Conditions: Traumatic Brain Injury (TBI) Hazardous and Harmful Alcohol Use
Keywords: TBI hazardous and harmful alcohol use Veterans co-occurring disorders pharmacotherapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
The goal of the project is to improve the care of Veterans with mild traumatic brain injury (mTBI) and unhealthy alcohol use.

Detailed description:
This is a pilot controlled clinical trial that aims to assess the efficacy of N-acetylcysteine (NAC) to reduce alcohol use and improve brain injury symptoms in Veterans with mTBI who consume alcohol at hazardous or harmful levels.

Arms:
arm 1: N-acetylcysteine capsules daily - up to 3200 mg arm 2: Placebo capsules daily - up to 3200 mg

Interventions: intervention 1: Medical Management Counseling intervention 2: N-acetylcysteine intervention 3: Placebo
Intervention descriptions: intervention 1: Brief alcohol counseling intervention 2: Experimental supplement intervention 3: Placebo comparator

Protocol document:
Prot_SAP_001.pdf: 
Veterans Alcohol TBI
PI:  Batki, Steven L.
10/30/17
N-ACETYLCYSTEINE TREATMENT OF ALCOHOL USE
DISORDER IN VETERANS WITH TBI
Principal Investigator: 
 Steven L. Batki, M.D.
San Francisco VA Medical Center
University of California, San Francisco
4150 Clement Street (116-E)
San Francisco, CA 94121
415/221-4810 x 23671
415/750-2187
steven.batki@ucsf.edu
Coinvestigator:
David L. Pennington, PhD
University of California, San Francisco
San Francisco VA Medical Center
PHASE 2
VERSION 6
10-30-17
NCT02791945


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TABLE OF CONTENTS
I. Synopsis
II. Research Plan
A. Goals and Specific AIMS
A.1. Primary Aims
A.2. Exploratory Aims
A.3. Future Plans
B. Background and Significance
B.1. Overview
B.2. Co-occurrence of TBI and Hazardous and Harmful Alcohol Use Among Veterans
B.3. Unhealthy Alcohol Use: Hazardous and Harmful Alcohol Use
B.4. Neurobehavioral Interactions of Heavy Alcohol Use and TBI
B.5. Limits of Current Pharmacotherapies for AUD and for HHAU in TBI
C. Preliminary Studies
C.1. N-acetylcysteine Background and Evidence for Use in Disorders for Addiction
C.2. N-acetylcysteine Evidence for Use in Brain Injury Symptom Treatment
C.3. N-acetylcysteine Evidence for Cognitive Enhancement
C.4. Genetic Moderation of Alcohol Pharmacotherapy Response
C.5. Preliminary Studies in the Addiction Research Program at the San Francisco VAMC
D. Research Design and Methods
D.1. General Design
D.1.a. Rationale for a Pilot Placebo-controlled Trial of NAC
D.1.b. Overview of Design
D.2. Study Participants
D.2.a. Overview of Participants
D.2.b. Inclusion Criteria
D.2.c. Exclusion Criteria
D.2.d. Modification of Inclusion and Exclusion Criteria
D.3. Study Procedures
D.3.a. Overview of Study Procedures
D.3.b. Recruitment
D.3.c. Prescreening
D.3.d. Consent
D.3.e. Screening
D.3.f. Random Assignment
D.3.g. Pharmacotherapy
D.3.h. Medical Management
D.3.i. Measures and Schedule of Data Collection
D.3.j. Phlebotomy and Urine Drug Testing
D.3.k. Participant Payment
D.4. Measures and Schedule of Data Collection
D.4.a. Overview of Measures
D.4.b. General Measures
D.4.b.1. Patient Screening Log
D.4.b.2. Patient Locator Information
D.4.b.3. Baseline Assessments
D.4.b.4. Eligibility Form
D.4.b.5. Maintenance of the Blind
D.4.b.6. Study Completion/Termination Form
D.4.b.7. Participant End of Study Questionnaire
D.4.c. Measures of Health and Biological Safety
D.4.c.1. Overview of Health and Biological Safety Measures
D.4.c.2. Medical History and Physical Examination
D.4.c.3. Clinical Laboratory Tests for Health and Safety Monitoring


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D.4.c.4. Birth Control/Pregnancy Assessment
D.4.c.5. Vital Signs
D.4.c.6. Concomitant Medications
D.4.c.7. Concomitant Treatment
D.4.c.8. Adverse Event Monitoring
D.4.d. Alcohol and Substance Use Measures
D.4.d.1. Timeline Followback (TLFB)
D.4.d.2. Obsessive Compulsive Drinking Scale (OCDS)
D.4.d.3. Breath Alcohol Concentration (BrAC)
D.4.d.4. Urine Drug Screen (UDS)
D.4.d.5. Ethyl Glucuronide (EtG)
D.4.d.6. Gamma Glutamyl Transpeptidase (GGT)
D.4.d.7. Phosphatidylethanol (PEth)
D.4.d.8. Penn Alcohol Craving Scale (PACS)
D.4.d.9. Alcohol Use Disorders Identification Test (AUDIT)
D.4.d.10. Short Index of Problems (SIP 2-R)
D.4.d.11. Clinical Institute Withdrawal Assessment for Alcohol (CIWA-AD)
D.4.d.12. Family Tree Questionnaire (FTQ)
D.4.d.13. Thoughts About Abstinence (TAA)
D.4.d.14. Readiness to Change Ruler (RTC)
D.4.d.15. Subjective High Assessment Scale (SHAS)
D.4.d.16. Alcohol Purchase Task (APT)
D.4.e. TBI Measures
D.4.e.1. Neurobehavioral Symptom Inventory (NSI)
D.4.f. PTSD Measures
D.4.f.1. PTSD Checklist (PCL)
D.4.g. Psychiatric/Psychological Measures
D.4.g.1. Structured Clinical Interview for DSM-IV, Patient Edition (SCID-I/P)
D.4.g.2. Beck Depression Inventory (BDI)
D.4.g.3. Beck Anxiety Inventory (BAI)
D.4.g.4. Difficulties in Emotion Regulation Scale (DERS)
D.4.g.5. Distress Tolerance Scale (DTS)
D.4.g.6. Insomnia Severity Index (ISI)
D.4.g.7. Pittsburgh Sleep Quality Index (PSQI)
D.4.g.8. Profile of Mood States (POMS)
D.4.h. Neuropsychological Assessment
D.4.h.1. Decision-making Assessments
D.4.h.1.a. Iowa Gambling Task (IGT)
D.4.h.1.b. Delay Discounting (DD)
D.4.h.2. Risk-taking Assessments
D.4.h.2.a. Balloon Analogue Risk Task (BART)
D.4.h.2.b. Evaluation of Risks Scale (EVAR-B)
D.4.h.3. Cognitive Functioning Assessments
D.4.h.3.a. WAIS-III Digit Span
D.4.h.3.b. WAIS-III Arithmetic
D.4.h.3.c. Controlled Oral Word Association (COWA)
D.4.h.3.d. Hopkins Verbal Learning Test (HVLT)
D.4.h.3.e. Trail Making Test (TMT) Parts A + B
D.4.h.3.f. Wechsler Test of Adult Reading (WTAR)
D.4.h.4. Impulsivity Assessments
D.4.h.4.a. Stroop Inhibition
D.4.h.4.b. Stop-Signal Task (SST)
D.4.h.4.c. Barrett Impulsivity Scale (BIS-11)
D.4.h.5. Alcohol Approach Bias Assessments


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D.4.h.5.a. Alcohol Approach Task (AAT)
D.5. Weekly Visit Schedule
D.5.a. Screening Phase
D.5.b. Treatment Phase
D.5.c. Follow-up Phase
D.6. Data Analysis
D.6.a. Primary Outcome Data Analytic Technique
D.6.b. Exploratory Outcome Data Analytic Technique
D.7. Time Sequence
E. Human Participants Research Concerns
E.1. Protection of Human Participants
E.1.a. Risk to Participants
E.1.a.1. Sources of Materials
E.1.a.2. NAC Medication Risks
E.1.a.2.a. Reproductive/Pregnancy Risks
E.1.a.3. Blood Drawing (Venipuncture) Risks
E.1.a.4. Risk to Privacy/Confidentiality
E.1.a.5. Randomization Risks
E.1.a.6. Risk of Relapse or Increased Alcohol Use
E.1.b. Adequacy of Protection Against Risks
E.1.b.1. Informed Consent
E.1.b.2. Protection Against NAC Medication Risks
E.1.b.2.a. Protection Against Reproductive/Pregnancy Risks
E.1.b.3. Protection Against Blood Drawing (Venipuncture Risks
E.1.b.4. Protection Against Risks to Privacy/Confidentiality
E.1.b.5. Protection Against Randomization Risks
E.1.b.6. Protection Against Risk of Relapse or Increased Alcohol Use
E.1.b.7. Reporting Unanticipated Problems Involving Risk to Participants or Others
E.1.c. Adverse Event Reporting
E.1.c.1. Introduction
E.1.c.2. Adverse Event Definition
E.1.c.3. Serious Adverse Event Definition
E.1.d. Participant Withdrawal
E.2. Data and Safety Monitoring
E.2.a. Plan to Monitor Study Progress and Safety: The Data and Safety Monitoring Plan 
E.2.b. The Data and Safety Monitoring Board (DSMB)
E.2.c. Research Monitor
E.2. d. Schedule of DSMB Meetings
E.2.e. List of Study Data and Event Items to be Reviewed by the DSMB
E.2.f. Procedures for Communicating DSMB findings to Appropriate Regulatory Bodies
E.2.g. Stopping Rules
E.2.h. Rules for Withdrawing Study Participants from the Study Interventions
E.2.i. Rules for Breaking the Blind
E.3. Benefits for Taking Part in the Study
E.4. Importance of the Knowledge to Be Gained


