 
PE and TOP Show Promise to Act Together to Improve AUD/PTSD Outcomes. While 
studies have found that individuals with AUD/PTSD can benefit from PE, and that PE is 
more effective for reducing alcohol use and PTSD symptoms for individuals with AUD/PTSD 
than other treatments, drop out is high and effects are modest relative to PE with individuals 
who do not have AUD [8]. Individuals with comorbid AUD/PTSD often drink alcohol 
maladaptively to cope with stress, PTSD symptoms, and problems associated with PTSD. In 
addition, some individuals who take part in PE may experience increases in cravings and 
PTSD symptoms early in PE treatment, which may lead to poor treatment engagement 
or  dropout. [9] Core PTSD symptoms such as avoidance and hyperarousal can interfere 
with ability to engage in or benefit from treatment. TOP is believed to decrease alcohol 
reinforcement and the propensity to drink by reducing craving for alcohol through 
antagonism of glutamate receptors and inhibition of dopamine release. In addition, TOP 
(which, as noted, is unique among AUD medications in that it helps to reduce PTSD 
symptoms) may reduce PTSD symptoms that may otherwise interfere with treatment 
engagement and may off-set PE-related PTSD symptom exacerbation which might 
otherwise lead to treatment dropout [10]. There is also evidence that TOP attenuates stress-
induced alcohol consumption [11], perhaps by modulating glutamatergic neuroplasticity [43], 
which further supports the hypothesis that TOP may help reduce drinking in individuals with 
PTSD who have exacerbation of stress or stress related symptoms during PE. Early 
reductions in PTSD symptoms and cravings during PE increase the likelihood that 
individuals with AUD/PTSD benefit from PE and successfully reduce their drinking [12]. 
Thus, by helping Veterans reduce cravings and symptoms that may cause dropout or poor 
engagement early in treatment, TOP may increase the likelihood that habituation and 


cognitive emotional processing are successful in PE, allowing psychological and functional 
recovery to occur.
 
We will evaluate parts of this proposed model regarding how TOP and PE will work together 
to improve AUD/PTSD outcomes through our exploratory aims (see Section 2). Thus, this 
proposed study will take the critical next step of evaluating whether adding TOP to PE to 
treat Veterans with AUD and PTSD improves psychological and functional recovery and will 
examine the mechanisms through which this combination of treatments may drive recovery.
 
Addition of saliva sample for genetic testing
Dr. Victoria Risbrough will help  to conduct genetic testing on our subject population to 
examine role of the candidate genes in predicting treatment response.  We will test the 
hypothesis that candidate genes related to topiramate pharmacokinetics and dynamics are 
associated with treatment response to topiramate.  We will also examine if the topiramate effects 
are moderated by genes known to moderate treatment response, such as COMTval158met. 
 
Repository:  We will  bank these samples with the CESAMH Biorepository (H150080) to be 
merged with other VA and NIH studies of PTSD genetic risk for future sequencing, methylation 
and Genome Wide Association Studies. 
 
 
 - Design and Methods
Section 9
Describe the research design and the procedures to be used to accomplish the specific aims of the 
9) 
project.  Provide a precise description of the planned data collection, analysis and 
interpretation.  Address sample size, inclusion of women and minorities.  Define in clear terms exactly 
what will be done to the human subjects.
Design. This prospective, randomized, controlled trial will assess the efficacy of PE+TOP as 
compared to PE+PLA. Medical providers, participants, and evaluators will be blinded to the 
intervention condition. TOP or placebo will be administered over 16 weeks (6 weeks of 
upward titration and 10 weeks at maximum target dose up to 250mg per day) of active 
treatment, and participants will be asked to complete 12 sessions of PE during those 16 
weeks (allowing for missed appointments, which are common among individuals with AUD 
and PTSD). Ongoing assessments of primary outcomes (i.e., heavy drinking days, PTSD 
symptoms, functional impairment) will be made at baseline, post-treatment, and 3- and 6-
months following treatment completion. Our hypotheses are that the combined intervention 
(PE+TOP) will be more effective in reducing heavy drinking events and PTSD symptoms 
and in improving functioning and quality of life than PE with placebo (PE+PLA) among male 
and female Veterans with AUD and PTSD diagnoses. One hundred twenty (120) 
participants will be recruited through San Diego VA addictions and mental health treatment 
programs and randomized at the individual level. All symptomatic and interested participants 
who do not receive TOP during the trial will be offered the treatment immediately after blind 
is broken following the final assessment. In order to ensure we are examining outcomes in a 
multifaceted and informative manner, we will include assessments of primary comorbid 
conditions and multiple domains of functioning to provide the most comprehensive and 
informative data to inform clinical practice with this complicated population. Biweekly self-
report assessment of substance use, cravings, and PTSD and depression symptoms will be 
completed. We will also examine differential drop out, early response, and treatment 
adherence.
 
Participants will have up to 16 weeks (while they take TOP or PLA) to complete the 12 
sessions. Consistent with our other studies of PE with AUD/PTSD samples, during the first 
five minutes of session, therapists will query participants about cravings and alcohol use 
since the last session and check in with participants regarding progress toward their alcohol 
use goals. This 1) allows therapists to assess whether there is increasing alcohol or other 
substance use that may necessitate referring the Veteran to a higher level of care (see 
Human Subjects), 2) gives therapists important clinical information about whether 
participants are using alcohol in a way that may interfere with PE mechanisms (e.g., drinking 
just before or after exposure assignments), and 3) gives therapists the ability to support 
participants in achieving their alcohol use goals in a fashion consistent with the approach 
used by study physicians at the medication appointments [63].


 
Participants will be informed of the risks associated with the use of Topiramate, including all 
clinically significant warnings provided by the manufacturer in the medication package insert. 
This includes all current warnings and cautions in the most recent FDA guidelines dates May 
2019[95]. Given our frequent monitoring and standardized assessment of mood changes, 
we are already in compliance with the FDA’s recommendation to monitor for this potentially 
rare adverse event. Participants will be informed that, as with any drug, Topiramate 
administration may involve other risks that are not known at the present time. If the study 
staff learns of any new possible risk or side effects of this drug, participants will be notified 
immediately. Participants will be informed that their condition may remain the same or 
deteriorate due to an ineffective treatment. They will also be informed of the availability of 
alternative treatments to facilitate alcohol use reduction. Participants will be told that if, in the 
opinion of the doctor, there are problems caused by their participation in the study that make 
it unwise for the participant to continue, their participation will be stopped. Patients who are 
discontinued from the study for any reason will be given a referral for further treatment if 
indicated.
 
TOP Titration Schedule, Dosage Considerations, and Duration of Treatment. To 
increase medication tolerability, dosages of TOP will be gradually titrated upward (weeks 1-5) on a 
fixed schedule as shown in Table 1 . Participants will continue on this dosage of medication for 10 
weeks (weeks 6-16) until a more rapid dosage titration (i.e., 50 mg twice daily for 4 days, then 25 mg 
twice daily for 3 days) downward occurs. This latter dosage titration is intended 
minimize any 
to 
discontinuation syndrome that may occur in patients treated with TOP.
 
Several prior studies of TOP have used a maximum target dose of 300 mg [5]. However, a 
recent meta-analysis of TOP found 200 mg to be effective for treating AUD [5] and VA/DoD 
guidelines recommend 200 mg per day for the treatment of AUD due to lower side effects 
than at 300 mg [2]. We made the decision to use TOP at a maximum target dosage of up to 
250 mg to take into account the recent findings and recommendations as well as the 
literature that used 300 mg as the maximum dosage. Therefore, we will use a maximal 
target dosage of 250 mg. in these AUD/PTSD participants and will carefully monitor adverse 
effects .
 
Every attempt will be made to maintain participants at the maximal TOP dosage specified 
above. Studies by us and other investigators using maximal dosages of TOP of 
approximately 200 mg per day have found that approximately 90% of participants were able 
to take the full maximal dosage. However, participants who are unable to tolerate the 
specified dose will be allowed to continue in the study at a reduced dose (the maximum 
tolerated dose) as determined by the research physician. Such participants may continue to 
participate in all other aspects of the study. When TOP/placebo dosage reduction is 
warranted due to adverse side effects, the research physician will decrease the medication 
dosage by one step at a time as shown in the dosage titration schedule from the maximum 
to the amount that is clinically tolerable. As dosage reductions are permissible in all groups, 
this will not break the blind. In the case of severe side effects, discontinuation of the study 
agent may be necessary. In such a situation, a research physician will evaluate the patient 
to determine whether the study agent should be discontinued immediately or should be 
tapered to discontinuation.
 
Participants will have medication appointments weekly for the first six weeks and every other 
week until week 16. Medication appointments will be 30 minutes in length. In order to 
maintain high compliance with the TOP regimen, all participants will receive Medical 
Management Counseling [MMC; 60] at their TOP appointments. MMC is a manualized 
supportive counseling method designed by the National Institute of Alcohol Abuse and 
Alcoholism to promote adherence to the medication regimen and reduction in alcohol use. 
Study physicians will complete a three hour training and participate in monthly calls led by 
Drs. Stein, Brody, and Matthews to ensure standardization of pill administration and the 
MMC protocol. 
 
The 16-week double-blind treatment phase is designed to incorporate the dosage titration 
period and to allow a 10-week period where active medication is at steady-state 
concentrations. Thus, both the medication period and the psychotherapy period will be 16 
weeks, during which participants are anticipated to attend up to 12 medication and 
psychotherapy appointments. This schedule also makes it such that patients will reach their 
maximum therapeutic dose of TOP at the time that they begin imaginal exposure in PE. 


Imaginal exposure is considered a high risk time for dropout or disengagement [14]. In our 
model, we propose that TOP’s GABA-facilitatory and glutamate inhibitory mechanisms will 
help participants engage in and benefit in PE by reducing cravings and PTSD symptoms 
early in treatment (see exploratory aims).
 
Our plan for slow titration and flexible dosage is consistent with other studies that have 
found TOP to be well tolerated, cognitive side effects to be transient, and no group 
differences in dropout between TOP and placebo due to adverse events [10].
 
Phone, mail, and Telehealth Appointments: Generally, all appointments typically conducted 
in-person (therapy, medication, consenting, assessments, etc.) can be conducted via phone, mail 
and/or VA approved secure Telehealth communication software as needed. This will help to 
ensure continuity of all study precedures while reducing other risks related to in-person contact.
 
Medication Blinding Plan. Study participants and treatment providers will be aware that 
participants will receive either active or inactive medications and that all are kept blind to 
medication received until the conclusion of the study. Dr. Steven Funk, the non-blinded VA 
San Diego Research Pharmacist, will assign participants to treatment group based on our 
randomization procedures and will manage the double blind. TOP and placebo tablets will 
be obscured by mixing with lactose, and over-encapsulated in identical opaque locking 
capsules to ensure blinding. The Research Pharmacist and a non-blinded, non-treating 
physician Safety Monitor (Tonya Masino, M.D.) will have access to the medication 
randomization record in the event that the blind must be broken on an emergent basis.
 
. Study medication will be stored in the VA San Diego Research 
Medication Dispensing
Pharmacy. Storage, packaging, dispensing and record keeping will be the responsibility of the 
Research Pharmacist, Dr. Funk, in coordination with the study staff (i.e, the study coordinator and 
therapists) and Study Physicians. During the two dosage titration periods, capsules will be 
packaged in vials in accordance with the graduated dosing schedule described in the 
Titration section above. During the 10-week maintenance phase, capsules will also be 
packaged in vials by the pharmacist to be dispensed to participants at each scheduled visit. 
In the event that a participant misses a morning dose in the twice-daily dosage schedule, 
they will be instructed to take it later in the day. In the event that the patient entirely misses a 
daily dose, they will be told not to double-up on the capsules the following day. Since 
medication adherence is the focus of one of the concomitant psychosocial interventions, 
missed doses, problems with adherence, and strategies to improve compliance will be 
discussed regularly with each study participant. Participants will be asked to return unused 
medication at each visit to the Research Associate for capsule counts. Unused medication 
will be destroyed as per VA San Diego Research  Pharmacy protocol.
 
All participants will receive PE psychotherapy for PTSD. Although several treatments have 
been found effective in treating PTSD, we have selected PE based on its particularly strong 
empirical record and its appropriateness given study aims. The evidence for PE efficacy is 
greater than that for any other PTSD intervention, and treatment effects are generally 
maintained during follow-up. Thus, the safety and tolerability of PE is well documented for 
patients with and without AUD, and, because of Dr. Norman and other investigators’ 
experience administering and disseminating PE for patients with and without AUD, the study 
team is exceptionally well prepared to utilize this intervention.
PE [19] includes breathing retraining; psychoeducation; prolonged, repeated 
exposure to trauma memories (imaginal exposure); processing of trauma related material 
that emerges during exposure; and repeated real life exposure (in-vivo) to trauma-related 
avoided situations. Participants will practice in vivo exposure and listen to audio of imaginal 
exposures between sessions. PE is delivered over 12 weekly sessions. Ideally, participants 
attend therapy each week; however, participants sometimes miss appointments. Therefore, 
participants will have up to 16 weeks (while they take TOP or PLA) to complete the 12 
sessions. Consistent with our other studies of PE with AUD/PTSD samples, during the first 
five minutes of session, therapists will query participants about cravings and alcohol use 
since the last session and check in with participants regarding progress toward their alcohol 
use goals. This 1) allows therapists to assess whether there is increasing alcohol or other 
substance use that may necessitate referring the Veteran to a higher level of care (see 
Human Subjects), 2) gives therapists important clinical information about whether 
participants are using alcohol in a way that may interfere with PE mechanisms (e.g., drinking 


just before or after exposure assignments), and 3) gives therapists the ability to support 
participants in achieving their alcohol use goals in a fashion consistent with the approach 
used by study physicians at the medication appointments [63].
 
Recruitment. Eligible participants will contact our study in response to 1) flyers posted in VA 
mental health, primary care, and alcohol and substance use treatment programs; 2) 
advertisements in print and web-based media; 3) referrals from VA primary care, SAMI, 
PTSD, and other psychiatry clinics and 4) from other research studies who's participants 
provided consent to contact. Following verbal consent, potential participants will undergo an 
initial screening that takes approximately 30-45 minutes to complete. The screening, used in the PI’s 
current CSR&D merit study, is intended to detect clinically significant alcohol use and PTSD 
symptoms. It consists of screening items from the SCID [52] and the Posttraumatic Stress Disorder 
Checklist-5 [PCL-5; 53] for disorders that are part of the inclusion and exclusion criteria. Those who 
meet study criteria will attend an in-person interview where they will sign informed consent documents 
and take part in a baseline assessment (see measures in 9.8. ). Following baseline assessment, 
participants will have the opportunity to meet with a  research study therapist  to talk about their goals 
for taking part in the study treatments and the pros and cons of taking part in the study. Following the 
session, participants who choose to proceed with study participation will be randomized to the 
intervention or control condition. Random permuted blocks will be used which ensure exactly equal 
treatment numbers at certain equally spaced points in the sequence of patient assignment. A computer-
generated randomization sequence will be provided by our and held by Dr. Steve Funk study 
pharmacist. Randomization will be stratified by whether or not the participant is on a anti-
relapse medication. It is expected that randomization will balance out severity of PTSD 
symptoms, severity of alcohol use, and functional impairment, and this will be assessed 
in analyses excluded.
 