I. SYNOPSIS
The goal of the project is to improve the care of veterans with mild traumatic brain injury (TBI) and alcohol use 
disorder (AUD). The PI and coinvestigator are conducting a pilot controlled clinical trial to assess the efficacy 
of N-acetylcysteine (NAC) to reduce alcohol use and improve brain injury symptoms in veterans with TBI who 
have AUD. This proposed project builds upon our current IMN-funded research on topiramate 
pharmacotherapy for unhealthy alcohol use in veterans with TBI. 
Exposure to injuries and stresses of combat is known to be associated with risk for both traumatic brain injury 
and hazardous and harmful alcohol use. Veterans, especially those involved in the Iraq and Afghanistan 
conflicts (Operation Iraqi Freedom [OEF], Operation Enduring Freedom [OEF] and Operation New Dawn  
[OND] have high rates of TBI.  Because of the adverse interaction of heavy alcohol use and TBI, there is a 
clinical need for effective treatments to reduce hazardous and harmful alcohol use in these veterans.  The 
proposed project directly builds on the PI’s current pilot controlled trial of topiramate in veterans with PTSD 
and alcohol dependence.  Acetylcysteine (NAC) has been shown to be efficacious in the treatment of 
dependence and may also have benefit in the treatment of PTSD, which often accompanies TBI.
Over 2 million veterans have served in the Iraq and Afghanistan conflicts -- Operation Iraqi Freedom (OIF) and 
Operation Enduring Freedom (OEF) and 23%-30% may have sustained mTBI1-3.  The prevalence of alcohol 
and other substance use disorders in OIF/OEF veterans with TBI is approximately twice that of veterans 
without TBI1,4. Although the majority of alcohol treatment studies have focused on AUD, the spectrum of 
unhealthy alcohol use includes both hazardous as well as harmful drinking. Hazardous alcohol use has been 
defined as drinking that exceeds recommended limits (≥14 drinks/week for men or 7 drinks/week for women or 
anyone over age 65) and is associated with higher prevalence of a wide range of medical and psychiatric 
morbidities. Harmful alcohol use is drinking that meets DSM-5 criteria for a diagnosis of AUD.  Hazardous and 
harmful alcohol use (HHAU) is common among veterans; recent large epidemiologic studies found that 22-
40% of OEF/OIF veterans screened positive for HHAU5,6.
Neurocognitive impairment may be both an important contributor to, as well as a result of, alcohol use and 
TBI. AUD is associated with, or causal to, a wide variety of neurobehavioral harms. These include impulsivity, 
risk-taking behavior, irritability/mood instability, depression, and suicide risk. HHAU is also associated with 
deficits in executive functioning, learning, memory, and decision making, with increased impulsivity and risk-
taking.  Both HHAU’s and TBI’s association with impairments in self-control and decision-making are linked to 
ventromedial and orbitofrontal cortex dysfunction. Thus, both TBI and HHAU may independently and additively 
alter cognitive, emotional, and behavioral functioning.  These alcohol- and TBI-related impairments can also 
synergistically increase the potential for risk-taking and contribute to many of the harmful behaviors seen in 
veterans with HHAU and TBI.  By extension, they also affect their families, and the community at large.
NAC has been proposed as a neuroprotective agent that may benefit TBI, mediated through antioxidant and 
anti-inflammatory effects7 and it may assist in reducing alcohol use. Reducing alcohol use and improving brain 
injury symptoms via NAC treatment may have the potential to improve cognitive functioning and reduce risky 
behavior in veterans with TBI. Reducing impulsivity and risk-taking propensity can be expected to reduce 
harmful behaviors that are tied to poor adherence to medical care, marital relationship problems, domestic and 
other forms of violence, and suicide. If, as expected, NAC treatment improves the management of TBI and 
AUD, it would have unambiguous benefits both for active duty military personnel and veterans.
Improving the care of veterans with TBI and unhealthy alcohol use is likely to help families and communities 
affected by the sequelae of these problems.  Moreover, treatments that help veterans with TBI and unhealthy 
alcohol use are likely to be applicable to the general population of individuals with these comorbid problems.
The objectives of the study are: (a) to successfully recruit 30 veterans with mild TBI and hazardous or harmful 
alcohol use; (b) to test primary and exploratory hypotheses as described below.
Outcomes, products and deliverables:  Outcomes: The primary treatment outcome will be percent heavy 
drinking days of alcohol per week.  The secondary outcome will be TBI symptom severity as measured by the 
Neurobehavioral Symptom Inventory (NSI).  The exploratory outcomes will be levels of executive functioning 
(impulsivity, risk-taking, and decision making) and other neurocognitive domains assessed over the course of 
the study. Products: Data will be collected on 8 weeks of treatment plus week 12 follow-up.  Deliverables: 


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Interim and final poster presentations at Research Society on Alcoholism (RSA); Final report as a manuscript 
submitted for publication to a peer-review alcohol/addiction scientific journal.
This study is being sponsored by the Department of Defense (DOD) Telemedicine and Advanced Technology 
Research Center (TATRC).


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II. RESEARCH PLAN
A. GOALS AND SPECIFIC AIMS
The overall goal of the project is to improve the care of veterans with traumatic brain injury and 
unhealthy alcohol use. We will conduct a pilot controlled clinical trial to assess the efficacy of N-
acetylcysteine (NAC) to reduce alcohol use and improve brain injury symptoms in veterans with TBI who 
consume alcohol at hazardous or harmful levels. This project builds upon our current ITN-funded research on 
topiramate pharmacotherapy for unhealthy alcohol use in veterans with TBI.
A.1. PRIMARY AIMS:  
Aims:
Measure both alcohol use and TBI symptom severity over the course of the 12-week study in order to detect 
differential efficacy of NAC and placebo.  Alcohol use treatment outcome will be the Percent Days of Heavy 
Drinking (PHDD) of alcohol
A heavy drinking day is defined using NIAAA (2007) criteria: any day with 5 or more drinks per day for men or 
4 or more drinks per day for women8.  The choice of PHDD as the primary outcome is based on its 
endorsement by a recent NIAAA consensus conference9 and its increasing use in clinical trials 10-12. TBI 
symptom severity will be measured with the Neurobehavioral Symptoms Inventory (NSI)13,14 a measure of 
postconcussive symptom severity.
Hypotheses: 
Our two primary aims examine group differences, to detect differential efficacy of NAC vs placebo (between-
group analyses). We will test the following hypotheses with between-groups analyses: 
1. NAC treatment combined with Medical Management (MM) alcohol counseling will have greater efficacy 
than placebo in reducing percent heavy drinking days (PHDD). A heavy drinking day is defined using 
NIAAA (2007) criteria: any day with ≥5 drinks for men or >4 for women8. PHDD as  primary outcome is 
based on recent NIAAA consensus9 and increasing use in clinical trials10-12.
2. NAC treatment will have a greater efficacy than placebo in reducing TBI related symptoms. TBI symptom 
severity will be measured by the Neurobehavioral Symptom Inventory (NSI)13,14. 
A.2. EXPLORATORY AIMS:  
Exploratory Aims:
Other exploratory aims will include obtaining additional measures of alcohol use, executive functioning (e.g., 
impulsivity and risk taking) and other domains of neurocognition, and examining the potential moderating 
effect of rs6465084 on NAC treatment response
Hypotheses:
NAC treatment will have greater efficacy than placebo in: a) reducing other alcohol use measures (percent 
drinking days per week, drinks/week, drinks/drinking day, alcohol craving, biomarkers); b) improving 
neurocognition. We will examine neurocognitive domains which include executive functioning (impulsivity, risk-
taking, decision making), auditory-verbal learning and memory, verbal fluency, processing speed and working 
memory. We will also explore the potential moderating effect of rs6465084 on NAC treatment response.
A.3. FUTURE PLANS
If the results of this pilot NAC HHAU/TBI project are positive, the investigators will seek funding for a larger 
controlled trial through the Department of Defense CDMRP and related funding programs and/or NIAAA R01 
mechanisms. We believe that we can derive a reliable estimate of effect size for planning a randomized 
controlled trial from this small parallel groups controlled pilot study. It will be useful to obtain estimates of 


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variability for the key outcome variables in this population of comorbid patients in order to inform future 
controlled trials. Furthermore, we would seek to partner with other investigators in future studies to include 
neuroimaging to examine potential pre to post treatment neurobiological changes which may occur with NAC 
treatment.
B. BACKGROUND AND SIGNIFICANCE
B.1. OVERVIEW
To achieve these aims, we will conduct a pilot prospective, parallel groups, randomized, double-blind, placebo-
controlled flexible-dose clinical trial of NAC in 30 veterans with TBI and hazardous or harmful alcohol use. The 
8-week treatment phase will consists of treatment with NAC or placebo, plus weekly manualized alcohol 
counseling, added to whatever usual TBI treatment participants may be receiving, including medication 
(exceptions being any alcohol treatment medications). The manualized counseling for alcohol use disorders 
will consist of Medical Management15, an NIAAA manual-driven, low-intensity supportive program to promote 
adherence to the medication regimen and retention. Participants will continue to receive usual care for TBI and 
other medical and/or psychiatric disorders from their primary medical and mental health treatment providers. 
Participants will meet with research staff weekly to receive medication, counseling, and research assessments 
during the 8 weeks of study treatment. Participants will also be assessed at the week-12 follow-up visit.
B.2. THE CO-OCCURRENCE OF TBI AND HAZARDOUS AND HARMFUL ALCOHOL USE AMONG 
VETERANS 
Over 2 million veterans have served in the Iraq and Afghanistan conflicts -- Operation Iraqi Freedom (OIF) and 
Operation Enduring Freedom (OEF) and 23%-30% may have sustained traumatic brain injury (TBI)1-3. 
Evidence indicates that the prevalence of alcohol and other substance use disorders in OIF/OEF veterans with 
TBI is approximately twice that of veterans without TBI1,4,16,17.  Post TBI, more service members have 
diagnoses of alcohol/substance abuse than any other selected condition except headache18. Evidence 
suggests that TBI may play a causal role in this relationship.  For example, in a recent study, airmen with TBI 
were shown to have an increased risk for addiction-related disorders compared with a similarly injured non-TBI 
comparison group. The hazards for alcohol dependence and nondependent abuse of drugs or alcohol were 
significantly elevated in those with TBI as compared to controls1.
B.3. UNHEALTHY ALCOHOL USE: HAZARDOUS AND HARMFUL ALCOHOL USE
Although the majority of alcohol treatment studies have focused on alcohol use disorder (AUD), the spectrum 
of unhealthy alcohol use includes hazardous as well as harmful drinking. Hazardous alcohol use has been 
defined as drinking that exceeds recommended limits (≥14 drinks/week for men or 7 drinks/week for women or 
anyone over age 69)8,19 and is associated with higher prevalence of a wide range of medical and psychiatric 
morbidities8. Harmful alcohol use is alcohol use that meets DSM-5 criteria for a diagnosis of AUD20.  
Hazardous and harmful alcohol use (HHAU) is common among veterans; recent large epidemiologic studies 
found that 22-40% of OEF/OIF veterans screened positive for HHAU5,6. 
B.4. NEUROBEHAVIORAL INTERACTIONS OF HEAVY ALCOHOL USE AND TBI
Both TBI and HHAU are associated with impulsivity and impaired decision-making and linked to ventromedial 
and orbitofrontal cortex dysfunction21.  Both TBI and HHAU are also associated with, or causal to, a wide 
variety of neurobehavioral harms. These include impulsivity, irritability/mood instability, depression, and suicide 
risk.  Other impairment  occur in attention, concentration,  visual-spatial memory, and executive functioning --  
including decision-making, risk-benefit analysis, and behavioral inhibition22. TBI and HHAU can synergistically 
increase the potential for these cognitive, emotional, and behavioral impairments and thereby increase risk-
taking behavior. 
Neurocognitive functioning has been shown to be an important moderator of substance abuse treatment 
outcome21,23.  Neurocognitive impairment may therefore be both an important contributor to, as well as a result 
of, continued alcohol use in TBI. However, cognitive functioning has been shown to improve even after brief 
periods of abstinence from alcohol21. Reducing alcohol use may thus have the potential to improve cognitive 
functioning, improve decision-making and reduce risk-taking behavior in veterans with TBI.


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B.5. LIMITS OF CURRENT PHARMACOTHERAPIES FOR AUD AND FOR HHAU IN TBI 
Although there are several FDA-approved medications for the treatment of AUD, no consensus exits regarding 
medications to reduce hazardous alcohol use, and there are no published reports of pharmacotherapies for 
either AUD or other forms of HHAU in patients with TBI. Disulfiram, acamprosate, as well as oral and 
extended-release injectable forms of naltrexone are approved by the Food and Drug Administration (FDA) for 
the treatment of AUD. Topiramate is also an efficacious medication although not FDA-approved for AUD. 
However, these medications have limitations and at best show only modest to moderate efficacy24. The most 
rigorous controlled trial of disulfiram showed only questionable efficacy25 and disulfiram treatment requires 
abstinence from alcohol. Naltrexone studies have generally supported its efficacy reducing drinking, although 
effect sizes are modest24. Naltrexone’s opioid antagonism precludes its use in patients who require opioid 
analgesic treatment, a salient issue for many injured veterans with chronic pain conditions. Acamprosate has 
been found to reduce alcohol relapse rates in European studies26, however, trials conducted in the United 
States, e.g. the COMBINE27 study, have failed to establish its efficacy in intent-to-treat analyses. Disulfiram 
and oral naltrexone also have hepatotoxic potential, although low. The available treatments also have other 
clinically significant adverse effect burdens. Topiramate treatment, for example, as demonstrated by the PI’s 
previous research (see below) is associated with cognitive impairment in veterans with AUD, a problem of 
particular relevance to individuals with TBI. Other difficulties with these medications are cost, with 
acamprosate and injectable naltrexone being the most costly. There is therefore a need to find novel 
alternative, safe, well-tolerated, and low-cost medications for the treatment of AUD, and in particular, for the 
treatment of  HHAU in veterans with TBI.
C. PRELIMINARY STUDIES
C.1. N-ACETYLCYSTEINE BACKGROUND AND EVIDENCE FOR USE IN DISORDERS OR ADDICTION  
N-Acetylcysteine (NAC) is FDA-approved, most commonly used as a mucolytic28 and in the treatment of 
acetaminophen overdose29. NAC’s potential as a treatment for substance use disorders is related to its roles in 
oxidative homeostasis and glutamate activity30. NAC is the acetylated precursor of the amino acid L-cysteine, 
and although it has a relatively low bioavailability (below 5%), NAC associated redox exchange reactions 
produce cysteine, which can cross the epithelial cell membrane and blood brain barrier in abundance31. 
Cysteine is involved in the synthesis of glutathione (GSH), a tripeptide composed of glutamate, cysteine and 
glycine, which serves as a ubiquitous antioxidant neutralizing oxidative free radicals32. NAC-derived cysteine 
also assists in the regulation of Glu through the cystine-Glu antiporter30. NAC increases activity of the catalytic 
subunit of the cysteine-Glu exchanger and Glu transporter 1 (GLT1)33-35. Through this system, glial astrocytes 
exchange cysteine for Glu, which is released into the extracellular space inducing an increase in the 
glutamatergic tone on presynaptic metabotropic Glu receptors 2/3 (mGluR2/3)36, which in turn has an inhibitory 
effect on presynaptic glutamate release36. Both acute and chronic alcohol consumption has been shown to 
increase extracellular levels of glutamate in the nucleus accumbens (NAcc)37,38. Extracellular Glu in the NAcc 
is associated with cue-induced reinstatement of alcohol-seeking behavior39. The alcohol-induced dysregulation 
of extracellular Glu is likely due to an alteration in the mechanism of relase and reuptake of Glu similar to that 
shown in cocaine addiction40-45. With repeated exposure to cocaine, extracellular Glu is reduced in the NAcc 
via decreased tonic activation of relase-regulating mGlu2/338,41,46-48. Modulation mGluR2/3 cysteine-Glu 
exchange via NAC restores basal extracellular levels of Glu and prevents cocaine40,49,50  and heroin51,52 
seeking. More importantly, reduction in glutamatergic transmission via activation of mGlu2/3 attenuates 
alcohol seeking behavior53,54. In sum, NAC may regulate elevated extracellular glutamate36 resulting from 
acute and chronic alcohol exposure55, thus repairing faulty communication between NAcc and prefrontal 
cortex56.
Medications that modulate the effects of Glu in the midbrain have shown clinical effectiveness in the treatment 
of AUD57-59. Additionally, animal models have demonstrated the ability of GSH to potentiate N-methyl-D-
aspartate receptor response to Glu30. NAC can aid in the synthesis of GSH and it also simultaneously 
modulates dopamine (DA) transmission and DA-associated reactive oxygen species60. Medications that 
modulate Glu may suppress conditioned cue responses to alcohol after short-term abstinence61, reduce 
aversive effects of alcohol withdrawal related to increased Glu and decreased central DA levels, particularly in 
the nucleus accumbens62,63, and inhibit neuronal hyperexcitability64 following withdrawal65,66. Moreover, NAC’s 


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anti-inflammatory effects have also been implicated as playing a role in its  potential therapeutic effects on the 
pathophysiology of substance use disorders67.
NAC has been shown to have possible efficacy in the treatment of cocaine68-70, cannabis71,72 and nicotine 
dependence73, 
pathological 
gambling74, 
and 
in 
other 
psychiatric 
disorders 
marked 
by 
impulsivity/compulsivity30,75-78. There have been four open label68,70,71,74 and six double-blind placebo-controlled 
randomized clinical trials (RCTs)33,36,37,43-45 of NAC for addiction treatment. In an 8-week RCT for cocaine 
dependence, 111 participants were assigned to receive 1200 or 2400 mg of NAC or placebo per day79. 
Participants assigned to 2400 mg of NAC took longer to relapse and had less craving compared to placebo. 
Two smaller (n=13/15) cocaine RCTs showed NAC to inhibit cocaine cue reactivity more than placebo69 and to 
reduce self-reported cocaine use, withdrawal symptoms, and craving80. An open study in 23 treatment seeking 
cocaine dependent individuals (26% with comorbid alcohol dependence) showed trends towards reductions in 
money spent and number of days of cocaine use68. In a four-week open-label trial of NAC in 24 treatment-
seeking cannabis dependent individuals, NAC was associated with decreased self-reported cannabis use and 
craving 71. Gray (2012)72 confirmed these findings in an RCT of NAC in 116 cannabis-dependent adolescents. 
In a four-week RCT in treatment-seeking nicotine dependent participants, NAC reduced the number of 
cigarettes smoked73. Of relevance to this application’s primary aims, Knackstedt et al.,73 reported that the daily 
number of cigarettes smoked strongly covaried with alcohol use, which suggests a reduction in alcohol use in 
the sample of alcohol users in that study. Finally, a six-week RCT of NAC in 13 pathological gamblers, 83% 
showed decreased OCS compared to only 28% of participants receiving placebo74. Finally, in an ongoing IMN-
funded pilot project (PI Kalivas), NAC appears to be efficacious in reducing alcohol and cocaine craving in 
individuals with PTSD and substance use disorder81.
Taken together, these findings  suggest NAC has utility in controlling reward-driven behavior in addictive 
disorders, potentially moderated through the glutamate system82. Additionally, in all of the mentioned studies, 
NAC was well tolerated, with only minor side effects. Of note, NAC, in combination with high-dose naltrexone, 
is being tested in an ongoing trial for the treatment of alcohol dependence (Gihyun Yoon; NCT01214083).
C.2. N-ACETYLCYSTEINE EVIDENCE FOR USE IN BRAIN INJURY SYMPTOM TREATMENT
NAC has been proposed as a neuroprotective agent that may benefit TBI. In TBI, a concussive force is 
imparted to the head from contact with an object or -- as is common among Iraq /Afghanistan veterans – a 
rapidly expanding pressure wave83. Injuries lead to dysfunction of the pulmonary and circulatory systems, with 
autonomic nervous system and neuroendocrine-immune system acitivation contributing to cellular brain 
injury84. The neuroprotective effects of NAC on TBI have been proposed to be mediated through antioxidant 
and anti-inflammatory effects7. In an RCT in 81 active duty service members with acute mTBI, NAC treatment 
resulted in improved cognitive test performance, reduced number of mTBI symptoms, and higher rates of 
complete symptom resolution after seven days of NAC treatment compared to controls7. Although this study 
was limited to acute mTBI, the authors suggest NAC treatment may be useful in other TBI settings.
In animal models, NAC has been shown to attenuate cellular injuries including oxidative stress84-87, axonal 
injury88,89, inflammation90,91, apoptosis92 and neurodegeneration93,94. Rodent models suggest NAC acts as an 
anti-inflammatory agent87,90 and may aid in reducing TBI related behavioral deficits91. NAC (combined with 
minocycline) has been shown to attenuate myelin loss and modulate neuroinflammation, thus improving 
spatial learning, memory and set-shifting in mildly brain injured rats91,95.  Chen et. al.90, demonstrated NAC 
attenuation of TBI-induced proinflammatory response. In addition to neuroinflammation and oxidative stress, 
increased synaptic release of glutamate is also characteristic of TBI96-99. Yi et. al.,94 demonstrated the effects 
of NAC to regulate both excitatory and inhibitory neurotransmission following TBI in rats. Similarly, Xiong et. 
al.100, demonstrated NAC’s ability to regulate GSH (glutamate regulator) in rat brain tissue in acute TBI. Taken 
together, NAC may be beneficial for the neuroprotective effects demonstrated in human and animal TBI 
studies in addition to its potential benefits in glutamatergic regulation.
C.3. N-ACETYLCYSTEINE EVIDENCE FOR COGNITIVE ENHANCEMENT
In AUD, deficits in executive functioning, learning, memory, and measures of decision making, impulsivity, 
risk-taking are well documented101. The neural circuitry in the prefrontal cortex plays an important role in 
inhibitory control102,103, thus making it a target for therapeutic intervention104. NAC’s ability to regulate 