Women and Minorities
Women comprise 11% (e.g., SAMI clinic) to 60% (Military Sexual Trauma clinic) of the 
Veterans seen in the clinics from which we will be recruiting, and approximately 24% of 
Veterans in the program are minorities. Consistent with SAMI demographics as a whole, 
10% of participants in our current Merit study over the past 3 years have been women. We 
have been able to obtain 26% Hispanic, 16% African American, and 20% other ethnic 
groups, for a total of 52% from minority groups. We will continue attempts to oversample 
these groups to obtain adequate recruitment of females and minorities to examine effect 
sizes for these groups relative to male and Caucasian counterparts.
 
Verification of Pregnancy Women that are pregnant , lactating, or plan to become 
pregnant during the period of participation in the study will be excluded from participation. All 
eligible participants will receive a laboratory diagnostic evaluation consisting of a chemistry 
panel, complete blood count, liver function tests (LFTs), urine toxicology screen and 
pregnancy test during their screening and/or randomization appointments so that 
participants with any illnesses that might adversely be affected by their participation in the 
trial will be excluded.  Veterans will be sent to VA laboratory to have blood work 
completed.  No research staff shall have contact with blood/specimens.
 
Treatment Setting. All work will be carried out at the Substance Abuse Mental Illness 
(SAMI) outpatient program of the Alcohol and Drug Treatment Program (ADTP) of the 
VASDHS. The SAMI program was established in 1991, with > 4500 outpatient visits per 
year. Referrals to SAMI come from ADTP (15,000 outpatient visits per year, and a 28 bed, 
28 day residential program with > 360 residents annually), inpatient Psychiatric Unit (> 800 
admissions/year), outpatient Mental Health Program (> 16,500 visits/year), and Primary 
Care (>12,000 Veterans/year). Services in the SAMI clinic have grown in recent years with a 
33% increase in the number of Veterans receiving care. The staff includes a clinical 
psychologist, social worker, and trainees (psychology interns and postdoctoral fellows, and 
social work interns); psychiatry providers are coordinated through the larger ADTP and 
Mental Health service.
 
 
Standard Pharmacotherapy. Pharmacological treatment will be provided at no cost to the 
proposed project. The VA follows treatment guidelines that require standardized prescribing 
practices for individuals with PTSD, depression, and AUD. We expect at least 85% of 


participants will be receiving medications based on these guidelines. We recognize that 
pharmacotherapy and changes in medications will be an uncontrolled source of variance but 
expect that any changes will be similar across treatment conditions and thus balanced by 
randomization. We considered recruiting participants who were not on medication or asking 
participants to be medication stable prior to study entry. However, psychotropic medications 
have well documented effectiveness for the treatment of PTSD and withholding such 
medication would be inappropriate for this high-risk population. The only exception is if 
participants are on addiction mediations they will be asked to stay on a stable approved 
dose at least two weeks before starting the study drug and throughout the study. Study 
coordinators will record from VA medical records and patient self-report all treatment 
(psychotherapy and medication) in which Veterans participate in the VA. Participants will 
also be asked about treatment outside of the VA. We will compare treatment as usual 
between our two conditions and, if differences in any variables are found, include these as 
covariates in analyses.
 
Blind. All investigators, clinicians, and study staff will be blind to treatment condition. Only 
the research pharmacist will know to which group participants have been randomized. The 
success of the blinding procedure will be evaluated by having the rater guess the patient’s 
assigned treatment condition after each assessment. If indicated, participants will be asked 
to go through detoxification prior to beginning the study. Detoxification programs are 
available on inpatient and outpatient bases through programs funded by the San Diego VA.
 
Sources of Materials: The data relevant to the proposed project will be gathered strictly for 
research purposes. Blood and urine specimens obtained are for clinical and research 
purposes only. Sources of research data will be demographic data collected from 
participants recruited for this study, ratings from independent clinical evaluators, patient self-
reports, toxicology screens, and through VA CPRS chart review.
 
Treatment Integrity Evaluation of PE. Treatment integrity consists of two components of 
therapist administration: (1) therapist adherence and (2) therapist competency [61]. 
Therapist adherence refers to the extent to which the therapist used the interventions 
prescribed in the intervention protocol. Therapist competency refers to the level of skill 
shown by the therapist in delivering the treatment. Therapist adherence and competency will 
be monitored by two methods: clinical supervision with Drs. Norman, Haller and Davis, and 
independent evaluation by Dr. Haller. Our approach to treatment fidelity and adherence 
utilizes accepted standards [62] including: (1) treatment manuals with weekly objectives, 
outcomes, and agendas, (2) therapist training, and (3) ongoing evaluation of treatment 
fidelity through audio-rating of therapy sessions and supervision. To identify problems early, 
one of the supervisors will listen to at least 3 audio-recordings of each therapist and 
complete fidelity rating sheets for each session. Corrective feedback will be provided as 
needed. Thereafter, the supervisors will rate occasional audio-recorded sessions . Further, 
the supervisors will have weekly supervision of therapists to evaluate their implementation of 
and adherence to the therapy manual. The participant evaluation method of quality 
assurance involves asking each participant to complete a brief checklist that queries the 
content of the session (e.g., “Did the therapist discuss common reactions to trauma?”). In 
addition, therapists will keep a session-by-session “PE Session Tracking Form” which 
includes self ratings about the “% of time” of each session was spent “using the manual” and 
covering the relevant module content.
 
Quality Control - Data entry and management. Data will be collected on paper forms and 
checked for missing items. Participants will be queried at time of collection to complete or 
clarify blank or illegible responses. Refusal or inability to respond to items will be 
documented with explanations. Data will be entered into SPSS databases using a system 
that incorporates checking for out of range values and requires all data to be entered twice, 
with discrepancies corrected at time of entry. Data will be stored in locked file cabinets.
 
Statistical Considerations:
Data Management. In the initial 3 months, data management procedures will be 
developed and implemented. Data entry and quality assurance will be ongoing during 
enrollment, with validation and double-entry procedures in place to ensure accurate 
data entry. Study staff will be trained to limit missing data by checking questionnaires 


immediately and prompting for additional response and re-contacting participants if 
necessary. Study staff will attempt to collect all post-randomization data regardless of 
treatment attrition.
Statistical Analysis. Data analysis will occur in a staged approach, moving from 
initial descriptive analyses to hypothesis tests. Descriptive statistics and plots will 
summarize and assess distributional properties of key variables. Randomized groups 
will be compared on baseline demographic and clinical variables using analysis of 
variance, 2, or Wilcoxon-rank sum tests. Any baseline variables potentially 
confounded with treatment condition will be incorporated in the primary analyses as 
covariates. Outliers will be assessed and variables whose distributions depart 
significantly from normality will be transformed.
Missing Data. The primary outcome will be tested using an intent-to-treat framework. 
If, the extent of missing data is small and the data appear to be consistent with a 
missing-at-random model (MAR) [84], then the maximum likelihood analysis using all 
randomized cases and the observed data is an appropriate method for handling the 
missing data [85]. In the MAR model the missingness can be a function of the 
observed covariates and observed outcomes. If the missingness is related to the 
unobserved outcome, then the missing values are considered missing not at random 
(MNAR). However, the MAR assumption has been shown to be plausible even in 
studies such as substance abuse in adolescents [86]. The critical element when 
conducting MAR-based analyses is to include covariates related to the missingness 
in the statistical model [87]. As a check on the sensitivity of our conclusions to the 
assumption that the missing data are MAR we will conduct pattern-mixture modeling, 
which is appropriate with data is likely MNAR [88, 89]. In these models participants 
are categorized into groups based on patterns of missing data over time. Missing 
data pattern groups are then included as covariates in the statistical model and the 
effect of missing data on parameter estimates can be determined. Parameter 
estimates can be averaged over the missing patterns to adjust for biased estimates.
Power analysis: We determined sample size for a two group design with PHDD as 
the primary outcome at post-treatment. A recent meta-analysis comparing the effects 
of TOP compared to placebo on heavy drinking found an overall standardized effect 
size of .406 [5]. The overall effect size was determined from seven studies with effect 
sizes ranging from .140 to .623. To ensure adequate power we calculated a sample 
size for a two-sample t-test by condition. The proposed primary analysis uses PHDD 
measured at baseline, post-intervention, 3, and 6 months in a random-intercepts 
regression model; however this use of additional data should serve to increase the 
power. A two-tailed test would require a sample size of 192 participants to detect an 
effect size of .406 with 80%. This is not a feasible sample size to recruit within the 
study’s recruitment window. Alternatively, a 1-tailed test requires a sample size of 120 
to have 72% power to detect the expected effect size. A one directional test is 
warranted given we are interested only in the improvement of PHDD for the TOP 
condition compared to the placebo condition. In addition, a sample size of N = 120 
provides 80% power for a two-tailed test to detect a sample size of .516, a somewhat 
larger effect size within the range of effect sizes pooled in the recent meta-analysis 
[5]. Overall, we believe a sample size of N = 120 balances three needs: (1) sufficient 
power to compare the study groups; (2) the reality of recruiting a sample of Veterans 
with AUD and PTSD; and (3) overall project cost considerations.
 
Aims:
Primary Aim Analysis. As stated in Aim 1, we will evaluate the efficacy of PE+TOP, 
as compared to PE+PLA, in percent heavy drinking days (PHDD) among Veterans 
with comorbid AUD/PTSD at post-treatment and 3- and 6-month follow-up. The 
statistical model will be a generalized linear mixed model with a log link and gamma 
distribution variance function. If the over-dispersion parameter is close to zero a 
Poisson regression model will also provide equivalent model fit. The model will 
include a factor for treatment condition (PE+TOP, PE+PLA) and a linear term for time 
(baseline, post-treatment, 3, and 6 month follow-up). This model can be expanded to 
determine an adjusted intervention effect by including covariates such as gender and 
era of service. The primary test of treatment effect will be a group x time interaction. 
This flexible analytic method provides maximum likelihood parameter estimates 
based on all of the available data, allowing for the inclusion of cases with missing 
data and the modeling of the covariance error structure of the data across the 


assessment points [90]. If the extent of missing data is small and the data appear to 
be consistent with a missing-at-random model, we will also carry out maximum-
likelihood based on a “completer-analysis” using the observed data.
Secondary Aim Analyses. As stated in Aims 2 and 3, veterans in PE+TOP, 
compared to PE+PLA, will show greater improvements in PTSD, depression 
symptoms, functional impairment and quality of life at post-treatment and 3- and 6-
month follow-up. We will first examine the relationships among these outcomes to 
determine if composite scores should be created from highly correlated variables. 
This will help to reduce the number of statistical tests. The statistical model for these 
analyses will be random effects regression models as described in the primary aim 
analysis section, using identity link for Gaussian distributed linear variables and log or 
logit link functions for discrete or skewed outcome variables. These analyses would 
be in an intent-to-treat framework using maximum likelihood as before.
Exploratory Aims: First, we will explore the extent to which lower drinking and PTSD 
symptoms are associated with better functional outcomes. Analyses will build on the 
secondary analysis models, where functional impairment (WHODAS, WSAS) serve 
as the dependent outcome variables in GLMMs. The exploratory analysis measures 
of percent heavy drinking days (PHDD) and PTSD symptom severity (CAPS) will be 
added as time-varying covariates in separate GLMMs, to examine whether lower 
drinking and lower PTSD severity are associated with better functioning. We will also 
explore prospective or “lagged” effects for these time-varying covariates (PHDD
/CAPS), to test temporal precedence as an indication of drinking/PTSD severity as 
potential mechanisms of improved functioning. Second, we will test the mediating 
effect of alcohol cravings and PTSD symptoms on the direct effect of the 
interventions on heavy drinking. Using the recommended analytic framework for 
multilevel mediation in interventions [91], separate HLMs will examine the “a” path 
(intervention effect on mediator) and “b” path (mediator effect on outcome). The 
mediated effect will be estimated using the product-of-coefficients approach and 
statistical significance estimated with 95% CI’s via the bias-corrected bootstrap [92]. 
Third, we will test the mediating effect of change in cognitive functioning from 
baseline to mid-treatment on the strength of the direct effect of the intervention on 
PTSD symptoms and SUDs. The same analytic framework for testing statistical 
mediation will be used as described above.
Genetic Testing
For each gene candidate we will conduct a 2 way repeated measures ANOVA on the data from 
the participants in the topiramate arm (approximately 74 participants), with genotype as a 
between subject factor and time (baseline, 2 mo, 5 mo and 8 mo) as a within subject 
factor.  We predict that genotype will moderate change in CAPS scores over time as supported 
by a genotype X time interaction.  The same analysis strategy will be used on the non-
topiramate arm to determine if genotype affects overall treatment response, or only response 
specific to topiramate
:  ancestry, sex, medication status, and baseline CAPS scores.  We will correct for 
Covariates
multiple comparisons based on number of gene candidates tested as appropriate.
 
DNA Sampling
Subjects will be asked for a saliva sample for immediate storage using an Oragene salivary 
sample kit. Using this kit allows for DNA quality that is similar to that of blood (99% 
concordance for SNP and CNV assessments between salivary and blood samples using this 
storage method), unlike mouthwash or buccal swab samples.  Mouthwash samples are also 
not ideal due to having alcohol content which is inappropriate for this participant group. We felt 
that an invasive blood draw was also unnecessary given the high quality DNA sampling 
allowed for by the Oragene Discover kit.  We will determine genetic ancestry using a small 
panel of 41 multiplex ancestry informative markers.  The genotypes from the ancestry markers 
will be used to determine continental ancestry to construct principal components to be included 
as covariates.
DNA extraction and genotyping
We will utilize the VMRF CFAR genomics core and standard extraction from Oragene salivary 
samples and polymerase chain methods as previously described by (Kolassa et al. 2010; 
Valente et al. 2011a) for COMTval158met genotyping. Genotype frequencies will be tested 


against Hardy Weinberger Equilibrium using Pearson’s goodness of fit 2.
 