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glutamate along with glutamate’s critical role in synaptic plasticity and corresponding learning and memory105 
make it a promising therapeutic candidate. NAC has been shown to improve learning, memory and set shifting 
in animals91,95, and is proposed as a potential treatment for dementia-related cognitive decline in humans106. 
Parachikova et al.,107 demonstrated that NAC (and other supplements) improved cognition and decreased 
Alzheimer’s neuropathology in mice. Increased cognitive functioning is beneficial in addiction treatment 
because it predicts greater motivation to change and better self-regulation of drinking behavior21. 
The combined evidence of NAC associated anti-oxidant84, anti-inflammatory7, glutamatergic108 and related 
cognitive-enhancing benefits104, tolerability7,82,109, and capacity to prevent hepatic injury29 provides support for a 
pilot trial of NAC treatment in veterans with TBI who are consuming alcohol at hazardous or harmful levels.
C.4. GENETIC MODERATION OF ALCOHOL PHARMACOTHERAPY RESPONSE 
Until now, as with most psychiatric disorders, it has been difficult to predict which AUD patients will respond to 
which medication. Recently, evidence has emerged showing genetic moderating effects on AUD medication 
response. For example, topiramate’s efficacy in reducing the frequency of heavy drinking days has been 
shown to be confined to C-allele homozygous carriers of the GRIK1 gene rs2832407 SNP, whereas there was 
no difference between topiramate and placebo for A-allele carriers110. This same SNP has been shown to be 
associated with topiramate side effects; 
carriers of the A-allele had more severe 
topiramate related side effects compared to 
those homozygous for 
the C-allele111. 
Pharmacogenetic 
advances have been 
made 
for 
other 
AUD 
treatment 
medications120, as summarized in Table 
1121. 
Genetic moderation has also been studied 
in medications acting on the serotonergic 
system with regard to their effects on 
alcohol consumption. Kranzler et al.117 
previously showed a moderating effect on 
sertraline treatment response by SNPs in 
the gene encoding the serotonin transporter 
protein (5-HTT) and age of onset of alcohol 
dependence. Similarly, 
5-HTT gene polymorphisms are implicated 
in 
moderating 
ondansetron 
treatment 
response in early onset AUD patients116. 
Studies of other medications used to treat 
AUD, such as acamprosate and disulfiram have also yielded promising findings. For example, acamprosate 
response has been linked to polymorphisms of the GATA4  gene (regulating atrial natriuretic peptide)118 and 
disulfiram-related adverse effects have been linked to functional polymorphisms of the dopamine-beta 
hydroxylase gene 119. 
NAC’s mechanisms of action include stimulation of mGluR2/3. The metabotropic Glu receptor 3 is a member 
of the mGlu2/3 family and has shown impact in animal studies of alcohol dependence122-126, including 
attenuation of alcohol self-administration and cue-induced reinstatement54. A recent human study found 
significant differences in the allelic and genetic frequency of the A allele of SNP rs6465084 in the GRM3 
region of an alcohol-dependent group compared to controls127. Genetic polymorphism associations of 
rs6465084 with AUD support mGlu2/3 as potential treatment targets and possible moderators of treatment 
outcome127. These genetic associations will be explored in the proposed project.
C.5. PRELIMINARY STUDIES IN THE ADDICTION RESEARCH PROGRAM AT THE SAN FRANCISCO 
VAMC
The PI’s Addiction Research Program at the SFVAMC has been testing the efficacy of pharmacotherapies for 
Table 1. Brief Review of Positive Findings of Genetic 
Influences in Alcohol Pharmacotherapy
Genetic 
Variants
Moderates
Notable 
Studies
Topiramate
GRIK1(rs2832407)% Heavy drinking 
days, Side effects
Kranzler, 2014 
110; Ray, 2009 111
Naltrexone
OPRM1 
(Asn40Asp), 
(rs1799971), 
DRD4 VNTR
% Heavy drinking 
days, abstinence 
rates, relapse to 
heavy drinking
Anton, 2008 112; 
Kim, 2009 113; 
Oslin, 2003 114; 
Tidey, 2008 115
Ondansetron LL/LS/SS (5-
HTTLPR) 
(rs1042173), 
SLC6A4 (5-
HTTLPR)
Drinks per drinking 
day, 
% days abstinent
Johnson, 2011 
116
Sertraline
5-HTTLPR tri-
allelic SLC6A4
% Heavy drinking 
days % drinking 
days
Kranzler, 2011 
117
Acamprosat
e
GATA4 
(rs1327367)
Relapse
Kiefer, 2011 118
Disulfiram 
DBH (rs161115)
Adverse Events
Mutschler, 2012 
119


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AUDs and has successfully completed a Department of Defense (DoD) funded pilot trial of topiramate in 
veterans with AUD and PTSD128, the results of which led to the funding of a large (n=150) clinical trial in the 
same population. 
Simultaneously, The PI obtained IMN funding for a preliminary investigation of topiramate in veterans with 
HHAU and TBI. Through the current conduct of this 12-week placebo controlled pilot trial of TOP in veterans 
with TBI and HHAU, we have built a strong alcohol clinical trials team, developed recruitment strategies, 
assessment procedures, and retention methods with an understudied and challenging veteran population. We 
plan to enroll a total of 32 participants over the course of 11 months, and at study midpoint we have enrolled 
53%. Of those who met basic eligibility criteria, 37% (28/75) expressed reluctance to take prescribed 
psychotropic medication, often citing concerns about adverse effects. Offering an over-the-counter 
supplement such as NAC, will likely result in greater acceptability of treatment than that which we have 
experienced in the current trial of TOP in HHAU and TBI. TOP has a problematic adverse event profile129, 
including transient reductions in learning and memory128. However, even with the barriers related to tolerability, 
our research team has been able to maintain high retention rates, with 81% completing the study, as defined 
by attending Week 12. 
Using data gathered from our completed and 
ongoing clinical trials of topiramate, we examined 
the associations of baseline characteristics in 47 
veterans with HHAU, PTSD with and without TBI. In 
group comparisons, there were no differences in 
drinking severity and groups were similar in PTSD 
symptom severity (Table 2). Groups were also 
similar in performance in various neurocognitive 
domains including risk-taking, motor inhibition, 
decision making, divided attention, auditory-verbal 
learning and memory, processing speed, working 
memory and verbal fluency130. Within the TBI 
group, high risk taking was related to the 
consumption of more standard alcohol drinks per 
week, and worse decision-making was related to 
more heavy drinking days per week (Table 3). 
Additionally, in the TBI group, higher total PTSD 
symptom severity was related to greater risk-taking 
and worse processing speed (Table 4). 
Table 2. Patient demographics and AUD/PTSD 
characteristic in veterans with AUD and PTSD, with 
and without TBI (mean ± SD)
 
TBI
no-TBI
p-value
n (female)
21 (2)
26 (2)
Age
44.7 ± 
12.7
52.0 ± 
10.8
.040
Education
12.5 ± 2.3
14.3 ± 2.0
.007
Comorbid 
SUD 
(%)
5 (24%)
11 (42%)
NS
CAPS Total
75.1 ± 
17.0
82.4 ± 
16.2
NS
     Intrusions
19.0 ± 5.3
21.7 ± 6.3
NS
     Avoidance
30.1 ± 9.5
35.2 ± 8.6
.043
     Arousal
26.5 ± 4.8
25.5 ± 5.1
NS
Drinking 
Days/Week 
(DD/Wk)
5.3 ± 1.8
5.8 ± 1.3
NS
Heavy Drinking 
Days/Week 
(HDD/Wk)
4.8 ± 1.9
4.8 ± 2.4
NS
Drinks/Week
65.8 ± 
38.4
62.9 ± 
41.4
NS
Drinks/Drinking 
Day
13.0 ± 6.3
11.1 ± 7.4
NS
Heavy drinking day (>4 standard alcoholic drinks 
for men, >3 standard alcoholic drinks for women). 
Standard alcoholic drink is defined as containing 
13.6 g of pure alcohol. Drink consumption was 
averaged over 90 days preceding study consent.
Table 3. Significant (p<.047) correlations (r) 
between alcohol use, self-regulation and 
processing speed in TBI and [no-TBI]
Measure
DD/W
k
HDD/W
k
Drinks/
Wk
Drinks/D
D
BART Pumps 
Adj Avg.
.49
IGT: Net Total t-
score
-.72
HVLT: Learning
[-43]
Stroop Word
[-77]
[-.81]
[-.78]


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As illustrated in Figure 1, we observed differences in 
associations 
between 
alcohol 
use, 
PTSD 
and 
measures of risk-taking between the TBI and no-TBI 
groups.  
Additionally, in the TBI group, higher 
frequency of drinking was associated with higher levels 
of danger-seeking131. NAC treatment could be hoped 
to lead to reduction in not just alcohol consumption, but 
possibly TBI symptom severity, and improved cognitive 
performance.
C.6. INNOVATION
This pilot prospective, double-blind, placebo-controlled clinical trial of NAC treatment in 30 veterans with TBI 
and HHAU. It is necessary to obtain a preliminary determination of the efficacy, safety, tolerability, and 
feasibility of NAC in a pilot study before proceeding to a larger, more resource-intensive clinical trial. Moreover, 
the resources available from the IMN funding mechanism do not permit the conduct of a larger trial of NAC in 
TBI and HHAU, which, in any case, may be premature, given the questions regarding its efficacy, feasibility, 
and safety in the specific population to be studied. A placebo-controlled trial is justified because it is the 
standard in the field and there are no proven medications for concurrent TBI and HHAU. Our primary aims will 
be to measure both alcohol use and TBI symptom severity over the course of the 12-week study in order to 
detect differential efficacy of NAC and placebo.  Alcohol use treatment outcome will be the Percent Days of 
Heavy Drinking (PHDD) of alcohol.  A heavy drinking day is defined using NIAAA8 (2007) criteria: any day with 
5 or more drinks per day for men or 4 or more drinks per day for women8.  The choice of PHDD as the primary 
outcome is based on its endorsement by a recent NIAAA consensus conference9 and its increasing use in 
clinical trials 10-12. TBI symptom severity will be measured with the Neurobehavioral Symptoms Inventory 
(NSI)13,14, a measure of postconcussive symptom severity. Other exploratory aims will include obtaining 
additional measures of alcohol use, executive functioning (e.g., impulsivity and risk taking) and other domains 
of neurocognition, and examining the potential moderating effect of rs6465084 on NAC treatment response. 
To achieve these aims, we will conduct a pilot prospective, parallel groups, randomized, double-blind, placebo-
controlled flexible-dose clinical trial of NAC in 30 veterans with TBI and hazardous or harmful alcohol use. The 
8-week treatment phase will consists of treatment with NAC or placebo, plus weekly manualized alcohol 
counseling, added to whatever usual TBI treatment participants may be receiving, including medication 
(exceptions being any alcohol treatment medications). The manualized counseling for alcohol use disorders 
will consist of Medical Management15, an NIAAA manual-driven, low-intensity supportive program to promote 
adherence to the medication regimen and retention. Participants will continue to receive usual care for TBI and 
Table 4. Significant (p,.048) correlations (r) 
between 
CAPS 
PTSD 
symptoms 
and 
cognition in TBI and [no-TBI]
Measure
Total
Intrusion
Avoidance
Arousal
BART: 
Pumps 
Adj. Avg.
.52
.49
.50
BART: 
Explosions
.49
Trails A
-.51
HVLT: Learning
[-.45]
Figure 1. 