Power Analysis:
Using Gpower we calculated that a total N of 75 will give us 0.9 power to detect a small-
moderate effect size (f=0.4) of genotype if the SNP is common (e.g. 25/50/25 ratio in general 
population) using a 2 way repeated measures ANOVA (gene with 2 levels and time with 4 
levels).  For a t-test comparing final outcome measures post treatment, we have 0.8 power to 
detect a d=0.75 effect size with this N
Repository:  We will also use these samples for future sequencing, methylation and 
Genome Wide Association Analysis  and merge genotype data and diagnostic data with 
other VA and/or NIH studies to increase power to discover new genetic  associations 
with PTSD and PTSD treatment response  
fMRI
         Participants will be asked if they are interested to take part in the optional fMRI study titled 
“Neuromarkers of Treatment for Comorbid Posttraumatic Stress Disorder and Alcohol Use 
Disorder IRB # H170116 (P.I. Andrea Spadoni-Townsend, PhD).   If participants consents to be 
contacted for the optional study,  Dr Spadoni-Townsend's approved research team will contact 
patient and if patient agrees they will consent them for the study.  Dr. Sonya Norman and her 
research team may share some of thier data with Dr. Spadoni-Townsend’s approved research 
staff for the purpose of data analysis if the participant initals the appropriate box in the consent 
form to allow data sharing.
COVID-19 Procedures 
Temporary procedures to allow for participation while maintaining social distancing:
          The protocol remains as approved with the following exceptions. If a Veteran is potentially 
interested in participation after the initial contact and screens eligible using the telephone 
screening, an enrollment appointment will be scheduled using VA approved secure Telehealth 
communication software or telephone. We will send an encrypted email (using VA Azure RMS), a 
message through MyHealtheVet and/or send documents by US mail containing (1) the approved 
ICF, (2) the approved HIPAA document, (3) the CA Experimental Subjects Bill of Rights, and (4) 
fillable PDF baseline assessment documents, and arrange a telehealth or through VA approved 
secure Telehealth communication software to complete the informed consent process, explain the 
HIPAA Authorization, and CA Experimental Subjects Bill of Rights. If the visit is completed by VA 
approved secure Telehealth communication software, the staff member will witness the signing of 
the ICF and HIPAA Authorization and will instruct the potential participant to provide 
documentation of written informed consent by one of the following methors: (1) returning images 
of the documents through MyHealtheVe (2) by allowing a screenshot of the signed documents 
(approval date and signature must be clearly visible) (3) study staff can have the participant 
digitally sign the fillable PDF documents which can be saved directly to the R Drive (4) or 
document can be signed and returned via encrypted email (using VA Azure RMS) (5) documents 
can be sent and signed via DocuSign. If documents were mailed, the patient will be instructed to 
mail back the signed documents. These electronic documents will be stored electronically 
separate from study data on the R: drive. Paper documents will be stored securely according to 
VA requirements.
If the visit is done by phone, the (1) the approved ICF, (2) the approved HIPAA document, (3) 
the CA Experimental Subjects Bill of Rights, and (4) baseline assessment documents will be 
emailed (using VA Azure RMS and the participant will need to print all documents) and/or hard 
copied will be mailed to the participant. Study staff will call the participant at the scheduled 
appointment time to complete the documents. Study staff along with the participant will complete 
the informed consent document, explain the HIPAA Authorization, and CA Experimental Subjects 
Bill of Rights. The participant will be instructed to mail back the signed consent and HIPAA forms. 
Once the forms are received by study staff, the baseline assessments will be scheduled and 
completed by phone or through VA approved secure Telehealth communication software.
Participants will be sent a copy of the signed and dated forms, regardless if the Informed Consent 
appointment was completed by VA approved secure Telehealth communication software or by 
phone.
Once documentation of written consent is received, the staff member will begin the 
baseline eligibility assessment. The participant may use the fillable PDF to complete the self-
report forms and return them via MyHealtheVet, may read their responses to the items to a staff 
member who will transcribe the responses into an electronic form behind the VA firewall or docum


ent can be signed and returned via encrypted email (using VA Azure RMS). The interview-based 
measures will be completed and electronically transcribed. Safety concerns will be reviewed with 
a licensed mental health provider (e.g., suicidality). Refer to the 
section of the 
Risk Management 
protocol for telephone safety procedures.
Eligible participants will be required to complete laboratory diagnostic testing at the VA 
location of their choice. This is the only visit that the veteran is required to attend in person. 
Following laboratory diagnostic testing, the veteran will be scheduled for all remaining baseline 
medical and psychology meetings by telephone and/or VA approved secure Telehealth 
communication software.  
Following the baseline eligibility appointments, if the veteran is found to be eligible for 
the treatment potion of the study, they will be randomly assigned to PE + Placebo or PE + 
Topiramate. All psychiatry and therapy appointments will be scheduled through VA approved 
secure Telehealth communication software or phone. We will send an encrypted email (using VA 
Azure RMS), a message to MyHealthyVet, or send documents by US mail containing all therapy 
and psychiatry materials to be used throughout the treatment portion of the trial. The participant 
may use the fillable pdf’s to complete the forms and return them via MyHealtheVet, may read 
responses to the items to a staff member who will transcribe the responses into an electronic 
form behind the VA firewall, or they may be returned via encrypted email (using VA Azure RMS).
Assessments will be administered again at mid-treatment, immediately after completion 
of the treatment potion of the study, at 3-month post-treatment, and finally at 6-month post-
treatment, using phone and/or VA approved secure Telehealth communication software. We will 
send an encrypted email (using VA Azure RMS), a message to MyHealthyVet, and/or send 
documents by US mail containing assessment materials to the veteran. The veteran will submit 
the completed assessment materials by either returning images of the documents through 
MyHealtheVet, mailing back completes self-report assessments, or a staff member may read 
questions and responses will be transcribe into an electronic form behind the VA firewall, or they 
may be returned via encrypted email (using VA Azure RMS). The interview-based measures will 
also be completed and electronically transcribed.
Participant compensation - Vendorizing is now accepting digital signatures on all 10091 
forms. Users who are registered in CEP (Customer Engagement Portal) will be able to submit 
vendor forms electronically. The participant may also use the fillable pdf to complete the form and 
return them via MyHealtheVet, they may be mailed a blank 10091 form to be mailed back to 
r they may be returned v
study staff for submission and payment, o
ia encrypted email (using VA 
Azure RMS).. 
 
Clinical Procedures
9.1 
Section 
Differentiate research procedures (or any procedures done for research purposes only) from clinical 
9.1) 
procedures (procedures that are done as part of standard care).
(Note: this differentiation should be clear in the consent form as well)
The experimental portion of this study is to test if existing psychotherapy (PE) + TOP or PE 
+Placebo (PL) will be effective in helping individuals who are having difficulties with alcohol use 
cope with the negative consequences of having experienced a traumatic event. Clinical 
procedures employed in this study are: the use of Exposure therapy (PE) and Topiramate(Top).
 
Non-IND Drugs
9.3 
Section 
List all other (non-IND) drug names and dosages given for research purposes.  Document why an 
9.3) 
IND is not required (see  for detail)
?
Non-IND Drugs:
The following are the FDA criteria for Exempt from IND requirements:
A clinical investigation of a marketed drug is exempt from the IND requirements if all of the 
criteria for an exemption in § 312.2(b) are met: 
• The drug product is lawfully marketed in the United States. - YES
• The investigation is not intended to be reported to FDA as a well-controlled study in support of 
a new indication and there is no intent to use it to support any other significant change in the 
labeling of the drug. - YES
• In the case of a prescription drug, the investigation is not intended to support a significant 


change in the advertising for the drug. - YES
• The investigation does not involve a route of administration, dose, patient population, or other 
factor that significantly increases the risk (or decreases the acceptability of the risk) associated 
with the use of the drug product (21 CFR 312.2(b)(1)(iii)). - YES
The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR 
part 56) and with the requirements for informed consent (21 CFR part 50). - YES
• The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the 
investigation is not intended to promote or commercialize the drug product). - YES
Topimarate ( TOP). TOP is approved by the FDA for three indications: treatment of epilepsy; 
prophylaxis of migraine headaches; and, in combination with phentermine, for obesity. It is also 
used clinically either to reduce drinking in problem drinkers, or as an aid to prevent alcoholism 
relapse in alcohol dependent participants. After reviewing the literature, we have chosen TOP as 
the optimal medication for the present trial for several reasons: 1) This medication has an 
extensive record of safety (several million patient-years) in a variety of diverse patient 
populations [55] that includes children, individuals with AUD, and patients with PTSD; and 
animal studies suggest that the abuse liability of TOP is low. Furthermore, TOP did not potentiate 
the cognitive and motor effects of alcohol in a clinical trial [56]. 2) It is the one medication that 
appears in meta-analytic reviews as an effective agent for both alcohol use disorder [5, 41] and 
PTSD [3, 57], and a recent pilot study [10] found that it decreased alcohol consumption, craving, 
and PTSD symptom severity in Veterans with AUD and PTSD. 3) TOP’s GABA-facilitatory and 
glutamate inhibitory (via AMPA/kainate receptor blockade) effects make it a promising 
pharmacotherapy in AUD/PTSD patients, and there is preclinical evidence that the drug mitigates 
stress-induced drinking [11]. These mechanisms differentiate it from other AUD medications 
such as naltrexone and make it uniquely promising for the treatment of comorbid AUD/PTSD 
together with evidence based PTSD psychotherapy. 4) Its metabolites are relatively inactive and 
its major elimination route is renal [58]. 5) The oral preparation is rapidly absorbed and has 
excellent (> 80%) bioavailability. 6) Its pharmacokinetic properties are also advantageous over 
some of the other agents in this class because they allow for twice daily dosing without the build-
up of long-acting metabolites, and the medication is regarded as safe with respect to 
pharmacokinetic drug interactions [59]. Initial side effects appear to subside; and slow titration, 
as we propose in our study (see 6.E.1.a.), is associated with low side effects [10] and high 
tolerability. 
• TOP Titration Schedule, Dosage Considerations, and Duration of Treatment. To increase 
medication tolerability, dosages of TOP will be gradually titrated upward (weeks 1-5) on a fixed 
schedule as shown in Table 1 below. 
Participants will continue on this dosage of medication for 10 weeks (weeks 6-16). until a more 
rapid dosage titration (i.e., 50 mg twice daily for 4 days, then 25 mg twice daily for 3 days) 
downward occurs. This latter dosage titration is intended to minimize any discontinuation 
syndrome that may occur in patients treated with TOP. 
Several prior studies of TOP have used a maximum target dose of 300 mg [5]. However, a 
recent meta-analysis of TOP found 200 mg to be effective for treating AUD [5] and VA/DoD 
guidelines recommend 200 mg per day for the treatment of AUD due to lower side effects than 
at 300 mg [2]. We made the decision to use TOP at a maximum target dosage of up to 250 mg 
to take into account the recent findings and recommendations as well as the literature that used 
300 mg as the maximum dosage. Therefore, we will use a maximal target dosage of 250 mg in 
these AUD/PTSD participants and will carefully monitor adverse effects. Every attempt will be 
made to maintain participants at the maximal TOP dosage specified above. Studies by us and 
other investigators using maximal dosages of TOP of approximately 200 mg per day have found 
that approximately 90% of participants were able to take the full maximal dosage. However, 
participants who are unable to tolerate the specified dose will be allowed to continue in the study 
at a reduced dose (the maximum tolerated dose) as determined by the research physician. Such 
participants may continue to participate in all other aspects of the study. When TOP/placebo 
dosage reduction is warranted due to adverse side effects, the research physician will decrease 
the medication dosage by one step at a time as shown in the dosage titration schedule from the 
maximum to the amount that is clinically tolerable. As dosage reductions are permissible in all 
groups, this will not break the blind. In the case of severe side effects, discontinuation of the 
study agent may be necessary. In such a situation, a research physician will evaluate the patient 
to determine whether the study agent should be discontinued immediately or should be tapered 
to discontinuation. 
Participants will have medication appointments weekly for the first six weeks and every other 
week until week 16. Medication appointments will be 30 minutes in length. In order to maintain 
high compliance with the TOP regimen, all participants will receive Medical Management 
Counseling [MMC; 60] at their TOP appointments. MMC is a manualized supportive counseling 
method designed by the National Institute of Alcohol Abuse and Alcoholism to promote 
adherence to the medication regimen and reduction in alcohol use. Study physicians will 
complete a three hour training and participate in monthly calls led by Drs. Stein, Brody, and 
Matthews to ensure standardization of pill administration and the MMC protocol. 
The 16-week double-blind treatment phase is designed to incorporate the dosage titration period 


and to allow a 10-week period where active medication is at steady-state concentrations. Thus, 
both the medication period and the psychotherapy period will be 16 weeks, during which 
participants are anticipated to attend up to 12 medication and psychotherapy appointments. This 
schedule also makes it such that patients will reach their maximum therapeutic dose of TOP at 
the time that they begin imaginal exposure in PE. Imaginal exposure is considered a high risk 
time for dropout or disengagement [14]. In our model, we propose that TOP’s GABA-facilitatory 
and glutamate inhibitory mechanisms will help participants engage in and benefit in PE by 
reducing cravings and PTSD symptoms early in treatment (see exploratory aims). For the 
reasons stated above, this study in my opinion meets all of the requirements, but this is the 
IRB's decision
 
Data Banking
9.5 
Section 
Identify what information will be retained, whether or not identifiers are included with the banked 
9.5) 
data, and provide future use examples.  Indicate how the study will comply with VHA Handbook 1200.12.
A varied set of information will be retained under this protocol, given the multiple sources of 
contribution. Demographics, medical history, mental health information, physiologic data, and 
biological specimens will be maintained in the biorepository for future use in larger studies of the 
biological mechanisms of trauma-related disorders. These data will be used for the following: 1) 
To perform biological assays to understand differences in genetic, transcriptomic, epidemic or 
proteomic signaling across trauma-exposed individuals and controls, 2) To support research of 
Veterans who give consent to release their data as part of other independent HRPP-approved 
protocols, and 3) To support clinical standards of care and enhance quality of care for veterans. 
Identifiers may be included in the biorepository (if available), but will be separated from the 
research data and protected by the use of subject identifiers, the use of a Master List, double 
locked storage at the VA San Diego Healthcare System for all physical data, and pass-code 
protected, limited access files located on the R: Drive in the PI’s study specific folder for all 
electronic data. Identifiers will be protected to the extent of the law as defined by the VA 
Handbooks 1200.12, 1605.01, and 1605.2. An example of a future use of this research 
information could be to test the role of a candidate gene in associations of PTSD with reduced 
hippocampal volume. A number of CESAMH investigators conduct imaging studies on their PTSD 
patients all of which collect structural imaging data. These data, along with salivary samples or 
genotype data if already established could be pooled across studies to test specific hypotheses of 
genetic interactions with PTSD that results in greater hippocampal volume differences compared 
to controls.
 
 Specimens
9.6
Section 
Identify the biological materials, procedures for obtaining material, the sources of the specimens.
9.6) 
All eligible participants will receive a laboratory diagnostic evaluation consisting of a chemistry 
panel, complete blood count, liver function tests (LFTs), urine toxicology screen and pregnancy 
test during their screening and/or randomization appointments so that participants with any 
illnesses that might adversely be affected by their participation in the trial will be excluded.
Research staff will not conduct any of the laboratory tests or handle or come in contact with any 
blood/samples. Study clinicians will request the laboratory work and veterans will go to the VA 
clinical laboratory to have the above lab work done.
DNA Sampling:
Subjects will be asked for a saliva sample for immediate storage using an Oragene salivary 
sample kit. Using this kit allows for DNA quality that is similar to that of blood (99% concordance 
for SNP and CNV assessments between salivary and blood samples using this storage method), 
unlike mouthwash or buccal swab samples. Mouthwash samples are also not ideal due to having 
alcohol content which is inappropriate for this participant group. We felt that an invasive blood 
draw was also unnecessary given the high quality DNA sampling allowed for by the Oragene 
Discover kit. We will determine genetic ancestry using a small panel of 41 multiplex ancestry 
informative markers. The genotypes from the ancestry markers will be used to determine 
continental ancestry to construct principal components to be included as covariates (Nievergelt 
et al. 2013).
 
Specimen Banking
9.7 
Section 
Select the specimen banking method(s):
9.7a) 


 Specimens will be banked at 
9.7a1)
VASDHS
 Yes  
 No
Specimens will be banked at 
 facility under the direction of the ACOS there
9.7a2) 
another VA
  Yes  
  No
Specimens banked at multi-site protocol banking facility 
9.7a3) 
approved by VA ORD
  Yes  
  No
External banking/storage 
9.7a4) 
waiver from ORD is approved.
  Yes  
  No
 External banking/storage 
 and pending.
9.7a5)
waiver from ORD is submitted
  Yes  
  No
External banking/storage 
 to ORD.
9.7a6) 
waiver will be submitted
  Yes  
  No
 Provide the banking detail - what tissues are banked, where, whether or not specimens are 
9.7b)
identified, status of waiver, etc.
Saliva will be labeled with a biorepository ID and visit number and stored in Dr. Risbrough’s VA 
research laboratories including freezers located on the 6th floor of Building 1 (room 6180). 
Samples and DNA will be identified by a unique subject number code. Specimens will be 
genotyped conducted by CFAR, a VA affiliated core.
 
Questionnaires & Surveys
9.8 
Section 
Provide the name and a reference for questionnaires/surveys that are standard or identify them here 
9.8) 
and attach a copy of the questionnaire/survey.
The primary efficacy outcomes of interest are reduction in alcohol use (percent heavy drinking 
days), PTSD symptoms, and improvement in functional impairment and quality of life at post-
treatment and follow-up. We will also examine rates of drop out, depression symptoms, and 
potential mediators and moderators such as treatment process variables and gender. 
Alcohol and Substance Use Measures. At baseline, participants will be administered the AUD and 
SUD sections of the Structured Clinical Interview for DSM-5 [SCID; 52]. The Timeline Follow-
back Procedure [TLFB; 63] will be employed at all assessment points to evaluate drinking and 
drug use during the 90 days preceding the screening visit. The Quantity-Frequency Index [64] 
and maximal consumption will be calculated for alcohol use. Drug use indices will be similarly 
derived for other drugs. The TLFB will be used at each follow-up to establish: % heavy drinking 
days (HDD), % days abstinent (PDA), time to relapse to heavy drinking, length of use episodes, 
severity of relapse, and current alcohol/drug use pattern. The Addiction Severity Index-5th 
edition (ASI) interview [65] which includes seven subscales (medical, employment, alcohol use, 
drug use, legal, family/social, and psychiatric), will be used to assess severity of alcohol 
problems. A self-report Substance Use Inventory [SUI; 66] will be administered at treatment 
sessions. It asks on which of the preceding seven days participants used alcohol or any of seven 
major types of drugs. Participants will complete an initial toxicology screen at baseline and 
random screens will be conducted during 25% of the assessment. Relapse episodes will be 
classified using the Modified Contextual Cue [MCC; 67] system for precursors using transcribed 
verbatim reports of relapse episodes, and using Shiffman and Wills’ framework of temptation, 
stress, or other [68]. Craving will be measured weekly using the Penn Alcohol Craving Scale 
[PACS; 69]. The PACS is a well validated five-item, self-report measure that includes questions 
about the frequency, intensity, and duration of craving, the ability to resist drinking, and asks for 
an overall rating of craving for alcohol for the previous week. The PTSD-specific Alcohol 
Expectancies Questionnaire [P-AEQ; 46] measures alcohol expectancies related to PTSD 
symptoms. The instrument differentiates between alcohol dependent and non-alcohol dependent 


individuals with PTSD, and has good psychometric properties. 
PTSD and Other Disorders. The Clinician-Administered PTSD Scale for DSM-5 [CAPS; 70] is a 
standard semi-structured interview used to assess PTSD severity. Respondents select up to three 
of the most traumatic events they have experienced, and those events are used as the basis for 
assessing PTSD. The CAPS assesses each of the 20 items from the DSM-5 criteria B, C, D, and E 
and it has demonstrated high internal consistency, good interrater reliability, and excellent 
convergent validity. The CAPS can be administered in about 60 minutes, and it has the 
advantages of categorical (diagnostic) or dimensional scoring of PTSD. The PTSD Checklist – 5 
[PCL-5; 71] is a brief self-report instrument to measure PTSD symptoms. It consists of 20 items, 
scored on a 0-point (not at all) to 3-point (extremely) scale, that correspond to the DSM-5 
symptoms of PTSD. The PCL-5 will be completed at every other session. The Patient Health 
Questionnaire-9 [PHQ-9; 72] is a self-report scale listing common symptoms of depression. It is 
among the most widely used self-report depression measure in clinical populations, again 
facilitating comparison between this investigation and others. Stem questions from the SCID are 
used during screening for initial screening of study inclusion and exclusion criteria. The 
screening, used in the PI’s current CSR&D merit study, is intended to detect clinically significant 
alcohol use and PTSD symptoms. It consists of screening items from the SCID [52] and the 
Posttraumatic Stress Disorder Checklist-5 [PCL-5; 53] for disorders that are part of the inclusion 
and exclusion criteria (see measures below and attached screening document).
The Columbia-Suicide Severity Rating Scale [C-SSRS; 73] is a standardized 8 point clinician-
administered suicidal rating system designed to track suicidal adverse events across a treatment 
trial and covering the wide spectrum of suicidality. 
Inventory of Psychosocial Functioning (IPF; 74). The IPF (Bovin et al., in press; Marx et al., 
2009) is an 80-item self-report questionnaire of functional impairment across several domains 
including relationships, work, parenting, education, and general daily functioning over the past 
30 days. Domain scores can range from 0 to 100 with higher values corresponding to higher 
functioning. Overall functioning score is calculated as the mean of all completed IPF domain 
scores. As participants may skip certain domains that do not apply to them (thus leading to 
different sample sizes for analyses predicting different domains of functioning), overall score is 
calculated as total sum of all completed IPF domain scores divided by the actual number of 
domains completed by the participant. In one study (Marx et al., 2009), the domain scores 
demonstrated internal consistency (subscale Cronbach's alphas between .76 and .91) and 
correlated highly with other established measures of functional impairment. 
The Work and Social Adjustment Scale [WSAS; 77], a well validated self-report measure that 
queries additional domains of functioning will also be included. The WSAS queries functional 
impairment attributable to an identified problem in five different areas: ability to work, home 
management, social leisure, personal leisure, and maintaining close relationships. This five-item 
scale, rating each of these areas of functioning from 0 to 8, has been used to study the 
treatment of depression, anxiety, and PTSD. The well validated World Health Organization 
Quality of Life – BREF [78] will be used to assess quality of life. It consists of 26 items that 
measure physical and psychological health, social relationships, and environment. The Montreal 
Cognitive Assessment [MoCA; 79] is a brief, clinician-administered well-validated cognitive 
screening test. The MoCA will be used as a screening measure for study exclusion. A score of less 
than 26 is indicative of moderate or severe cognitive impairment. Participants who score less 
than 26 will be referred for additional evaluation and excluded, unless a qualified clinician 
provides clearance to participate. We will evaluate verbal memory and learning using the 
Hopkins Verbal Learning Test-Revised [80] and processing speed using the WAIS-IV digit symbol 
and digit search at baseline, mid-treatment, and post-treatment. Alternate forms will be used for 
administrations at different time points. 
The Insomnia Severity Index (ISI; Morin & Barlow, 1993) is a widely used measure of insomnia 
with well established
reliability and validity. The ISI consists of seven items, three of which assess severity of 
insomnia (i.e.,
degree of difficulty falling asleep, staying asleep, and waking too early). The remaining questions 
tap satisfaction
with sleep pattern, effect of sleep on daytime and social functioning, and concern about current 
sleep difficulties.
The Military to Civilian Questionnaire (M2C-Q; Sayer et al., 2011) a 16-item self-report measure 
of post-deployment
community reintegration difficulty.
Trauma Related Guilt Inventory [TRGI] is a 32-item validated self-report measure assessing
traumatic guilt. The TRGI has three scales – Guilt Severity, Distress, and Guilt Cognitions. We 
will use the TRGI as
one of our eligibility criteria (see inclusion criteria, section 9.4) and to monitor changes in guilt 


and related
cognitions over time. Guilt severity will be the primary outcome of interest. It is computed by 
adding items regarding
guilt frequency and guilt intensity. Changes in guilt cognitions will be examined as a partial 
mediator of treatment
outcomes. Internal consistency is high for the TRGI (guilt severity = .90, distress = .86, guilt 
cognitions = .86).
Constrain environment- short assessment to inquire if patient had been in a constrained 
environment (jail, in patient, etc.) since their last study visit.
The Patient Reported Outcomes Information Systems (PROMIS) Pain Interference item banks 
assess self-reported consequences of pain on relevant aspects of one’s life. This includes the 
extent to which pain hinders engagement with social, cognitive, emotional, physical, and 
recreational activities. Pain Interference also incorporates items probing sleep and enjoyment in 
life, though the item bank only contains one sleep item. The pain interference short forms are 
universal rather than disease-specific. All assess pain interference over the past seven days.
Measures of Mechanism and Mediation. The Expectancy of Therapeutic and Medication Outcome 
[ETO; 81], This measure will be used to understand treatment credibility and participant’s beliefs 
about how much the study treatments will help their trauma symptoms and alcohol problems. 
The Expectancy of Therapeutic and Medication Outcome is a 22-item self-report scale to evaluate 
participant’s expectancies and beliefs about treatment credibility. It will be administered in 
Session 1. Questions are rated on a Likert-type scale (0-8).
The Additional Treatment Inventory (ATI) assesses additional psychiatric medications and 
psychotherapy sought during and after the completion of study treatment. The Client Satisfaction 
Questionnaire [CSQ; 82] is an 8-item self-report scale measuring satisfaction with treatment that 
will be used to measure participants’ satisfaction with the interventions. Participants will also 
complete content specific questionnaires for each intervention at the end of each session. 
Process measures will include number of sessions attended, homework compliance, and 
tardiness. 
Medication Adherence and side effects. We will use interview and pill counts as the primary 
assessments to measure adherence. To expand upon the reliability of this information, 
medication will be dispensed weekly in vials showing morning and evening doses separately. Our 
staff will review this information with the participant at each weekly visit and we will supplement 
pill counts with the ACTG Interview of Antiretroviral Medication Use which was developed by the 
Adult AIDS Clinical Trials Group to assess in detail HIV medication adherence over the previous 
four days and takes about 10 minutes to complete [83]. The measure was modified for the 
current study to assess adherence to TOP. Side effects will be collected weekly using a checklist 
of 18 common AE’s associated with TOP as indicated in the FDA-approved labeling for TOP [12].
Cannabis assessment (frequency and use): A single item assessing frequency of use for different 
forms of cannabis. To better assess for participants' cannabis use. 
The DTS (Simons & Gaher, 2005) is a 15-item self-report measure that assesses the ability to 
experience and tolerate aversive emotional states using a Likert type scale (1= Strongly Agree to 
5 = Strongly Disagree). Specifically, the DTS measures the tolerance of aversive emotional 
states, appraisal of distress, attention absorbed by distress, and efforts to regulate distress. The 
DTS displays good internal consistency, convergent and discriminant validity, and temporal 
stability. 
Medication Adherence form: A 2 item questionnaire regarding medication adherence
Coronavirus Stressor Survey - This survey will be used to determine stressors patients face 
during the coronavirus pandemic. This assessment will be given at all assessment timepoints. 
(McLean, C. P. & Cloitre, M., 2020). 
COVID Impact on Therapy Participation survey - This survey is meant to measure how COVID-19 
has impacted participants ability to participate in evidence-based psychotherapy research at the 
VA.
 
 Data Safety Monitoring Board or Plan
9.9
Section 
Provide a Data Safety Monitoring Plan (DSMP) or the details of a Data Safety Monitoring Board.
9.9) 


Data Safety Monitoring (DSM). DSM will include periodic review and reporting of participant 
accrual, adverse event rates, treatment compliance, and drop-out rates. Study termination will 
be triggered by excessive drop-outs or adverse events. Adverse events includes 1) need to break 
confidentiality, 2) loss of data, 3) inadvertent harm caused by study participation, 4) patient 
suicidality. If treatment is needed during the follow-up phase due to increased alcohol 
consumption or serious psychiatric/medical symptoms, patients will be referred to appropriate 
treatment and followed by the PIs and study therapist until treatment is initiated. Adverse events 
will be reported to the San Diego VA’s IRB and the VA ORD (serious adverse events within 48 
hours) and clinically managed as appropriate. A summary of all adverse events will be submitted 
to VA ORD and RR&D annually. The PI (licensed in the state of California) will be available by 
phone 24-hours a day. The PI will be responsible for initial determination of serious adverse 
events from non-serious adverse events. This study would report to the VA DSMB and follow all 
criteria for reporting.
An Adverse Event (AE) is any unexpected medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product, which does not necessarily have a causal 
relationship with the treatment. This includes any clinical or laboratory change that does not 
commonly occur in that participant and is considered clinically significant. All observed or 
volunteered AEs regardless of treatment group or suspected causal relationship to the study 
treatment will be recorded throughout the study. The study physician will also be responsible for 
determining causal relationship between the study treatment and all AEs. Withdrawal from the 
study as a result of an AE or of therapeutic measures taken to treat an AE shall be at the 
discretion of the study clinicians. If a participant withdraws from the study for any reason, the 
study team will follow all participants with any ongoing AE until the AE is resolved or until it is 
deemed stable.
FDA 21CFR312.32 defines a serious adverse drug experience (SAE) as any adverse drug 
experience occurring at any dose that results in any of the following outcomes: death; a life 
threatening adverse drug experience; inpatient hospitalization or prolongation of existing 
hospitalization; a persistent or significant disability/incapacity; or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse experiences when, based on appropriate 
medical judgment, they may jeopardize the patient or participant and may require medical or 
surgical intervention to prevent one of the outcomes in this definition. The judgment of whether 
a particular AE meets the above criteria for an SAE shall be at the discretion of Dr. Norman.
It will also be the responsibility of Dr. Norman to document all SAEs and/or make referrals for 
appropriate care. All SAEs will be reported to the IRB, within 48 hours of their discovery. The 
blind can be broken at any point throughout the study as needed to protect participants’ safety. 
Dr. Norman will meet with the research staff on a weekly basis to discuss study progress and 
potential problems, and will review collected data weekly, to ensure compliance with study 
protocols and data integrity. She will convene monthly meetings of investigators and project staff 
to ensure high levels of communication within the study team.
Participants in need of additional services. A plan is in place for identifying and referring 
individuals who report suicidality, either through self-report on assessment measures (e.g., PHQ-
9 C-SSRS), or during a clinical contact. Participants identified as at imminent risk will be further 
evaluated by the site PI or, if needed, escorted to the emergency services at the VA. If indicated, 
referrals for treatment will be provided. In our ongoing trials, we have used this procedure and 
have provided referrals for both alcohol use and mental health treatment.
 