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other medical and/or psychiatric disorders from their primary medical and mental health treatment providers. 
Participants will meet with research staff weekly to receive medication, counseling, and research assessments 
during the 8 weeks of study treatment. Participants will also be assessed at the week-12 follow-up visit.     
D. RESEARCH DESIGN AND METHODS
D.1. GENERAL DESIGN
D.1.a. Rationale for a Pilot Placebo-controlled Trial of NAC:  
We propose a pilot prospective, double-blind, placebo-controlled clinical trial of NAC treatment in 30 veterans 
with TBI and HHAU. It is necessary to obtain a preliminary determination of the efficacy, safety, tolerability, 
and feasibility of NAC in a pilot study before proceeding to a larger, more resource-intensive clinical trial. 
Moreover, the resources available from the IMN funding mechanism do not permit the conduct of a larger trial 
of NAC in TBI and HHAU, which, in any case, may be premature, given the questions regarding its efficacy, 
feasibility, and safety in the specific population to be studied. A placebo-controlled trial is justified because it is 
the standard in the field and there are no proven medications for concurrent TBI and HHAU. 
D.1.b. Overview of Design:  
Our primary aims will be to measure both alcohol use and TBI symptom severity over the course of the 12-
week study in order to detect differential 
efficacy of NAC and placebo.  Alcohol use 
treatment outcome will be the Percent 
Days of Heavy Drinking (PHDD) of 
alcohol.  A heavy drinking day is defined 
using NIAAA (2007) criteria: any day with 
5 or more drinks per day for men or 4 or 
more drinks per day for women9.  The 
choice of PHDD as the primary outcome is 
based on its endorsement by a recent 
NIAAA consensus conference98 and its 
increasing use in clinical trials99-101. TBI symptom severity will be measured with the Neurobehavioral 
Symptoms Inventory (NSI)102,103, a measure of postconcussive symptom severity. Other exploratory aims will 
include obtaining additional measures of alcohol use, executive functioning (e.g., impulsivity and risk taking) 
and other domains of neurocognition, and examining the potential moderating effect of rs6465084 on NAC 
treatment response. To achieve these aims, we will conduct a pilot prospective, parallel groups, randomized, 
double-blind, placebo-controlled flexible-dose clinical trial of NAC in 30 veterans with TBI and hazardous or 
harmful alcohol use. The 8-week treatment phase will consists of treatment with NAC or placebo, plus weekly 
manualized alcohol counseling, added to whatever usual TBI treatment participants may be receiving, 
including medication (exceptions being any alcohol treatment medications). The manualized counseling for 
alcohol use disorders will consist of Medical Management106, an NIAAA manual-driven, low-intensity supportive 
program to promote adherence to the medication regimen and retention. Participants will continue to receive 
usual care for TBI and other medical and/or psychiatric disorders from their primary medical and mental health 
treatment providers. Participants will meet with research staff weekly to receive medication, counseling, and 
research assessments during the 8 weeks of study treatment. Participants will also be assessed at the week-
12 follow-up visit. 
D.2. STUDY PARTICIPANTS
D.2.a. Overview of Participants
Participants will be recruited from the San Francisco VA Medical Center and will be men and women, ages 18 
through 69, with a diagnosis of mild TBI plus current (past month) alcohol use disorder. 
We will recruit 30 participants from the San Francisco Veterans Affairs Medical Center (SFVAMC). 
Recruitment will be through direct outreach to patients via notices and cards in patient areas and asking 
clinicians to refer patients.  Research staff will conduct brief pre-screening to assess possible eligibility.  At the 
3-Visit Screening 
Assessment
NAC + Weekly Medical 
Management Counseling
Placebo + Weekly Medical 
Management Counseling
Weekly Visits
1
2
3
4
5
6
7
8
12
Follow-up 
Visit
Follow-up 
Visit
Random 
Assignment


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SFVAMC, sites will include the Primary Care, Neurology, TBI, Mental Health and Substance Abuse clinics, and 
affiliated satellite clinics (Community-Based Outpatient Clinics [CBOCs] in Downtown San Francisco, Santa 
Rosa, CA, and San Bruno, CA), regional Vet Centers and mental health clinics. The Investigator and 
Research Coordinators will work with staff in outpatient units at the SF VAMC to explain the study, including 
eligibility criteria, potential risks and benefits to study involvement, how to refer a potential study candidate and 
how prospective participants can contact study staff.  Once a prospective participant has been identified, 
research staff will conduct a brief telephone or in-person pre-screening interview to assess possible eligibility.  
If pre-screening is successful, research staff will obtain written informed consent and gather demographic and 
locator information including contact information for the patient’s treatment providers.  Written permission will 
be obtained for research staff to review mental health records and consult with the participant’s primary care 
provider, psychiatrist, and other clinicians to obtain clinical information to assist in the assessments of medical 
status, psychiatric diagnoses, and substance use.  The participant’s primary care and/or mental health 
providers will also be asked for their assent to any patient entering the study.
This study will actively recruit women as participants. Specifically, non-pregnant females, ages 18 to 69, will be 
eligible to participate. Pregnant females will be excluded from the study because NAC’s effects on the 
developing fetus is unknown and it is not known whether NAC is excreted in human milk. 
We anticipate that the majority of research participants may be males due to the significantly higher 
prevalence of alcohol use disorders among men and due to the fact that the SFVAMC will be the major 
recruitment site.  Based on our recruiting experience in our current research, we expect that approximately 
10%-15% of participants in the project may be women as outlined in the female breakdown in the 
Targeted/Planned Enrollment Table.  However, we hope to increase the recruitment rate of female participants 
as much as possible, by actively recruiting in the SFVAMC’ Women’s Clinic and other sites likely to have 
higher numbers of women. 
The projected cohort is diverse and well-represented in ethnic categories of Hispanic or Latino and in the 
racial categories of African-American, Asian and Pacific Islander. This project will recruit members of minority 
groups in all of its research activities. A diverse population of study participants is expected to be recruited 
from the SFVAMC as it has a rich mix of ethnic/racial groups represented among the patient population. The 
anticipated ethnic and racial breakdown is outlined in the Targeted/Planned Enrollment Table.  In addition, the 
clinical staff at the SFVAMC who help to recruit prospective participants are both ethnically and racially 
diverse. 
Moreover, the current research staff in our lab are both men and women, as well as African-American, Asian, 
and Native American racial representation and both Hispanic and non-Hispanic ethnicity representation. 
    
We will take a number of steps to emphasize the recruitment of women and minorities for this project.  These 
include:  a) encouraging clinicians to be particularly attentive to the identification of female patients and those 
of ethnic and racial minority who may be appropriate for, and benefit from, the study, b) continuing to hire a 
research team of diverse gender and ethnicity to increase the likelihood of recruiting prospective participants 
with diverse backgrounds, c) consulting with the appropriate diversity enhancement staff of  UCSF/NCIRE, 
and SFVAMC  to identify additional strategies designed to increase recruitment of women and minorities.
D.2.b. Inclusion Criteria
INCLUSION CRITERIA
1.
Male and female Veterans eligible for VA services.
2.
Ages 18-69 (inclusive)
3.
A history of TBI, as defined by ACRM, in the chronic, stable phase of recovery (>6 months from injury). 
The ACRM defines TBI as a traumatically-induced physiological disruption of brain function, as 
manifested by at least one of the following:
(3a) any period of loss of consciousness;
(3b) any loss of memory for events immediately before or after the accident;
(3c) any alteration in mental state at the time of the accident (eg, feeling dazed, disoriented, or 


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confused); AND
(3d) focal neurological deficit(s) that may or may not be transient
4.
Current (within last 12 months) moderate (4-5 symptoms) or severe (6+ symptoms) alcohol use disorder 
by DSM-5 criteria. 
5.
Current (past month [30 days]) Hazardous Alcohol Use: Hazardous use is drinking that meets NIAAA 
criteria12: Current (past 30 day) weekly drinking, consisting of an average > 15 standard drinks/week for 
men or > 8 standard drinks/week for women.
6.
Participants must express a desire to reduce or stop alcohol use. 
7.
Female participants must have a negative urine pregnancy test and must be either postmenopausal ≥ 
one year or practicing an effective birth control method. 
8.
Participants must have a Breath Alcohol Concentration (BAC) of 0.00% when signing the informed 
consent.
D.2.c. Exclusion Criteria.
EXCLUSION CRITERIA
1.
Unstable psychotic or bipolar disorders, dementia, or other psychiatric disorders judged to be unstable in 
the clinical judgment of the PI or study physician.
2.
Clinically significant unstable medical conditions, in the clinical judgment of the PI or study physician.
3.
Female patients who are pregnant or nursing.   
4.
Concurrent participation in another alcohol treatment study, or in any research study involving 
medications. 
5.
Requiring acute medical detoxification from alcohol based on a score of 12 or more on the Clinical 
Institute Withdrawal Assessment of Alcohol Scale (CIWA-AD);  
6.
NAC use in the past week prior to study entry. 
7.
Use of AUD treatment medications (disulfiram, naltrexone, or acamprosate) within the past week.
8.
Participants who are legally mandated to participate in an alcohol treatment program. 
9.
Participants who in the opinion of the investigator should not be enrolled in the study because of 
precautions, warnings or contraindications outlined in the NAC package insert.
10.
Participants who are taking the following medications that have been reported to have adverse drug-drug 
interactions with NAC: carbamazepine and nitroglycerin.
11.
Participants with known hypersensitivity to acetylcysteine.
12.
Participants with an increased risk of upper GI bleed (such as those with esophageal varices) that could 
be exacerbated by vomiting.
13. 
Participants who have had a suicide attempt in the past 3 months or suicidal ideation, with intent, in the 
30 days prior to enrollment.
D.2.d. Modification of Inclusion and Exclusion Criteria.
As of the modification submitted on 6/15/17, we are expanding our inclusion criteria to include Veterans with 
moderate and severe TBI. Expanding inclusion criteria to include Veterans with moderate and severe TBI. 
We are requesting this revision in order to facilitate recruitment. Limiting inclusion to only those Veterans with 
mild traumatic brain injury (TBI) has slowed recruitment.  Too many potential participants have been excluded 
because they have had TBI histories that cross into the moderate or severe TBI range.  
Our original reason for excluding Veterans with moderate or severe TBI history included concerns about the 
possibility of residual medical, psychiatric or cognitive problems of such severity that study participation would 
be judged to be unsafe.  In fact, many Veterans with moderate or severe TBI histories are stable medically, 
psychiatrically, and cognitively, and would be appropriate for safe study participation.
In the judgment of the study investigators, simply having a history of moderate or severe past TBI does not 
necessarily mean that patients have severe or unstable medical, psychiatric, or cognitive problems that would 
make study participation unsafe.