Laboratory Tests
9.10 
Section 
For each 
 laboratory test (not lab tests used as part of standard care), identify the test and 
9.10) 
research
indicate if the test results will or will not be used clinically for diagnosis, treatment, or prevention of 
disease.  Please note, only results from properly accredited laboratories can be used for diagnosis, 
.
treatment, and prevention of disease
DNA extraction and genotyping: 
o We will utilize the VMRF CFAR genomics core and standard extraction from Oragene salivary 
samples and polymerase chain methods as previously described by (Kolassa et al. 2010; Valente 
et al. 2011a) for genotyping. Genotype frequencies will be tested against Hardy Weinberger 
Equilibrium using Pearson’s goodness of fit χ2. 
 
Pictures and Audio/Video Recordings of Patients
9.11 
Section 
Describe the purpose and of photographs (facial) or audio or video recordings of patients
9.11) 


Audio Recordings: All therapy sessions as well as select assessments will be audio-recorded. 
Study therapists and Assessors will receive weekly feedback and supervision on their skillfulness 
and adherence to treatment guidelines using review standards developed by Carroll et al. and 
refined in our lab [61].Audio recordings will only be reviewed for supervision, reliability, and 
treatment adherence purposes, and recordings will be erased as soon as data are analyzed.
All treatment sessions and interviews will be recorded on digital audio recorders “Sony ICD-
UX533”"Sony ICD-PX333", “Olympus VN-1800”, “Olympus VN-6200PC”, “Olympus Vn-7200”, 
“Olympus DP-201 and the “Olympus VN-6300pc” or other VA approved recording technology. All 
recordings will be placed on the VA server behind the VA firewall. Audio recordings will be 
reviewed by study investigators, and a random sample will be selected for reliability, and 
treatment adherence purposes.
 
 - Human Subjects
Section 10
Describe the characteristics of the proposed subject population. Include age, gender, ethnicity, and 
10) 
health status as appropriate.  
 
 Provide inclusion and exclusion criteria as appropriate.  Indicate the 
 
number of VASDHS participants to be studied.  For multisite studies, also provide the total number of 
  
subjects from all sites.  Indicate the estimated number of 
 subjects that will fail the screening 
consented
process, if any.
Protection of Human Subjects
1. Risks to the Subjects.
1.a. Human Subjects Involvement and Characteristics
The participants in this study will be 120 outpatient male and female Veterans (60 per treatment 
condition), ages 18 or older, with alcohol use disorder (AUD) and PTSD. 
In order to ensure that our sample represents the diversity of comorbidity in Veterans with 
PTSD, exclusion criteria are minimized and include only those factors that contraindicate primary 
treatment for PTSD, prevent the Veteran from benefiting from the current program, or may 
interfere with the mechanisms under study. 
Inclusion criteria are: 
1) Veterans of the U.S. military and/or Reserve/National Guard members, 
2) at least 18 years of age, 
3) survivors of a psychological trauma meeting DSM-5 criterion A, and are at least one month 
post-trauma, 
4) have current DSM-5 diagnoses of AUD and PTSD based on semi-structured diagnostic 
interviews,
5) have at least 20 days of heavy drinking (>= 5 drinks/day for men and >= 4/drinks per day 
for women) in the last 90 days spent in a non-restricted environment and meet criteria for heavy 
drinking at least 4 days in the last 30 days prior to screening, 
6) are not currently receiving trauma-focused psychotherapy, 
7) are literate in English and intend to stay in the San Diego area during the study, 
8) are willing to attend psychotherapy, medication, and assessment sessions, 
9) trying or planning to try to cut down on or abstain from alcohol, 
10) for females of childbearing potential, agree to use an approved form of contraception for the 
duration of the study, including hormonal contraceptives (e.g., oral contraceptives or implantable 
devices), intrauterine device (IUD), or double barrier methods (e.g., diaphragm with spermicidal 
condom); barrier method is preferred as topiramate may make birth control less effective,
11) Individuals with clinically significant renal disease and/or impaired renal function, as defined 
by clinically significant elevation of blood urea nitrogen (BUN) or creatinine or an estimated 
creatinine clearance of < 60 mL/min, can be included with physician approval, however the 
dosing schedule and maximum dose will be adjusted in accordance with FDA prescribing 
guidelines,
12) if individual is on another addiction medication, they should be on a stable approved 
addiction medication dose (at least two weeks before starting study drug) throughout the study,
13) are capable of giving informed consent. 
Exclusion criteria are: 
1) Subjects known to have clinically significant unstable medical or psychiatric conditions, where 
participation is deemed by investigators and study physicians to be risky, including but not 
limited to:
-AST and/or ALT >5 times the upper limit of the normal range and/or an increased serum 
bilirubin >2 times the upper limit of normal. 
-Seizure disorders
2) have been treated with Topiramate for any reason in the past and discontinued the drug due 


to hypersensitivity reaction
3) in the opinion of the investigator, should not be enrolled because of the precautions, 
warnings, or contraindications listed on the Topiramate package insert, (e.g., certain types of 
glaucoma), 
4) are pregnant, lactating, or plan to become pregnant during the period of participation in the 
study
5) in the judgment of the investigator, represent a significant risk of suicidal or homicidal 
behavior 
Women and Minorities
Women comprise 11% (e.g., SAMI clinic) to 60% (Military Sexual Trauma clinic) of the Veterans 
seen in the clinics from which we will be recruiting, and approximately 24% of Veterans in the 
program are minorities. Consistent with SAMI demographics as a whole, 10% of participants in 
our current Merit study over the past 3 years have been women. We have been able to obtain 
26% Hispanic, 16% African American, and 20% other ethnic groups, for a total of 52% from 
minority groups. We will continue attempts to oversample these groups to obtain adequate 
recruitment of females and minorities to examine effect sizes for these groups relative to male 
and Caucasian counterparts.
1.b. Sources of Materials: The data relevant to the proposed project will be gathered strictly for 
research purposes. Blood and urine specimens obtained are for clinical and research purposes 
only. Sources of research data will be demographic data collected from participants recruited for 
this study, ratings from independent clinical evaluators, patient self-reports, toxicology screens, 
and through VA CPRS chart review.
 
 Verification of non-pregnancy
Section 10.6
To include women of child bearing potential but exclude pregnant women, indicate how it will be 
10.6) 
determined that the women are not pregnant:
Women that are pregnant , lactating, or plan to become pregnant during the period of 
participation in the study will be excluded from participation. All eligible participants will receive a 
laboratory diagnostic evaluation consisting of a chemistry panel, complete blood count, liver 
function tests (LFTs), urine toxicology screen and pregnancy test during their screening and/or 
randomization appointments so that participants with any illnesses that might adversely be 
affected by their participation in the trial will be excluded.
 
 - Recruitment
Section 11
Describe the plans for recruitment of subjects (or selection of subjects as in record review). This 
11) 
description must include how, when, and where potential subjects are approached as well as procedures 
such as data mining, physician referral, etc. Include how selection is equitable.  Indicate if vulnerability 
to coercion may be present and if so plans to ensure voluntary participation.
Recruitment Methods. Potential participants will contact our study in response to 1) flyers posted 
in VA mental health, primary care, and alcohol and substance use treatment programs; 2) 
advertisements in print and web-based media; 3) referrals from VA primary care, ADTP/SAMI, 
PTSD, and other psychiatry clinics and 4) from other research studies who's participants agreed 
to be re-contacted. We plan to recruit 3-4 participants per month for this study. Following verbal 
consent, potential participants will undergo either an in-person screening or a phone screening 
that takes approximately 30-45 minutes to complete. The screening, used in the PI’s current 
CSR&D merit study, is intended to detect clinically significant alcohol use and PTSD symptoms. It 
consists of screening items from the SCID [52] and the PCL-5 [53] for disorders that are part of 
the inclusion and exclusion criteria. Study staff will review their CPRS record to determine if 
there are any exclusion criteria that was not disclosed in the screening before eligibility is 
determined. Those who meet study criteria will attend an in-person interview where they will 
sign informed consent documents and take part in a baseline assessment. Following baseline 
assessment, participants will be randomized to the intervention or control condition. 
In regards to specific VA clinic recruitment (3) Erika Blanes, Project coordinator is part of the 
SAMI clinic and has access to all ADTP/SAMI CPRS consults. In an effort to provide veterans with 
more treatment options, she will review all consults to ADTP/SAMI for eligibility for this research 
study. Those who meet study criteria after record review will be presented information about the 
research study in the SAMI evaluation group, and provide a “Consent to Contact” form that gives 


research staff permission to contact the Veteran to describe the study and details of study 
participation. Based on chart review, intake diagnostic interview, and staff consensus, if 
appropriate, the veteran will be scheduled for a consent and baseline assessment. As with our 
prior Merit studies, study interventions will be delivered within the SAMI program. Laura 
Westendorf and Julia Katawazi will provide back up assistance to Erika Blanes as needed for 
recruitment in these clinics. 
Veterans referred to the PTSD Clinical Team or MST services at the San Diego VA will have the 
study described to them during orientation group by one of the group leaders and be provided a 
“Consent to Contact” form that gives research staff permission to contact the Veteran and 
describe the study and details of study participation. Interested Veterans will have the 
opportunity to meet with the study coordinator to discuss participation. Veterans who sign the 
consent to contact form will have their CPRS record reviewed prior to determining eligibility to 
insure there is no exclusion criteria noted on their record. If appropriate, they will be scheduled 
for an in-person screening to determined eligibility. 
In regards to recruitment from other research studies, we will collaborate with Dr. Sonya Norman’
s "Integrated Alcohol Disorder and PTSD Treatment" protocol number H130080 and 
"Effectiveness of evidence based treatments for PTSD symptoms and trauma-related mental 
health problems among Veterans" study protocol number H130296. For veterans who agreed to 
re-contact, study staff will first review their CPRS record to determine if there are any exclusion 
criteria prior to contacting the veteran to ensure there are no immediate exclusion criteria that 
would make the veteran ineligible. Veterans who are recruited through these studies who did not 
have any indication of exclusion criteria in their CPRS record and who have agreed to be re-
contacted about other research, will be contacted by letter and/or phone after record screen if no 
immediate exclusion criteria are found. If the participant did not agree to initial contact by 
phone, a letter will be sent first. After a period of 2 weeks if a letter is sent, and if no contact is 
made by the veteran, study staff will follow up by phone to provide the veteran with more 
information about the study. If participants are interested, they will be scheduled for an in-
person or telephone screening session to determine eligibility. 
fMRI
Participants will be asked if they are interested to take part in the optional fMRI study titled 
“Neuromarkers of Treatment for Comorbid Posttraumatic Stress Disorder and Alcohol Use 
Disorder IRB # H170116 (P.I. Andrea Spadoni-Townsend, PhD). If participants consent to be 
contacted for the optional study, Dr. Spadoni-Townsend's approved research team will contact 
patient and if patient agrees they will consent them for the study. (see recruitment for protocol 
H170116)
 
Recruitment Materials
11.1 
Section 
Identify all recruitment materials (flyers, advertisements, letters, etc.) that will be used. The text 
11.1) 
of all communications with prospective participants must be reviewed and approved by the IRB before it 
can be used.  You will be reminded to attach copies of recruitment materials to the initial submission 
packet.
Flyers and brochures will be available to interested participants and posted in various locations 
thought the VA. Advertisements in both print and web-based media will be used for recruitment.
 
 - Informed Consent
Section 12
Indicate whether or not each category of consent is involved in this study:
12) 
 informed consent
12a) Signed
 Yes  
 No
12b) Signed consent for 
 (VA form 10-3203) [NO LONGER REQUIRED]
picture/voice recording
 Yes  
 No
Waiver of documented consent (e.g., 
consent)
12c) 
oral 
  Yes  
  No


12d) Request for a 
 of consent (i.e., a "full" waiver, not just for screening)
waiver
  Yes  
  No
 Alteration of 
 of consent.
12e)
other required elements
  Yes  
  No
12f) Child assent to participate (Director approval will be required)
  Yes  
  No
Will any language 
 be used by those obtaining consent and understood 
12g) 
other than English
by the prospective participant or the legally authorized representative?
  Yes  
  No
 to determine if participants have the capacity to 
12h) Decisional Capacity Assessment
consent for themselves.
  Yes  
  No
 consent (legally authorized representative)
12i) Surrogate
  Yes  
  No
 
Informed Consent Process
12.1 
Section 
Will consent be obtained before any study procedures are performed (including screening 
12.1a) 
procedures except screening procedures with Consent/HIPAA waiver approval)?
 Yes  
 No
Will the information being communicated to the participant or legally authorized representative 
12.1b) 
during the consent process include exculpatory language through which the participant or legally 
authorized representative is made to waive or appear to waive any of the participant’s legal rights or 
release or appear to release the Researcher, Sponsor, the VA or its agents from liability for negligence.
  Yes  
  No
A master list of all VA subjects consented (written or not) under this protocol number will be 
12.1c) 
maintained.  (If a waiver of the master list entry requirement is requested below and will be approved, 
.
indicate Agree)
 Agree
 Disagree
Identify the circumstances under which consent will be obtained including where the process will 
12.1d) 
take place; any waiting period between describing the research and obtaining consent including sufficient 
time for the prospective participant to consider participation, and any steps taken to minimize the 
possibility of coercion or undue influence.
After the veteran completes the screening, the project coordinator will discuss the results with 
the PI as soon as possible. This will also provide the veteran time to review the requirements of 
the study and their interest in participating. If it is determined that the veteran is eligible for the 
study, they will be scheduled for a consent and intake appointment. Consenting will take place in 
a private room in the VA Hospital which will take approximately 45 minutes – 1 hour. 
Immediately following consent, the veteran will complete their intake assessment which can take 
around 5 hours. 
Enrollment appointments can also be scheduled using VA approved secure Telehealth 
communication software or telephone. We will send an encrypted email (using VA Azure RMS), a 


message through MyHealtheVet and/or send documents by US mail containing (1) the approved 
ICF, (2) the approved HIPAA document, (3) the CA Experimental Subjects Bill of Rights, and (4) 
fillable PDF baseline assessment documents, and arrange a telehealth or through VA approved 
secure Telehealth communication software to complete the informed consent process, explain 
the HIPAA Authorization, and CA Experimental Subjects Bill of Rights. If the visit is completed by 
VA approved secure Telehealth communication software, the staff member will witness the 
signing of the ICF and HIPAA Authorization and will instruct the potential participant to provide 
documentation of written informed consent by one of the following methods: (1) returning 
images of the documents through MyHealtheVet, (2) by allowing a screenshot of the signed 
documents (approval date and signature must be clearly visible), (3) study staff can have the 
participant digitally sign the fillable PDF documents which can be saved directly to the R Drive, 
(4) or document can be signed and returned via encrypted email (using VA Azure RMS) 
(5) documents can be sent and signed via DocuSign. If documents were mailed, the patient will 
be instructed to mail back the signed documents. If documents were mailed, the patient will be 
instructed to mail back the signed documents. These electronic documents will be stored 
electronically separate from study data on the R: drive. Paper documents will be stored securely 
according to VA requirements.
If the visit is done by phone, the (1) the approved ICF, (2) the approved HIPAA document, (3) 
the CA Experimental Subjects Bill of Rights, and (4) baseline assessment documents will be 
emailed (using VA Azure RMS and the participant will need to print all documents) and/or hard 
copied will be mailed to the participant. Study staff will call the participant at the scheduled 
appointment time to complete the documents. Study staff along with the participant will 
complete the informed consent document, explain the HIPAA Authorization, and CA Experimental 
Subjects Bill of Rights. The participant will be instructed to mail back the signed consent and 
HIPAA forms. Once the forms are received by study staff, the baseline assessments will be 
scheduled and completed by phone or through VA approved secure Telehealth communication 
software.
Participants will be sent a copy of the signed and dated forms, regardless if the Informed 
Consent appointment was completed by VA approved secure Telehealth communication software, 
by phone, or in person.
The veteran will be reminded that their consent must be given freely and that their VA benefits 
will not be affected should they choose not to participate or if they drop out of the study. The 
veteran is free to stop participation in the study at any time for any reason. 
 