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We therefore request approval for broadening of inclusion criteria to include all Veterans with TBI histories, 
whether mild, moderate or severe.
We propose continuing our present practice -- as per the current study protocol -- of excluding any potential 
participants who, in the opinion of the study physician, have medical, psychiatric, or cognitive problems judges 
to be too unstable or too severe to allow safe participation in the study.
As of the modification submitted on 9/25/17, we are expanding our inclusion criteria to include Veterans 
between the ages of 18 and 69, inclusive. Similar to the revision described above, we are requesting this 
revision in order to facilitate recruitment. 
D.3. STUDY PROCEDURES
D.3.a. Overview of Study Procedures
The study has three phases: screening; 8-week treatment; Week-12 follow-up. The 8-week treatment phase 
will consists of treatment with NAC or placebo plus weekly Medical Management (MM), a manual-driven, low-
intensity supportive program to foster, maintain and promote compliance with study medication and to promote 
continuation in the study, added to whatever usual treatment participants may be receiving (except AUD 
medication). Participants will meet weekly with research staff at the San Francisco VA Medical Center clinics. 
D.3.b. Recruitment
The process for screening for eligibility will commence as soon as all approvals have been obtained from all 
regulatory bodies. 
We will employ many methods to recruit 30 participants that meet inclusion and exclusion criteria.
Previous Participants
Participants that have participated in research studies conducted in the SFVAMC Addiction Research Program 
and who have opted in to be contacted about future research studies will receive a call from study staff. 
Search of SFVAMC Medical Records
Study staff will search the SFVAMC medical records for veterans that have a co-occurring alcohol use disorder 
and a mild traumatic brain injury diagnosis.  A study staff member will contact the care provider of the potential 
participant once identified. The care provider will be asked to inform the potential participant about the study, 
to gauge interest and assess the fit of the veteran for the study.  If, and only if, a veteran expresses interest in 
the study to their care provider, then a member of the research team will initiate contact.  To be clear, a 
potential participant will never be contacted about the study by anyone other than their direct (mental or 
primary) care provider until the potential participant gives verbal consent to be contacted. Providers are asked 
to tag the PI on notes placed in the medical record of Veterans who seem like they would be a good fit for the 
study, have expressed interest in the study and have agreed to a study staff member reaching out to Veteran 
with more information.
Presentations for and Emails Sent to Patient Care Providers: 
Research staff will explain the purpose and scope of the study, including eligibility criteria, to care providers 
and will engage in a continuous process of publicizing the study.  Hospital and clinic staff will be told whom to 
contact to refer a potential study candidate and how to have prospective participants contact study staff. 
Clinicians will receive brochures and/or handouts to pass out to their patients as they see fit.  The primary care 
and mental health providers will also be asked for their assent to any patient entering the study.
Posted Recruitment Materials
Veterans may become aware of the study through posted recruitment materials placed in patient areas of the 
the clinics in the San Francisco VA Medical Center, as well as other VA Medical Centers in the San Francisco 
Bay Area.  Materials will also be posted in the associated Community Based Outpatient Clinics (CBOCs) in 
San Bruno, San Rafael and the San Francisco VA Downtown Clinic.


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Intake Screener
A brief, 3-question screener (See Intake Screener) asking about alcohol use, posttraumatic stress disorder 
(PTSD) diagnosis and the occurrence of a traumatic brain injury (TBI) will be passed out to veterans attending 
intake visits in the mental health and primary care clinics at the San Francisco VA Medical Center and CBOCs. 
Veterans will not be required to fill out the form if they are not interested in the study. If they are interested in 
the study, but do not want to fill out the screener, they may contact study staff directly via phone.  If a veteran 
does complete the Intake Screener, he/she will be asked to place the screener in a sealed envelope and 
return to the front desk at the clinic.  The screener-in-envelope will be placed in the VA inter-office mail folder 
and returned directly to study staff.  Because the Intake Screener contains PHI (Last Name; Last 4 digits of 
social security number; and Phone Number) in addition to sensitive information concerning alcohol use, PTSD 
and TBI, we will follow the VA Directive 6609 and place the screener in an envelope labeled with VA Directive 
6609, Appendix B, to ensure that special attention is given to the contents in the rare chance that it is 
intercepted or lost.  When study staff receives an Intake Screener, it will be stored separately from de-
identified data, in a locked cabinet in a locked room. 
Opt-Out Packet
Packets will be mailed to potential participants identified by a referring clinician or through a medical record 
search. Packets will include an Opt-Out Letter, a Study Information Sheet, and an Opt-Out Postcard. The Opt-
Out Letter will introduce the research study, explain how the PI obtained their name and addresses. The letter 
will provide a general, brief description of the research study and invite the recipient to call the lab manager if 
interested in learning more (see Opt-Out Letter). The opt-out packet will also include an information sheet 
describing the time commitment, compensation and other general details study participation (See Information 
Sheet).  A pre-addressed, stamped postcard will be included in the letter which a patient can return to indicate 
that they do not wish to be contacted for this study (See Opt-Out Postcard).
Study staff will wait to contact potential participants for 2 weeks after the initial mailing to allow them time to 
opt-out if they do not wish to be contacted.  If the team does not receive an "opt-out" postcard at least 14 days 
after the original mailing, then they will attempt to contact the veteran by telephone, but will adhere to strict 
confidentiality.  Staff will speak only to the patient once identified.  If study staff were to reach a non-study 
participant, he/she would state only that they are calling from the SFVAMC and will not disclose any 
information pertaining to the study.  If a patient states that he/she does not wish to be in the study, staff will 
respectfully remove from the call list and never call again. If an opt-out letter is returned to the SFVAMC due to 
an incorrect mailing address, staff will try to make contact via phone.  If staff are unable to reach a patient 
after 3 attempts, efforts will stop. 
Clinical Trial Management Software (CTMS) Database
Study staff will access a pool of shared participants utilizing a password-protected database called Clinical 
Trial Management Software. Individuals in this database have been asked brief screening questions from a 
Program Wide Prescreen, which is described in depth in approved Protocol 12-09158, or from a specific 
study. Recruiters will contact individuals from this database who can decide if they want to answer the study 
specific screen. Informed consent will be obtained by research staff prior to beginning any procedures.
D.3.c. Prescreening
Prospective participants will undergo a brief CPRS pre-screen (see CPRS Screen) and an in-person or 
telephone pre-screen (see Phone Screen) to establish that they are: 18-69 years of age, screen positive for 
TBI, drink at hazardous or harmful levels by NIAAA criteria8 and wish to reduce or stop alcohol use.
D.3.d. Consent
Breath Alcohol Test Prior to Consent
If the breath alcohol test reading is greater than 0.00%, the participant will be asked to return later that day, or 
on another day, to be retested.  
Consenting
After passing the pre-screen, participants will provide written informed consent in compliance with IRB 


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regulations. During the consent process, Veterans are asked to abstain from driving to study visits while 
intoxicated. They are informed that if they do drive and their breath alcohol level is above 0.08, then a clinician 
will assess their safety before they are allowed to leave the SF VA Medical Center.
D.3.e. Screening
After consent, participants will be scheduled for screening assessments. The screening phase is 
accomplished over a total of approximately three to four visits extending over one week.  
D.3.f. Random Assignment
Participants will be randomly assigned, sequentially as they qualify for the study, to either NAC or placebo in a 
1:1 ratio per a computer-generated list provided by a biostatistician. Randomization will be balanced using 
permuted blocks. Participants and investigators will be blinded to assignment. To maintain the blind, sealed 
envelopes containing the study drug identification (e.g. NAC or placebo) will be kept together, in a limited 
access area (the study pharmacist’s office) that will be available to the investigators should the blind need to 
be broken for any individual participant.
D.3.g. Pharmacotherapy
Random assignment will be followed by 8 weeks of treatment with NAC or placebo. Study medications will be 
identical in appearance. Participants will be provided with 10 days of medication at each weekly visit to 
increase the likelihood of medication continuity in case of a missed visit.  Extra medication will be collected 
from participants at each visit. Study medication (NAC or placebo) will be started at a dose of 600 mg bid 
(1200 mg per day), for 3 days, then 1200 mg bid for 4 days, (2400 mg per day), then 1800 mg  bid (3600 mg 
per day) for weeks 2 through 8.  Similar doses have been shown to be an effective dose in other addiction 
studies (see A.2.). If the participant experiences significant side effects during the titration period, the dosage 
may be adjusted as necessary. Patients will be treated with the highest dose tolerated, not to exceed a total of 
3600 mg per day, but may be reduced by 600mg increments as needed. Wellspring Compounding Pharmacy, 
a compounding Pharmacy – a compounding pharmacy recommended by the University of California, San 
Francisco School of Medicine Pharmacy -- will supply NAC study capsules and matching placebo capsules. 
The policies and procedures concerning good compounding practices and environmental, instrumental and 
procedural quality assurance have been approved by the California State Board of Pharmacy. The SFVAMC 
Research Pharmacist will directly receive all study medications from Wellspring Compounding Pharmacy and 
store in appropriate environmental conditions. The dosage is to be determined by a study physician at each 
weekly visit, using the titration schedule as a guide.  An official VA prescription form must be filled out by a 
study physician for each patient at each visit. A research associate will pick up the prescription from the 
SFVAMC pharmacy. The date, time and amount of study compound dispensed will also be recorded in the 
subject’s electronic medical file. Participants are instructed to return all unused study medication weekly. The 
number of returned capsules will be documented.
D.3.h. Medical Management 
We selected a manualized version of the NIAAA Project COMBINE alcohol counseling, “Medical Management” 
(MM)27. This intervention helps increase problem recognition, enhance motivation, and facilitate engagement 
in alcohol treatment. Participants will receive weekly MM sessions for a total of 120-240 minutes consisting of 
8 weekly individual sessions lasting 15-30 minutes each. The goal of MM is to help patients maintain 
adherence with the medication regimen using strategies that can be delivered by a typical health care 
provider.  MM approximates a primary care approach to alcohol dependence and supports the use of 
pharmacotherapy. During the initial visit, the clinician reviews the patient’s assessments, highlighting 
symptoms of alcohol use disorder and the need for treatment. The patient is advised to stop drinking, 
educated about unhealthy alcohol use, provided a rationale for taking the study compound, and instructed on 
the importance of daily medication adherence. The clinician and participant also jointly develop an 
individualized medication-adherence plan; the patient is encouraged to attend support groups and is given 
information on the medications. At follow-up visits, drinking behavior and medication adherence are 
ascertained, and plans for reducing drinking or achieving abstinence are revised as needed.  In each session, 
the MM administrator will communicate and discuss medication effects, participants’ concerns about any side 
effects and compliance barriers with the participant in understandable terms. Training will be provided to the 
research MD, RN and psychologist who will be MM administrators. The PI and his appointees will monitor MM 