HIPAA Authorization
12.9 
Section 
For each category below, indicate whether or not this study involves the indicated process:
 HIPAA Authorization
12.9a) Signed
 Yes  
 No
HIPAA/consent waiver or alteration for
 purposes only
12.9b) 
 screening
 Yes  
 No
Full HIPAA 
 or alteration
12.9c) 
waiver
  Yes  
  No
HIPAA 
or waiver is 
 for some or all of the study subjects (e.
12.9d) 
Authorization 
not required
g. no health data)
  Yes  
  No
 
 HIPAA Waivers and Alterations
12.10
Section 
Describe the purpose/nature of the HIPAA waiver or alteration and 
12.10a) 
list specifically, what 
identifiers and health information are being requested under the waiver/alteration and identify whether 
the waiver is for access, use, and/or collection of this information. 


For potential participants that call in from the flyers/brochures/websites, those that are referred 
from VA clinics and those who are recruited through re-contact list from other research studies, 
we will request a partial waiver of HIPAA Authorization for screening. Study staff will review their 
CPRS record to determine if there are any exclusion criteria prior to the in-person screening to 
ensure there are no immediate exclusion criteria that would make the veteran ineligible (name 
and last 4 of SS# will be requested). If the participant is eligible based on their CPRS record 
findings and they are interested participating, they will be scheduled for an in-person screening. 
If participants are deemed to be ineligible after the in-person screening, then all information, 
including their responses will be shredded. If participants are eligible after the in-person 
screening, they will be scheduled for an in-person consent where Subject's Bill of Rights will be 
given, informed consent (VA form 10-1086) and HIPAA will be completed followed by a baseline 
assessments. The nature of the study will be explained, portions repeated as necessary, and 
questions answered. 
Participants who are recruited through VA clinics will be offered the option of study involvement 
via their clinicians at standard appointments (i.e., orientation session, intake appointment, 
regular psychotherapy/medication appointments). Interested participants will give their clinician 
either their verbal consent to be contacted regarding the study, and their information will be 
given to the study coordinator, via a CPRS note, or the Research Contact Form to complete with 
their contact information which will be given to/collected by the study coordinator or a flyer 
about the study, with the study coordinator’s information
The use or disclosure of PHI involves no more than a minimal risk to the privacy of individuals.
12.10b) 
 Agree
 Disagree
12.10c) The plan to protect the identifiers from improper use and disclosure is adequate.
 Agree
 Disagree
Describe the plan
Hard copy data will be collected by approved research staff and stored with other sensitive 
information according to the data security plan. Full HIPAA forms will be signed along with the 
consenting process
An adequate plan to destroy the identifiers at the earliest opportunity consistent with conduct of 
12.10d) 
the research, unless there is a health or research justification for retaining the identifiers or such 
retention is otherwise required by law (VA Records Control Schedule does not currently permit 
destruction)
 Agree
 Disagree
Describe the plan
12.10d2) 
Data will only be destroyed according to RCS-10 under Records Control Manager guidance.
By signing this protocol for submission, the PI is providing written assurance that the PHI will 
12.10e) 
not be reused or disclosed to any other person or entity, except as required by law, for authorized 
oversight of the research project, or for other research for which the use or disclosure of protected health 
information would be permitted by the Privacy Rule. 
:  If the waiver of HIPAA 
38 U.S.C. 7332 Information
authorization is for the use of 38 USC 7332 information (applicable to drug abuse, alcohol abuse, HIV 
infection, and sickle cell anemia records), by signing this protocol for submission the PI is providing 
written assurance that the purpose of the data is to conduct scientific research and that no personnel 
involved may identify, directly or indirectly, any individual patient or subject in any report of such 
research or otherwise disclose patient or subject identities in any manner. (Ref:  38 U.S.C. 7332(b)(2)(B))
 Agree
 Disagree
The research could not practicably be conducted without the waiver or alteration
12.10f) 
 Agree
 Disagree
Describe how the waiver/alteration enables the research to be conducted
12.10f2) 


The HIPAA waiver enables study to be conducted because by reviewing patients CPRS records we 
will be able to determine if there are any exclusion criteria prior to the in-person screening to 
ensure there are no immediate exclusion criteria that would make the veteran ineligible (name 
and last 4 of SS# will be requested). If the participant is eligible based on their CPRS record 
findings and they are interested participating, they will be scheduled for an in-person screening. 
If participants are deemed to be ineligible after the in-person screening, then all information, 
including their responses will be shredded
The research could not practicably be conducted without access to and use of the PHI
12.10g) 
 Agree
 Disagree
12.10g2) Describe why it would be impracticable to conduct this research without the PHI 
described 12.10a. (v3/8/18)
We request the use of PHI (name and last 4 of SS# will be requested) for screening purposes, 
appointment scheduling, and follow up (contact information), electronic payment as well as 
record review for inclusion exclusion criteria.
 
 - Alternatives to Participation
Section 13
Describe the alternatives to participation in this research study (see  for guidance)
13) 
?
Alternatives are to not participate in the study. All participants who do not wish to participate in 
the study or who are not eligible will complete the regular outpatient program at the VASDHS. 
Referrals to appropriate mental health services within VASDHS will be given if needed and/or 
requested.
 
 - Potential Risks
Section 14
Describe any potential or known risks or discomforts and assess their likelihood and 
14) 
seriousness.  (see  for guidance)
?
Potential Risks: Potential risks associated with participation in the study are: 1) loss of 
confidentiality; 2) feeling uncomfortable during the assessment or therapy process either due to 
talking about trauma, emotional topics, or symptoms; 3) becoming more anxious, depressed, or 
developing suicidal thinking; 4) increasing one’s alcohol or other illicit drug use; 5) therapeutic 
risks associated with Topiramate use; 6) discomfort, bruising, or other possible risks of 
venipuncture (inserting a needle into a vein to draw blood). Number 1 and 6 are research risks, 
number 2 is both a therapeutic and research risk; numbers 3, 4, and 5 are therapeutic risks; 7) 
The genetic testing portion of the study entails a small chance for loss of confidentiality which 
could affect employment or insurance. However, discrimination based on genetic information is 
now illegal. 
Numbers 1), 6)and 7) are research risks, number 2) is both a therapeutic and research risk; 
numbers 3), 4) and 5) are therapeutic risks.
 
 - Risk Management
Section 15
Describe the procedures for protecting against or minimizing any potential risks/discomforts, and the 
15) 
adequacy of resources for conducting the study and resources participants may need as a consequence of 
the research.  See  for further requirements.
?
The following steps will be taken to minimize the risk to confidentiality. 
1) All data and saliva samples will be identified only with participant numbers, never with names 
or initials. All data will be stored in locked filing cabinets in offices at the VA or the PI’s secure VA 
research folder in the VA research drive, and only study personnel will have access to the data. 
The list associating names and participant numbers will be stored in a locked cabinet separate 
from that in which other study data will be stored, and only the PI and project coordinator will 
have access to the key. Research staff will not release any information to anyone other than the 


participant without that participant’s consent. Participants will not be identified by name or other 
identifying features in any publication resulting from this research. Audio recordings will only be 
reviewed for supervision, reliability, and treatment adherence purposes and recordings will be 
erased as soon as data are analyzed.
2) To minimize the risk of patient discomfort, confidentiality will be stressed, participants will be 
offered breaks as needed, they will be informed that they have the right to refuse to answer 
questions or to terminate their participation in the study at any time without prejudice, and 
everyone who interacts with participants will be trained and supervised. Clinical staff will be 
available at each location if immediate in-person evaluation is required for medical or mental 
health issues.
3) and 4) To minimize the risk of patients becoming more anxious or depressed or increase 
drinking, every patient will be given a 24-hour contact phone number to call in the event of 
increased symptoms. During each assessment, the independent evaluator (IE) will assess for any 
major changes in health (e.g., overnight hospitalizations), possible adverse events, suicidal 
ideation, and general well-being. Study clinicians, during medication and psychotherapy visits, 
will assess for clinical worsening as part of the session protocols. If worsening symptoms are 
detected at any visit, a study clinician will be available to evaluate the patient and refer to 
appropriate treatment if needed. When in doubt, the decision whether continued participation in 
the study is safe and clinically warranted will always be on the side of patient safety. If a 
therapist or assessor identifies worsening substance use, the study investigators will evaluate 
whether best clinical care indicates a need for continuation in the study or more intensive SUD 
treatment. Participants will complete the Substance Use Inventory (SUI) at each session which 
will show worsening substance use. Therapists will be trained to contact the PI if a participant 
reports three or more days per week of alcohol use with more than four standard drinks or three 
or more days of illicit drug use in a week. If more intensive treatment is appropriate, we will 
assist the participant in obtaining the appropriate treatment. If the treatment is counter to study 
criteria, then we will discontinue the participant from the study following a final evaluation.
Adverse events, including those unlikely to be the result of participation in the research (e.g., 
hospitalization due to an automobile accident), will be monitored at every study contact, 
including medication, psychotherapy and assessment visits. They will be reported to the 
appropriate human subjects committees as per policy.
There is always a risk associated with the management of patients with AUD or PTSD that they 
will develop suicidality. This risk will be carefully mitigated by the systematic and careful 
assessment of suicidality throughout the protocol. This will be carefully done via the assessment 
measures to be completed by the participants, in-session assessments made by the therapists, 
and through comprehensive suicide risk assessments that are part of standard VA care. 
Participants who develop suicidality will be evaluated by a study clinician and investigators to 
determine whether continued participation in the study is safe and clinically warranted. If the 
study personnel and participant feel that treatment not allowed in the protocol is indicated (e.g., 
a different form of medication or psychotherapy, or hospitalization), an endpoint evaluation will 
be done, the participant will be discontinued from the study, and the participant will be referred 
for appropriate treatment.
5) Participants will be informed of the risks associated with the use of Topiramate, including all 
clinically significant warnings provided by the manufacturer in the medication package insert. 
This includes all current warnings and cautions in the most recent FDA guidelines dated May 
2019 [95]. Given our frequent monitoring and standardized assessment of mood changes, we 
are already in compliance with the FDA’s recommendation to monitor for this potentially rare 
adverse event. Participants will be informed that, as with any drug, Topiramate administration 
may involve other risks that are not known at the present time. If the study staff learns of any 
new possible risk or side effects of this drug, participants will be notified immediately. 
Participants will be informed that their condition may remain the same or deteriorate due to an 
ineffective treatment. They will also be informed of the availability of alternative treatments to 
facilitate alcohol use reduction. Participants will be told that if, in the opinion of the doctor, there 
are problems caused by their participation in the study that make it unwise for the participant to 
continue, their participation will be stopped. Patients who are discontinued from the study for 
any reason will be given a referral for further treatment if indicated.
All eligible participants will receive a laboratory diagnostic evaluation consisting of a chemistry 
panel, complete blood count, liver function tests (LFTs), urine toxicology screen and pregnancy 
test during their screening and/or randomization appointments so that participants with any 
illnesses that might adversely be affected by their participation in the trial will be excluded.
6) The risks of simple venipuncture commonly include the occurrence of discomfort and/or 
bruising at the site of the puncture. Less commonly, fainting, the formation of a small blood clots 
or swelling of the vein and surrounding tissue, or bleeding from the puncture site may occur. 


There could be infection at the site where the blood was drawn. All blood draws will occur at the 
VA lab by certified professionals.
Additional safety measures are as follows: 1) we will recruit individuals with AUD/PTSD who are 
seeking treatment to reduce alcohol use and symptoms; 2) a careful intake assessment will be 
conducted and patients in need of immediate psychiatric treatment for severe depression or 
other conditions will not be enrolled and provided referrals; 3) our team consists of clinicians 
with extensive experience in the treatment of patients with AUD and PTSD; 4) study therapists 
will review all active cases weekly with the PI and therapy supervisor, and all members of the 
research team will immediately communicate any health or psychiatric-related problems to the 
PIs who will ensure that necessary safety steps are implemented; and 5) participants who are 
discontinued from the study will be scheduled for a final evaluation within one week and given 
appropriate treatment referrals. Participants discontinued due to a serious adverse event will be 
followed clinically by medical staff until the adverse event is resolved or becomes stable. Reasons 
for discontinuation and referrals made will be documented in the participants’ casebooks.
Psychiatric Emergencies
If exacerbation of psychological symptoms occurs, members of the research team will 
discontinue assessment and assist the subject to access care.
Telephone assessments - All risk management and emergency response procedures would be 
followed in accordance with the protocol and we will use all procedures to mitigate risk when 
talking with a participant by phone during screening or scheduling appointments. In an effort to 
decrease risks associated with telephone screening, the veteran will be given the information to 
the nearest VA Health Center to their new residence and a licensed clinical psychologist will be 
available over the phone for crisis counseling if such an even should occur during any research 
procedure for the study.
 
 - Privacy and Confidentiality
Section 16
 Provide a brief description of how participant privacy and confidentiality will be protected in this 
16a)
study.
Only approved study personnel will have access to study data, and all study personnel have been 
trained regarding privacy and security issues. In the event of a real or suspected breach of 
security, the VA Police, the VA Information Security Officer, and the VA Privacy Officer will be 
notified. Secure information will be accessed, stored, and destroyed according to a data security 
plan that will promote security and privacy, including, but not limited to the following:
Identifiers will be removed from study data following guidelines outlined by VA Handbook 
including 1605.1 Appendix B. We will assign Veterans a study identification number unrelated to 
identifying information. We will create a master list linking the study identification number to the 
Veteran record. The master list will be maintained by the Principal Investigator and stored in a 
locked cabinet in her laboratory. Access to the master list will be limited to the P.I. and her 
designees, all of whom will have completed VA IRB training requirements.
We will create and maintain a separate password-protected electronic study database containing 
the study identification number and study data specified above as well as genotype data from 
salivary samples. Individually identifiable health information (IIHI), as defined by Health 
Insurance Portability and Accountability Act of 1996 (HIPAA, Title II) will not be included in the 
study database. Specifically, we will exclude the 18 elements outlined by the Privacy Rule of 
HIPAA (section 164.514 and VA Handbook 1605.1 Appendix B) and “safe harbor” definition. 
Social security numbers will only be used to look-up medical records, and will not be maintained 
as data. Further, we will make all necessary efforts to insure a Veteran may not be identified via 
extraction of any combination of the data maintained in the study database in which identifiers 
have been removed. Access to the study database will also be limited to the P.I. and her IRB 
trained designees.
Electronic VASI
Audio Recordings: All treatment sessions and interviews will be recorded on digital audio 
recorders "Sony ICD-UX533", "Sony ICD-PX333",“Olympus VN-1800”, “Olympus VN-6200PC”, 
“Olympus Vn-7200”, “ Olympus DP-201 and the “Olympus VN-6300pc” will be used in this study 
and placed on VA service for potential review by supervisors. These recorders will be stored in a 
locked cabinet in bldg. 1,room 2341. The audio recordings will be downloaded to the VA R:\drive. 
Copies of randomly selected interviews will be reviewed by Dr. Sonya Norman, who is a VASDHS 
employee and can review the information without removing it from VA grounds. Recordings will 


be destroyed in accordance with the most current VA Records Control Schedule guidelines and in 
consultation with the VASDHS ISO and VASDHS IT Department Personnel.
In the event of a suspected security breach, we will notify the VA Privacy Officer, VA Police, and 
VA Information Security Officer. 
Refer to the VA Privacy and Data Security Plan for further detail.
See Privacy and Data Security Plan for further details.
16a2) 
 Yes  
 No
 Is SSN used for any purpose other than scanning Consent/HIPAA into the medical record?  (e.g., 
16b)
subject payments, use of clinical record)
 Yes  
 No
If YES, indicate purpose and justification:
16b2) 
Social security numbers will only be used for use of clinical records, or subject payments and will 
not be maintained as data. Further, we will make all necessary efforts to insure a Veteran may 
not be identified via extraction of any combination of the data maintained in the study database 
in which identifiers have been removed.
 Section 16.1 Entry of CPRS Notes
Entry of a CPRS 
 is required if any of the following apply:
16.1) 
Research Informed Consent Note
   
The subject is admitted as an inpatient or treated as an outpatient for research
The study involves research medical care or may affect medical care.
The Informed Consent and HIPAA Authorization indicate notes will be entered
    Notes: Scanning the Consent and HIPAA Authorization into CPRS is 
.  Linking the 
no longer required
Consent to the Research Informed Consent Note is permitted (Unless the study has a Certificate of 
        
Confidentiality) and may be especially useful for trials involving the Research Pharmacy.
·
For Non-
Veterans, if Research Informed Consent Notes are entered then the 
 must be 
NOPP Acknowledgement
        
       
scanned in.
·
A 
 should also be entered for each procedure or intervention.
Research Progress Note
·
 
Address the CPRS note requirement:
Is entry of CPRS notes required based on the above criteria?
16.1a) 
 Yes  
 No
Are CPRS notes entered?
16.1b) 
 Yes  
 No
Is a CPRS waiver is requested instead?
16.1c) 
  Yes  
  No
 
 - Potential Benefits
Section 17
Discuss benefits that may be gained by the subject as well as potential benefits to society in 
17) 
general.  (see  for guidance)
?
The potential benefits for participants include decreased distress and alcohol use and improved 
quality of life. Study of the effectiveness of Topiramate and PE will also benefit individuals who 
have AUD and PTSD and society more generally by providing information about how best to treat 
co-occurring AUD and PTSD.
 
 - Risk/Benefit Ratio
Section 18


Discuss why the risks to subjects are reasonable in relation to the anticipated benefits to subjects 
18) 
and in relation to the importance of the knowledge that may reasonably be expected to result.
The potential benefits of improved understanding of how to manage patients with PTSD and AD 
outweighs the potential risks of this study.
 
 - Compensation for Participation
Section 20
Provide all details and justifications of the compensation plan.  See  for detailed requirements.
20) 
?
Compensation. Participants will be compensated up to $230 for their time and effort for 
completing assessments: $40 baseline, $20 mid-treatment , $50 post-treatment, and $60 each 
post-treatment follow-up. Participants will complete the 2nd post treatment assessment 
interview and set of questionnaires 3 months after the 1st post treatment appointment. 
Participants will be scheduled for their 3rd and last post treatment interview 3 months after 
completing their 2nd post treatment assessment. Participants will be compensated $20 for DNA 
sample. Payments will be made directly to their bank accounts using electronic funds transfer 
when possible.
 
 - Responsibilities and Qualifications
Section 21
Here are the identified study staff members
Sonya B. Norman, PhD
Abigail Candare Angkaw, PhD, Andrea Spadoni Townsend, PhD, Arthur L. Brody, MD, Brian Martis, 
MD, Brittany C Davis, Katharine I. Lacefield, PhD, Michelle Pitts, PhD, Murray B. Stein, MD, Scott 
Christian Matthews, MD, Victoria B. Risbrough, PhD, Julia G. Katawazi, Julie M. Holcomb, Kaitlyn 
E. Panza, PhD, Alexandra O. Higdon, PsyD, Jae Eun Park, Matthew T. Luciano, PhD, Morgan E. 
Marvin, BA, Ruth Klaming Miller, PhD, Alexander C. Kline, PhD, Alexandra Klein, PhD, Robert C. 
Lyons, PhD
 Identify here by name those staff working on this protocol, unless they have no contact with subjects 
21)
or identifiable data.  Indicate their role and qualifications.  Also indicate which of the study staff are 
authorized to obtain consent for subjects of VA research.
Sonya Norman, Ph.D. (Principal Investigator)-Dr. Norman will be responsible for oversight of all 
scientific, logistical and financial aspects of the study and for securing and maintaining 
appropriate approvals. She will coordinate the efforts of the Co-Investigators (Abigail Candare 
Angkaw, PhD, Arthur L. Brody, M.D., Brittany C Davis, PhD, Ryan Trim, PhD, Katherine Lacefield, 
PhD, Murray Stein, Scott Christian Matthews, Victoria Risbrough, PhD and Andrea Spadoni-
Townsend, PhD, Brian Martis, MD., Michelle Pitts, PhD) and consultants and be responsible for 
hiring, training and supervising the study staff and overseeing supervision for the therapists. 
Andrea Spadoni-Townsend, PhD is a co-investigator. She is the PI for the optional fMRI study 
titled " Neuromarkers of Treatment for Comorbid Posttraumatic Stress Disorder and Alcohol Use 
Disorder"; H170116. Participants who provide consent to contact on the consent form and are 
interested in hearing more about her study will be referred to her study staff.
All Investigators have the appropriate certifications and licenses to complete this study. Dr 
Norman will work with Dr. Matthews, (Co-I) Dr. Brody (Co-I) and Dr. Stein (Co-I) on the 
biomedical aspects of the study to complete data analyses and will author manuscripts.
Drs. Norman, Angkaw, Davis are privileged at the VA and are licensed psychologists in the state 
of California. Drs. Matthews, Brody, Martis and Stein are privileged at the VA and are licensed 
psychiatrist. 
Drs. Matthews, Brody and Martis will provide psychiatry services for study participants. 
Kaitlyn Panza, PhD, will serve as the primary recruiters and coordinators for the project under 
the supervision of Dr. Norman and the Co-Investigators. They will be responsible for daily 
research activities, including screening of potential study participants, recruitment, conducting 


research assessments, training and supervising research assistants, and data management. 
Julia G Katawazi, MA will be a Research Assistant with responsibilities for conducting research 
assessments and data entry. They are supervised by Dr. Norman. 
Additionally, study therapists conducts individual psychotherapy interventions: Michelle Pitts, 
PhD., and Kaitlyn Panza, PhD, Alexander Kline, PhD, Matthew Luciano, PhD, and Alexandra 
Higdon, PhD. 
Robert Lyons, M.S. is a Psychology graduate student in the San Diego State University/University 
of California, San Diego Joint Doctoral Program in Clinical Psychology. 
Ruth Klaming Miller, Morgan Marvin, Julie Holcomb, Alexandra Klein, Jae E Park will provide 
administrative research support.
 
 - Bibliography
Section 22
List relevant articles that the IRB can use to provide necessary background for the protocol. Do not 
22) 
include an extensive NIH-grant-style bibliography.  (Up to 5 recommended, but use more if needed to 
support the protocol or citations above.)
References 
1. Foa, E.B., et al., Concurrent naltrexone and prolonged exposure therapy for patients with 
comorbid alcohol dependence and PTSD: a randomized clinical trial. Journal of American Medicine 
(JAMA), 2013. 310(5): p. 488-95. 
2. VA/DoD, VA/DoD Clinical Practice Guidline Management of Substance Abuse Disorder (SUD). 
2015. 
3. Watts, B.V., et al., Meta-analysis of the efficacy of treatments for posttraumatic stress 
disorder. The Journal of Clinical Psychiatry, 2013. 74(6): p. e541-50. 
4. Ralevski, E., M. Taylor, and I. Petrakis, Pharmacotherapy and psychotherapy studies designed 
to treat alcohol use disorders and co-occurring PTSD: A Review. The American Journal of Drug 
and Alcohol Abuse, In press. 
5. Blodgett, J.C., et al., A Meta#Analysis of Topiramate's Effects for Individuals with Alcohol Use 
Disorders. Alcoholism: Clinical and Experimental Research, 2014. 38(6): p. 1481-1488. 
6. Del Re, A., et al., Prescription of topiramate to treat alcohol use disorders in the veterans 
health administration. Addict Sci Clin Pract, 2013. 8(1): p. 12. 
7. Seal, K.H., et al., Substance use disorders in Iraq and Afghanistan veterans in VA healthcare, 
2001–2010: Implications for screening, diagnosis and treatment. Drug and Alcohol Dependence, 
2011. 116(1): p. 93-101. 
8. Roberts, N.P., et al., Psychological interventions for post-traumatic stress disorder and 
comorbid substance use disorder: A systematic review and meta-analysis. Clinical Psychology 
Review, 2015. 38: p. 25-38. 
9. Larsen, S.E., et al., Symptom exacerbations in trauma-focused treatments: Associations with 
treatment outcome and non-completion. Behaviour research and therapy, 2016. 77: p. 68-77. 
10. Batki, S.L., et al., Topiramate Treatment of Alcohol Use Disorder in Veterans with 
Posttraumatic Stress Disorder: A Randomized Controlled Pilot Trial. Alcoholism: Clinical and 
Experimental Research, 2014. 38(8): p. 2169-2177. 
11. Farook, J.M., et al., Topiramate attenuates the stress-induced increase in alcohol 
consumption and preference in male C57BL/6J mice. Physiology & Behavior, 2009. 96(1): p. 189-
193. 
12. McLean, C., Su, Y.J., and E.B. Foa, Mechanisms of symptom reduction in a combined 
treatment for comorbid posttraumatic stress disorder and alcohol dependence. Journal of 
Consulting and Clinical Psychology, 2015. 83(3): p. 655-661. 
13. Sommer, B., E. Mitchell, and T. Wroolie, Topiramate: Effects on cognition in patients with 
epilepsy, migraine headache and obesity. Ther Adv Neurol Disord, 2013. 6(4): p. 211-227. 
14. Foa, E.B., et al., Does imaginal exposure exacerbate PTSD symptoms? Journal of Consulting 
and Clinical Psychology, 2002. 70: p. 1022-1028. 
15. Debell, F., et al., A systematic review of the comorbidity between PTSD and alcohol misuse. 
Social Psychiatry and Psychiatric Epidemiology, 2014. 49(9): p. 1401-25. 
16. Ouimette, P., R.H. Moos, and J.W. Finney, PTSD treatment and 5-year remission among 
patients with substance use and posttraumatic stress disorders. Journal of Consulting and Clinical 
Psychology, 2003. 71(2): p. 410-414. 
17. Tate, S.R., et al., Health problems of substance-dependent veterans with and those without 
trauma history. Journal of substance abuse treatment, 2007. 33(1): p. 25-32. 
18. McDevitt-Murphy, M.E., et al., PTSD symptoms, hazardous drinking, and health functioning 
among U.S. OEF and OIF veterans presenting to primary care. Journal of Traumatic Stress, 
2010. 23(1): p. 108-111. 