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sessions and provide training and guidance to the MM administrators as needed.
D.3.i. Measures and Schedule of Data Collection Overview 
All alcohol, substance use, psychiatric, and medical measures are validated and reliable, and are only briefly 
outlined below due to space limits. Efforts to reduce missing data will include use of: (a) collateral informants 
to assist in locating participants; (b) telephone contact for missing participants; (c) flexible time periods for the 
completion of assessments. 
Measures of Health/Biological Safety 
Baseline blood draw (genetics). Urine pregnancy at baseline, Wks 4 & 8. A participant who becomes pregnant 
during participation in the study will be withdrawn. Vital signs, weight, concomitant medications, suicide risk 
assessment133, adverse events (AEs), and alcohol withdrawal (Clinical Institute Withdrawal Assessment for 
Alcohol, DSM-IV Version (CIWA-AD)134 will be monitored weekly. 
Alcohol and Substance Use Measures
Time-Line Follow-Back (TLFB)135,136 for alcohol and drug use covering the 90 days prior to entry, then at Wks 
1-8, and 12. TLFB will be used to calculate the primary outcome measure, PHDD, and exploratory alcohol 
measures of percent drinking days, drinks per drinking day, etc. Standard drink conversions will be used for 
participant reports of alcohol consumption8. Cigarette and other substance use will also be collected by 
TLFB137. The Intoximeters Alco-Sensor IV instrument will be used for Breath alcohol concentration (BrAC)138 at 
each weekly visit. The following measures will be at baseline, Wks 4, 8 and 12: Obsessive Compulsive 
Drinking Scale (OCDS)139 as an exploratory measure, assesses thoughts and compulsions associated with 
alcohol craving; Urine Drug Screen for opioids, cocaine, cannabis, and methamphetamine at baseline; Ethyl 
Glucuronide (EtG), a direct metabolite of ethanol140 used to provide an exploratory objective biological 
measure alcohol use within the last 80 hours; Gamma Glutamyl Transpeptidase (GGT), a marker for alcohol 
consumption141, will provide a biological measure of heavy alcohol use.
Traumatic Brain Injury Symptoms
Neurobehavioral Symptoms Inventory (NSI)13,14, a measure of postconcussive symptom severity at baseline, 
Wks 4, 8 and 12. 
Psychiatric Diagnosis/Psychological Measures
Baseline: 
•
Structured Clinical Interview for DSM-IV, (SCID-I/P)142: Alcohol and other substance use diagnoses will 
be established using the Substance Use Disorders (SUDs) module of the SCID I/P143. The SCID-I/P is 
the standard SCID-I designed for research participants identified as psychiatric patients.
The following measures will be at baseline, Wks 4, 8 and 12: 
•
The PTSD Checklist (PCL)145, a self-report measure PTSD symptom severity over the prior 30 days
•
Beck Depression Inventory146: provides a measurement of depression severity147
•
Beck Anxiety Inventory (BAI): a measure of anxiety severity148; well suited for monitoring change with 
treatment148
Neurocognitive Assessment
The battery was developed to assess performance in cognitive domains commonly affected by TBI and/or 
alcohol use and contains standardized instruments with good-to-excellent norms administered (~1.5 hours) at 
baseline, Wks 4,8 and 12. Domains and constituent measures: 
•
Risk Taking, Decision-making, and Motor/Choice Impulsivity: Balloon Analogue Risk Task 149-151; Iowa 
Gambling Task152; Stop-signal153, Delayed Discounting154-158
•
Executive Functioning: Stroop Color-Word 159,160, Trail Making B161
•
Verbal Fluency: Controlled Oral Word Association Test162 
•
Processing Speed: Trail Making A161, Stroop Color-Word159,160
•
Working Memory: WAIS-IV Arithmetic and Digit Span163
•
Learning and Memory: 
o
Auditory-verbal: Hopkins Verbal Learning Test (HVLT-R)164 
o
Visuospatial: Brief Visual Memory Test-Revised165,166


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•
Premorbid verbal intelligence: Wechsler Test of Adult Reading167,168 
•
Alcohol Approach Bias: Alcohol Approach Task (AAT)209
Raw scores are converted to z-scores based on norms. Domain-specific summary score will be calculated by 
averaging z-scores of the constituent measures. To minimize practice effects, when feasible, alternate forms 
will be used for repeated administrations.
Statistical Plan and Data Analysis
The proposed study has primary and exploratory outcomes.
Primary Outcome
The Primary hypotheses are that NAC treatment will be more efficacious than placebo in reducing PHDDs and 
TBI symptom severity (NSI). Data analytic technique: Percent Heavy Drinking Days (PHDD): Negative 
binomial regression accommodates over dispersion and derives as an alternative to Poisson regression (most 
natural for analyzing count data). Heavy percent drinking days is often over-dispersed, positively skewed count 
data. Therefore, we will use random-intercept zero-inflated negative binomial model, modeling week (week 1 - 
week 8) as a continuous variable to analyze group differences in PHDD. Neurobehavioral Symptom Inventory 
(NSI):  We will use random-intercept linear mixed models to explore the efficacy for NAC related reduction in 
TBI symptom severity measured by the NSI. Time period will be treated as a repeated effect, with correlations 
between time periods within participants modeled by an unstructured correlation matrix where appropriate. 
Model assumptions will be tested and required modifications will be performed. Both models will included fixed 
effect for week, treatment group (NAC and placebo), and the interaction between treatment group and week. 
Baseline alcohol consumption and NSI means will be used as respective covariates in group comparisons to 
control for pre-study and study enrollment effects. 
Exploratory Outcomes
Our exploratory hypotheses are that NAC treatment will be more efficacious than placebo in reducing other 
measures of alcohol use, producing significant improvement in cognitive performance (see section H.4.e), and 
will be moderated by rs6465084. Data analytic technique: Exploratory hypotheses will be analyzed in a parallel 
fashion, with separate negative binomial models applied to non-normally distributed count data and mixed 
linear models used for the remaining normally distributed outcome measures. Assumptions of each model will 
be tested and any required modifications will be performed. To investigate the potential moderating effect of 
rs6465084, we will use linear mixed models crossing treatment group with a two-level genotype group (A-allele 
vs. non A-allele carriers)110,121, looking for a treatment group-by-genotype interaction on PHDD, and other 
secondary exploratory outcome measures of alcohol use. 
Multiple Comparisons
Adjustment for multiple comparisons will be made for the separate families of primary outcomes (PHDD, NSI, 
cognitive performance) using a modified Bonferroni method169.
Estimates of NAC vs placebo for a larger study of HHAU and TBI. 
We plan to derive a reliable estimate of effect for planning a large RCT from this small controlled pilot study. It 
will be useful to obtain estimates of variability in order to inform future controlled trials of NAC treatment for 
alcohol use. Our sample of n=30, with power of .80 will have the ability to detect an effect size of 
approximately .65 (one-tailed, alpha = .05). This is conventionally considered a medium effect size. To test for 
efficacy, we plan to implement intent-to-treat analyses, therefore including all participants randomized to trial. 
To examine estimates of harm, we will complete Per-Protocol analyses using data from participants exposed 
to study medications. 
Study Limitations/Potential Problems. 


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Recruitment, retention, missing data, and safety issues have been the 
most difficult hurdles facing clinical trials in AUDs. We believe that our 
research team is demonstrating a high level of success in recruiting 
(See Table 5) and retaining similar participants with TBI and HHAU, 
with 81% of participants completing the PI's pilot trial of TOP, a 
medication with a much higher adverse event profile129. Similarly, there 
has been little missing data, with 81% of weekly study visits attended.  
Moreover, the use of a mixed-effects model allows for all available data 
in model estimation.  Finally, human participant safety, although a 
prime concern, is relatively low in the use of NAC170 (See Human 
Subjects Section)
D.3.j. Phlebotomy and Urine Drug Testing
Phlebotomy will be performed at screening, week 4, 8, and 12. Urine drug testing will be performed at 
screening, week 4, week 8, and week 12.
D.3.k. Participant Payment
Participants will be compensated in cash or check for their time, effort and travel costs after each completed 
visit.  The screening visits at baseline will be reimbursed based on the completion of tasks up to $85.  The 
payment schedule for baseline/screening measures and procedures is listed below.  Participants will receive 
$20 for completed visits on Weeks 1, 2, 3, 5, 6, and 7.  The longer visits of Weeks 4 and 8 will be 
compensated at a rate of $35 and the follow-up visit $40.   Participants will also be paid $5 at each study visit 
during weeks 1-8 for returning study medication bottles.  Additionally, if participants attend all 9 study visits, 
they will receive an additional $50 at the follow-up visit. Details regarding compensation are outlined below and 
in the informed consent form.  Participants can therefore earn up to a total of $410 for the full 12-week study 
participation.
If a participant lives outside of the San Francisco city limits and it takes over an hour to get to the SFVAMC, 
then the participant will receive $0.51 per mile (NCIRE travel reimbursement policy).  Mileage will be 
calculated using the Google maps "DIRECTIONS" function, using the participant's home address as the 
starting point and the SFVAMC address as the point of destination.
PAYMENT SCHEDULE FOR BASELINE/SCREENING MEASURES/PROCEDURES
MEASURES/PROCEDURES
AMOUNT
Informed Consent
---
TLFB/Patient Locator
$10
SCID
$5
TBI Evaluation
$10
CTSI
$10
Self-report measures – (21 total)
$20
Neurocog
$20
Med Mgmt
$5
AEs/ConcomMeds/Concom Txt
$5
TOTAL AMOUNT
$85
WEEKLY COMPENSATION SCHEDULE
Week
Attend study visit 
Return MEMS 
cap
Attend all 
study visits
Total per visit
Screening Visits
$85*
 
 
$85
Week 1
$20 
$5
 
$25 
Week 2
$20 
$5
 
$25 
Week 3
$20 
$5
 
$25 
Week 4
$35 
$5
 
$40 
Table 5. PI’s current trial of 
topiramate in HHAU and mTBI
Prescreened
255
Screened (Signed 
Consent)
25
Randomized
17 (53%)
Percent Visits Attended 80.88%
Percent Attended Week 
12
81.25%


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Week 5
$20 
$5
 
$25 
Week 6
$20 
$5
 
$25 
Week 7
$20 
$5
 
$25 
Week 8
$35 
$5
 
$40 
Week 12
$40 
$50
$90
POTENTIAL TOTAL AMOUNT PAID
$405
D.4. MEASURES AND SCHEDULE OF DATA COLLECTION
D.4.a Overview (See Table 1 for Schedule of Measures) 
Efforts will be made toward reducing the amount of missing data by: (a) use of a collateral informant to assist 
in locating patients; (b) telephone follow-up to make contact with missing patients; (c) establishment of flexible, 
but acceptable, time periods for the completion of each assessment; and (d) some self-report and interview 
measures may be administered by telephone to collect missing data from patients unwilling or unable to visit 
research sites to participate in a scheduled assessment session. All phone visits will include a Medical 
Management counseling session, during which a trained psychologist or psychiatrist (the Medical Manager) 
will assess adverse effects, concomitant medications, suicidality and general well-being. During phone visits, 
study coordinators will skip the question on the Adverse Event checklist, “Have you had suicidal thoughts or 
actions since the last study visit”. Instead, the Medical Manager will ask that question and report back to 
coordinator after the Medical Management counseling session. If a Medical Management counseling session 
becomes logistically impossible, the PI will file a protocol violation.
Establishment of flexible, but acceptable time frames for completion of research assessments:  
All research assessments should be completed within an established window.  Assessments scheduled for 
weeks 1, 2,3,5, 6, and 7 will have a window of ±3 days for completion. Assessments scheduled for weeks 4, 8, 
and 12, have a window of ±1 week for completion.  This flexibility will enhance the ability of staff to schedule 
patients for assessments as close as possible to the protocol defined period.  Patients likely to miss 
appointments should be scheduled early in the window to allow for successive attempts to complete ratings 
within the desired time frame.
After receiving CHR and R&D approval, we will be converting most of our questionnaire measures to a digital 
format, so that this questionnaire data can be collected and managed using the San Francisco VA Medical 
Center’s Stress and Health Research Program Data Management Research Database System. 
The Research Database System will include FDA regulated and non-regulated research studies. The SQL 
Server Database Engine is the core service for storing, processing, and securing data within the enterprise.  
Clinical study databases built in sql server also have a data change tracking mechanism,  (i.e. audit trail) 
identifying data changes made by who, when, what changed, and reason for change. 
Electronic data transfer is serviced from a number of external computer applications where data points are 
generated and stored based on a participant interfacing with a computer application.   Implementation of 
process flow allows the transfer of data between the sql server database and a wide variety of data formats.  
Additional safeguards include using user authentication to access data on the research server.  Different user 
profiles allow access to specific tables of the sql server database. For example, investigators and their 
research staff can view and edit data on their own participants only.  Furthermore, unique study identification 
numbers are used to identify participants on data forms and transmitting participant names or other identifying 
information over the internet is not permissible. 
The central system consists of a Dell PowerEdge 2970 mid-range server. Its features include 4GB of RAM and 
storage allocated to provide 72GB for the operating system and 145GB for the data. There are 2 quad-core 
processors installed. For fault tolerance and redundancy the server has five 73GB hard drives.