19. Foa, E., E. Hembree, and B.O. Rothbaum, Prolonged exposure therapy for PTSD: Emotional 
processing of traumatic experiences therapist guide. 2007, New York, NY: Oxford University 
Press. 
20. VA/DoD, VA/DoD Clinical Practice Guidelines: Management of Post-Traumatic Stress Disorder 
and Acute Stress Reaction. 2010. 
21. Kessler, R.C., et al., Posttraumatic stress disorder in the National Comorbidity Survey. 
Archives of General Psychiatry, 1995. 52: p. 1048-1060. 
22. Reynolds, M., et al., Trauma and post-traumatic stress disorder in a drug treatment 
community service. The Psychiatrist, 2011. 35(7): p. 256-260. 
23. Driessen, M., et al., Trauma and PTSD in patients with alcohol, drug, or dual dependence: A 
multi center study. Alcoholism, Clinical and Experimental Research, 2008. 32(3): p. 481-488. 
24. Jacobsen, L.K., S.M. Southwick, and T.R. Kosten, Substance use disorders in patients with 
posttraumatic stress disorder: a review of the literature. American Journal of Psychiatry, 2001. 
158(8): p. 1184-1190. 
25. Drapkin, M.L., et al., Baseline functioning among individuals with posttraumatic stress 
disorder and alcohol dependence. Journal of substance abuse treatment, 2011. 41(2): p. 186-
192. 
26. Ouimette, P.C., P.J. Brown, and L.M. Najavits, Course and treatment of patients with both 
substance use and posttraumatic stress disorders. Addictive Behaviors, 1998. 23(6): p. 785-795. 
27. Sartor, C.E., et al., Posttraumatic stress disorder and alcohol dependence in young women. 
Journal of Studies on Alcohol and Drugs, 2010. 71(6): p. 810-818. 
28. Seal, K.H., et al., Substance use disorders in Iraq and Afghanistan veterans in VA healthcare, 
2001-2010: Implications for screening, diagnosis and treatment. Drug and Alcohol Dependence, 
2011. 116(1-3): p. 93-9101. 
29. Stappenbeck, C.A., et al., The effects of alcohol problems, PTSD, and combat exposure on 
nonphysical and physical aggression among Iraq and Afghanistan war veterans. Psychological 
Trauma: Theory, Research, Practice, and Policy, 2014. 6(1): p. 65-72. 
30. Coffey, S.F., et al., Trauma-focused imaginal exposure for individuals with comorbid 
posttraumatic stress disorder and alcohol dependence: revealing mechanisms of alcohol craving 
in a cue reactivity paradigm. Psychology of Addictive Behaviors, 2006. 20(4): p. 425-435. 
31. Saladin, M.E., et al., PTSD symptom severity as a predictor of cue-elicited drug craving in 
victims of violent crime. Addictive Behaviors, 2003. 28(9): p. 1611-1629. 
32. Coffey, S.F., et al., Exposure Therapy for Substance Abusers with PTSD Translating Research 
to Practice. Behavior Modification, 2005. 29(1): p. 10-38. 
33. Foa, E.B., et al., Processing of threat-related information in rape victims. Journal of Abnormal 
Psychology, 1991. 100(2): p. 156-162. 
34. Foa, E.B., et al., Randomized trial of prolonged exposure for posttraumatic stress disorder 
with and without cognitive restructuring: outcome at academic and community clinics. Journal of 
Consulting and Clinical Psychology, 2005. 73: p. 953-964. 
35. Rauch, S.A., et al., Prolonged exposure for PTSD in a Veterans Health Administration PTSD 
clinic. Journal of Traumatic Stress, 2009. 22(1): p. 60-64. 
36. Institute of Medicine, Treatment of posttraumatic stress disorder: An assessment of the 
evidence. 2007: Washington, D.C. 
37. Brown, P.J. and J. Wolfe, Substance abuse and post-traumatic stress disorder comorbidity. 
Drug and Alcohol Dependence, 1994. 35(1): p. 51-59. 
38. Dansky, B.S., K.T. Brady, and M.E. Saladin, Untreated symptoms of PTSD among cocaine-
dependent individuals: Changes over time. Journal of Substance Abuse Treatment, 1998. 15(6): 
p. 499-504. 
39. Schnurr, P.P., et al., Cognitive behavioral therapy for posttraumatic stress disorder in 
women: a randomized controlled trial. JAMA, 2007. 297: p. 820-830. 
40. Johnson, B.A., et al., Topiramate for treating alcohol dependence: a randomized controlled 
trial. The Journal of American Medical Association, 2007. 298(14): p. 1641-1651. 
41. Arbaizar, B., et al., Topiramate in the treatment of alcohol dependence: a meta-analysis. 
Actas Esp Psiquiatr, 2010. 38(1): p. 8-12. 
42. Petrakis, I.L., A Commentary on Topiramate Treatment of Alcohol Use Disorder in Veterans 
with PTSD: A Randomized Controlled Pilot Trial. Alcoholism: Clinical and Experimental Research, 
2014. 38(8): p. 2167-2168. 
43. Mozhui, K., et al., Strain differences in stress responsivity are associated with divergent 
amygdala gene expression and glutamate-mediated neuronal excitability. The Journal of 
Neuroscience, 2010. 30(15): p. 5357-5367. 
44. Norman, S.B., E. Schmied, and G.E. Larson, Predictors of continued problem drinking and 
substance use following military discharge. Journal of Studies on Alcohol and Drugs, 2014. 75
(4): p. 557-66. 
45. Tate, S.R., et al., Context of relapse for substance-dependent adults with and without 
comorbid psychiatric disorders. Addictive Behaviors, 2004. 29(9): p. 1707-1724. 
46. Norman, S.B., et al., Development of the PTSD-alcohol expectancy questionnaire. Addictive 
Behaviors, 2008. 33(6): p. 841-847. 
47. Norman, S.B., et al., Maximizing the utility of a single site randomized controlled 
psychotherapy trial. Contemporary clinical trials, 2015. 42: p. 244-251. 
48. Norman, S.B., et al., Prolonged Exposure With Veterans in a Residential Substance Use 


Treatment Program. Cognitive and Behavioral Practice, 2016. 23(2): p. 162-172. 
49. Larson, G.E. and S.B. Norman, Prospective prediction of functional difficulties among recently 
separated Veterans. J Rehabil Res Dev, 2014. 53(1): p. 415-27. 
50. Norman, S.B., et al., Student Veteran perceptions of facilitators and barriers to achieving 
academic goals. Journal of Rehabilitation Research & Development, 2015. 52(6): p. 701-713. 
51. Schulz, K.F., D.G. Altman, and D. Moher, CONSORT 2010 statement: updated guidelines for 
reporting parallel group randomised trials. BMC Medicine, 2010. 8(1): p. 1-9. 
52. First, M., et al., Structured Clinical Interview for DSM-5 Disorders–Research Version (SCID-5-
RV). Arlington: American Psychiatric Assocation, 2014. 
53. Weathers, F., et al., The PTSD Checklist for DSM-5 (PCL-5). Scale available from the National 
Center for PTSD (online), 2013. 
54. Riggs, D.S. and E.B. Foa, Treatment for co-morbid posttraumatic stress disorder and 
substance use disorders, in Anxiety and Substance Use Disorders. 2008, Springer. p. 119-137. 
55. Arnone, D., Review of the use of Topiramate for treatment of psychiatric disorders. Annals of 
General Psychiatry, 2005. 4(1): p. 1-14. 
56. Likhitsathian, S., et al., Cognitive changes in topiramate-treated patients with alcoholism: a 
12-week prospective study in patients recently detoxified. Psychiatry and Clinical Neurosciences, 
2012. 66(3): p. 235-41. 
57. Jonas, D.E., et al., Psychological and Pharmacological Treatments for Adults With 
Posttraumatic Stress Disorder (PTSD), Agency for Healthcare Research and Quality (US), Editor. 
2013: Rockville, MD. 
58. Mimrod, D., et al., A comparative study of the effect of carbamazepine and valproic acid on 
the pharmacokinetics and metabolic profile of topiramate at steady state in patients with 
epilepsy. Epilepsia, 2005. 46(7): p. 1046-54. 
59. Bialer, M., et al., Pharmacokinetic interactions of topiramate. Clinical Pharmacokinetics, 
2004. 43(12): p. 763-780. 
60. Pettinati, H.M., et al., A structured approach to medical management: a psychosocial 
intervention to support pharmacotherapy in the treatment of alcohol dependence. Journal of 
Studies on Alcohol, Supplement, 2005(15): p. 170-178. 
61. Carroll, K.M., et al., A general system for evaluating therapist adherence and competence in 
psychotherapy research in the addictions. Drug and Alcohol Dependence, 2000. 57(3): p. 225-
238. 
62. Perepletchikova, F. and A.E. Kazdin, Treatment integrity and therapeutic change: Issues and 
research recommendations. Clinical Psychology: Science and Practice, 2005. 12(4): p. 365-383. 
63. Sobell, L.C. and M.B. Sobell, Timeline follow-back: a technique for assessing self reported 
alcohol consumption, in Measuring alcohol consumption: Psychological and Biochemical Methods, 
R. Litten and J.P. Allen, Editors. 1992, Humana Press: Clifton, NJ. p. 41-72. 
64. Cahalan, D., I.H. Cisin, and H.M. Crossley, American drinking practices: A national study of 
drinking behavior and attitudes. Monographs of the Rutgers Center of Alcohol Studies. Vol. 6. 
1969, New Haven, CT: College and University Press. 260. 
65. McLellan, A.T., et al., The Fifth Edition of the Addiction Severity Index. Journal of Substance 
Abuse Treatment, 1992. 9(3): p. 199-213. 
66. Weiss, R., et al., Weekly substance use inventory. Unpublished measure, Harvard University 
Medical School, Boston, MA, 1995. 
67. Marlatt, G. and J. Gordon, Relapse prevention: Maintenance strategies in the treatment of 
addictive behaviors. 1985, New York, NY: Gilford Press. 
68. Wills, T.A. and S. Shiffman, Coping and substance use. 1985, New York, NY: Academic Press. 
69. Flannery, B.A., J. Volpicelli, and H. Pettinati, Psychometric properties of the Penn Alcohol and 
Craving Scale. Alcoholism: Clinical and Experimental Research, 1999. 23(8): p. 1289-1295. 
70. Blake, D.D., et al., The development of a clinician#administered PTSD scale. Journal of 
Traumatic Stress, 1995. 8(1): p. 75-90. 
71. Weathers, F.W., et al., PTSD Checklist for DSM-5 (PCL-5), National Center for PTSD, Editor. 
2014: Boston, M.A. 
72. Kroenke, K. and R.L. Spitzer, The PHQ-9: a new depression diagnostic and severity measure. 
Psychiatric Annals, 2002. 32(9): p. 509-515. 
73. Posner, K., et al., Columbia-Suicide Severity Rating Scale (C-SSRS). 2008, The Research 
Foundation for Mental Hygiene, Inc: New York, NY. 
74. Bovin, M. J., Black, S. K., Rodriguez, P., Lunney, C. A., Kleiman, S. E., Weathers, F. W., 
Schnurr, P. P., Spira, J., Keane, T. M., & Marx, B. P. (revise and resubmit). Development and 
validation of a measure of PTSD-related functional impairment: The Inventory of Psychosocial 
Functioning. 
75. Marx, B.P., et al., Using the WHODAS 2.0 to assess functioning among veterans seeking 
compensation for posttraumatic stress disorder. Psychiatric Services, 2015. 66(12): p. 1312-
1317. 
76. Bastiaens, L., J. Galus, and M. Goodlin, The 12 Item WHODAS as Primary Self Report 
Outcome Measure in a Correctional Community Treatment Center for Dually Diagnosed Patients. 
Psychiatric Quarterly, 2015. 86(2): p. 219-224. 
77. Mundt, J.C., et al., The Work and Social Adjustment Scale: a simple measure of impairment 
in functioning. The British Journal of Psychiatry, 2002. 180(5): p. 461-464. 
78. Skevington, S.M., et al., The World Health Organization's WHOQOL-BREF quality of life 


assessment: psychometric properties and results of the international field trial. A report from the 
WHOQOL group. Quality of Life Research, 2004. 13(2): p. 299-310. 
79. Nasreddine, Z.S., et al., The Montreal Cognitive Assessment, MoCA: a brief screening tool for 
mild cognitive impairment. Journal of the American Geriatrics Society, 2005. 53(4): p. 695-699. 
80. Brandt, J. and R. Benedict, Hopkins Verbal Learning Test–Revised. Professional manual. 
2001, Lutz, FL: Psychological Assessment Resources. 
81. Devilly, G.J. and T.D. Borkovec, Psychometric properties of the credibility/expectancy 
questionnaire. Journal of Behavior Therapy and Experimental Psychiatry, 2000. 31(2): p. 73-86. 
82. Larsen, D.L., et al., Assessment of client/patient satisfaction: development of a general 
scale. Eval Program Plann, 1979. 2(3): p. 197-207. 
83. Chesney, M.A., et al., Self-reported adherence to antiretroviral medications among 
participants in HIV clinical trials: the AACTG adherence instruments. AIDS care, 2000. 12(3): p. 
255-266. 
84. Little, R. and D. Rubin, Statistical analysis with missing data. 2nd ed. 2002, New York, NY: 
Wiley. 
85. Schafer, J.L. and J.W. Graham, Missing data: our view of the state of the art. Psychol 
Methods, 2002. 7(2): p. 147-177. 
86. Graham, J.W., et al., eds. Analysis with missing data in prevention research. The science of 
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87. Collins, L.M., J.L. Schafer, and C.M. Kam, A comparison of inclusive and restrictive strategies 
in modern missing data procedures. Psychological Methods, 2001. 6(4): p. 330-351. 
88. Little, R., Modeling the drop-out mechanism in repreated-measures studies. J Am Stat Assoc, 
1995. 90: p. 1112-1121. 
89. Hedeker, D. and R.D. Gibbons, Application of random-effects pattern-mixture models for 
missing data in longitudinal studies. Psychological Methods, 1997. 2(1): p. 64-78. 
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occurrence 2003, New York, NY: Oxford University Press. 
91. Krull, J.L. and D.P. MacKinnon, Multilevel mediation modeling in group-based intervention 
studies. Evaluation Review, 1999. 23(4): p. 418-444. 
92. Williams, J. and D.P. MacKinnon, Resampling and Distribution of the Product Methods for 
Testing Indirect Effects in Complex Models. Struct Equ Modeling, 2008. 15: p. 23-51.
93. Marx, B. P., Schnurr, P. P., Rodriguez, P., Holowka, D. W., Lunney, C. A., & Weathers, F. W. 
(2009, November). Development of a functional impairment scale for active duty service 
members and veterans. In K. M.Lester (Chair), Beyond PTSD symptom reduction: Social and 
health-related benefits of trauma focused treatment. Symposium conducted at the meeting for 
the International Society for Traumatic Stress Studies. Atlanta, GA.
94.Garin, O., et al., Validation of the" World Health Organization Disability Assessment Schedule, 
WHODAS-2" in patients with chronic diseases. Health and Quality of Life Outcomes, 2010. 8: p. 
15-51.
95. U. S. Food and Drug Administration. (2019, May). Medication Guide and Full Prescribing 
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accessdata.fda.gov/drugsatfda_docs/label/2019/020505s060,020844s051lbl.pdf
 
 - Sponsors and Collaborators
Section 23
Clarify any industry financial or other support (e.g., NIH funds the study or Company X provides the 
23) 
assay kits). Identify non-VASDHS Research collaborators and their role in this protocol, including 
whether or not they have access to subjects or identified data.
Dr. Gregory Norman from the UCSD School of Medicine will provide statistical support. He will 
not have access to identifiable data.
If genotyping is conducted outside the VA it will be via approved VA vendors for this service with 
an MTA. DNA extraction will be conducted by CFAR, a VA affiliated core.
 
 - Biological Materials Transfer Agreement (BMTA)
Section 24
Describe what material is transferred, the persons/institutions that send and receive the material, 
24) 
and the status of the BMTA for this purpose.  (see  for further guidance)
?
The material to be transferred is DNA from saliva samples collected under this protocol. If 


genotyping is conducted outside the VA it will be via approved VA vendors for this service with 
an MTA. DNA extraction will be conducted by CFAR, a VA affiliated core.
 
 - Impact on Clinical Services
Section 25
Which VA Clinical Services participate in the performance of the project? 
25) 
(NOTE: All clinical trials and 
any use of clinical services will require project review and approval by the Office of Research Agreements 
Management (ORAM) to assure availability of those clinical resources. Prior discussion with the 
appropriate clinical service chief is strongly encouraged)
Check all that apply
Pharmacy
Laboratory
Cardiology
Radiology
Nursing
Nuclear Medicine
MAS (Charts)
Other (list below)
List others here
 
 - Protocol Attachments
Section 27
If there is any material, such as tables or figures, that are referenced in the protocol text above but not 
pasted into the protocol application these can be attached in the Submission form along with other 
documents such as Consents and HIPAA Authorizations. press Save and Continue
 
Protocol Association to New or Existing Project
Section 28 - 
  
Is this a new R&D Project?.
28) 
 Before you go on to complete the 
 
Initial Review Submission Form
(which is used for attachments), please address the association of this Protocol to an R&D Committee 
Project.  This Protocol may represent a new R&D Project, or it may be an additional Protocol under an 
  
existing R&D Project (such as when a single grant supports multiple Protocols).  Will this Protocol be 
 
submitted to the R&D Committee as a new Project?
  Yes  
  No
 
Existing Project Association
Section 29 - 
  
The associated R&D Project should already exist in the database.
29) 
 Identify the R&D Project(s) that 
 
correspond to this protocol.
Project Status
Proposal Number
Project Title
Principal 
Investigator
No Projects are Linked to this Study
 The Protocol Application is now complete for a Protocol attached to an 
existing Project.
 


Next you will go on to the Initial Review Submission Form.  This form is used 
to collect the Application and any other needed attachments for submission to 
the IRB for review.
Press Save and Continue