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Operating system installed with Microsoft Windows Server 2003 R2 and SQL Server 2005 database server for 
processing and housing of clinical data. Microsoft Internet Information Services (IIS) functions as the Web 
Server for intranet use.
For backup and disaster recovery of the system and data, a dedicated Dell PowerVault LTO-3 tape drive is 
employed along with Symantec Backup Exec 2010 R3 as the management software. The LTO-3 system has a 
capacity (per tape) of 400GB native / 800GB compressed.  Backup tape media is encrypted to comply with the 
Federal Encryption Standard, FIPS-140-2 and stored offsite in a secure vault.
The server is located in the SFVAMC Information Research Management Systems (IRMS) server room which 
has 24-hour surveillance, restricted access and resides within the SFVAMC firewall, providing an extra level of 
security. This room has air-conditioning units, and provides battery backup in case of a power failure. The 
server is also kept current with virus protection software and security patches. The server components have 
been validated through a series of installation, qualification and performance protocols.
There are future plans to bring in an additional server machine configured as an application server as well as a 
library tape system.
Study management is further supported by a Clinical Trial Management System (CTMS) application providing 
the ability to track many aspects of a clinical trial.  Study start-up includes numerous administrative and clinical 
activities.  All of these tasks involve tedious, manual process for collecting and aggregating information from 
different data sources.  The CTMS system consolidates these efforts (i.e. reduce duplications and 
inconsistencies) and provide efficiencies and cost savings for the clinical operations. Users also manage 
recruitment outreach activities, track recruitment progress, and search through a pool of potential participants 
for future studies. The system provides real-time and comprehensive study management metrics to support 
the day-to-day business operations. This CTMS system is a commercial off-the shelf product that hooks into 
the research database server for added data integration.
D.4.b. General Measures
D.4.b.1. PATIENT SCREENING LOG
Written informed consent will be obtained prior to screening for study eligibility and completion of baseline 
assessments.  All patients who undergo eligibility screening will be listed on the Patient Screening Log to 
provide information about the number of patients screened. 
D.4.b.2. PATIENT LOCATOR INFORMATION
This form includes information about how to contact the participant.
D.4.b.3 BASELINE ASSESSMENTS 
Measures will be recorded on several forms and will include demographic information (such as age, gender, 
race, and ethnicity), work history, medical history, physical examination, laboratory evaluation DSM-IV 
psychiatric diagnoses, alcohol, substance use, and cigarette smoking history, current medications, and family 
history.
D.4.b.4 ELIGIBILITY FORM
The listing of inclusion and exclusion criteria will serve as a screening format for eligibility which will be 
completed following baseline assessments.
D.4.b.5. MAINTENANCE OF THE BLIND
This questionnaire is administered at Week 12 to assess the  maintenance of participants’ and physicians' 
blindness.  Participants are asked to speculate on their assignment to either topiramate or placebo. Each 
participant’s treating physician is also asked to speculate on the participant’s assignment to topiramate or 
placebo. 
D.4.b.6. STUDY COMPLETION/TERMINATION FORM


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This form is to be administered upon completion of the study (as defined by attending Week 12 visit) or at 
termination to document the last day of study medication ingestion, number of visits attended and/or reasons 
for terminating.
D.4.b.7. PARTICIPANT – END-OF-STUDY QUESTIONNAIRE
This measure is administered at Week 12 to assess the  participant’s opinion of participation and what was 
helpful/useful during treatment.
D.4.c. Measures of Health/Biological Safety
D.4.c.1. OVERVIEW OF HEALTH/BIOLOGICAL SAFETY MEAUSURES 
Safety evaluations will include: entry medical history and physical examination, weekly vital signs monitoring, 
weekly breath alcohol concentration (BrAC), weekly CIWA-AD (clinical alcohol withdrawal assessment), 
weekly monitoring for adverse events, suicide risk assessment at baseline, periodic clinical laboratory tests 
(complete labs including urinalysis at baseline, periodic renal function and liver function tests, and urine 
pregnancy tests performed every 28 days on women of childbearing potential. 
D.4.c.2. MEDICAL HISTORY AND PHYSICAL EXAMINATION
A medical history and physical examination will be completed at baseline during the screening period.  Study 
physicians will screen medical records. This information will be recorded on the physical examination form.  
D.4.c.3. CLINICAL LABORATORY TESTS FOR HEALTH AND SAFETY MONITORING
The following tests will be performed by the San Francisco VAMC clinical laboratory.
Clinical laboratory tests at baseline (Screening phase):
Blood samples will be collected for serum chemistry, liver panel (LFTs), renal panel and complete blood count 
(CBC) and a urine sample will be collected for urinalysis, and, for women – urine pregnancy test. 
If AST or ALT are >5 times the upper limit of the normal range, or if serum bilirubin is >2 times the upper limit 
of normal, these tests will be repeated, and if the repeat tests still exceed these limits, the participant will be 
excluded.
Clinical laboratory tests for health and safety monitoring throughout the study:
Renal and hepatic panels will be repeated at Visits 4 and 8 for all participants.  
D.4.c.4. BIRTH CONTROL/PREGNANCY ASSESSMENT
Birth Control/ Pregnancy Assessment will be done at baseline/screening at weeks 4, 8, and 12. Any participant 
who becomes pregnant during participation in the study will be withdrawn. The results will be recorded on a 
Birth Control/pregnancy Assessment Form.
D.4.c.5. VITAL SIGNS
Vital signs (temperature, heart rate, and blood pressure) will be measured weekly.  Weight will be monitored 
monthly.  The results will be recorded on a Vital Signs Form.
D.4.c.6. CONCOMITANT MEDICATIONS 
All concomitant medications (prescription or over-the-counter medications) taken at the time of screening as 
well as those started during the study will  be documented on a Concomitant Medication Form completed 
weekly.
D.4.c.7. CONCOMITANT TREATMENT
All concomitant treatments for mental health and well-being, with a focus on alcohol and substance use, PTSD 
and TBI will be recorded on a monthly basis.  At screening, participants will be asked to report on the history of 
the mental health treatment.  At weeks 4, 8, and 12 they will be asked to report on any new treatments they 
have started while in the study.  Information will be recorded on the Concomitant Treatment form.


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D.4.c.8. ADVERSE EVENT (AE) MONITORING 
All adverse events that occur between the first study-related procedure and the last study-related procedure 
will be reported. Serious adverse events occurring within 30 days following the last dose of study medication 
will also be handled according to this procedure. Those meeting the definition of serious adverse events will be 
reported using the Serious Adverse Event Form.   Active monitoring of Adverse Events (AEs) will begin as 
soon as a study participant initiates study treatment, and will continue until the end of study for each 
participant.  AEs will be monitored weekly in two ways:
a. An open-ended question will be asked about presence of any AEs weekly (AE Spontaneous).
b. A checklist of expected topiramate-related AEs will be asked of each participant weekly (AE Checklist).
All Adverse Events will be recorded on the appropriate forms.
D.4.d. Alcohol and Substance Use Measures
D.4.d.1. TIMELINE FOLLOWBACK (TLFB)
Alcohol and drug use will be assessed using the Time-Line Follow-Back (TLFB) )135,136.  This is a self-report 
test which will be performed at baseline/screening and will cover the 12 weeks prior to entry, with particular 
attention to the 4 weeks immediately preceding entry to the study.  In addition, the TLFB will be done weekly 
for the preceding 7 days at weeks 1-8, and at week 12.  The TLFB will be used to calculate percent of days 
abstinent from alcohol, drinks per drinking day, and percent heavy drinking days.  The (TLFB) is a method to 
assess the quantity of alcohol consumption on a daily basis. With a calendar as a guide, the participant 
provides a retrospective estimate of daily drinking over a specified period. For this study participants will 
estimate their daily drinking for the 28-day period prior to the initial screening and for the 7-day period prior to 
each weekly visit. The TLFB provides a calendar of the targeted period for recording the number of standard 
drinks consumed on each day. The TLFB can be used to obtain the number of days on which drinking 
occurred and the number of drinks per day. Standard Drink Conversions will be used to standardize all 
participant reports of alcohol consumption 8. 
The following variables will be derived from the standard drinks consumed per day: 1) Percent Days Abstinent 
(the number of non-drinking days divided by the number of study days) 2) Percent Heavy Drinking Days (the 
number of days for which the number of drinks was at least 5 drinks for men and at least 4 drinks for women, 
divided by the number of study days); 3) Drinks/Day (the number of drinks consumed divided by the number of 
study days); and 4) Drinks/Drinking Day. The TLFB will be administered in interview format. It takes 5-10 
minutes to complete the TLFB for a 28-day period. Interviewers require no clinical expertise but some training. 
Prior to reviewing alcohol use, the interviewer will prepare the TLFB calendar outlining the time period to be 
assessed and noting holidays and other general important or newsworthy events that have occurred (e.g., 
Super Bowl Sunday). During Screening and at each weekly visit thereafter, participants will be provided with a 
diary card for recording the number of drinks consumed each day. The diary is intended as a memory aid and 
interviewers should discuss and verify any information collected on the diary and verify if any days without 
entries are actually non-drinking days or drinking occurrences that were not recorded. Differences will be 
discussed with the participant and the site personnel will clarify the number of drinks per day. 
Cigarette (Brown et al. 1998) and other non-alcohol substance use will also be collected using the Timeline 
Followback. Participants are shown the same calendars used for Alcohol TLFB and asked to use recall to 
record the number of cigarettes smoked and days of cannabis, cocaine, opiate, and methamphetamine use. 
Cigarette and other non-alcohol substance use TLFB data will be collected at baseline for the previous 28 day 
time period. Data will also be collected at each subsequent visit for the time since the last visit. Purpose:  To 
calculate the primary outcome measure, PHDD. To assess alcohol use frequency and amount on a daily 
basis, in order to calculate percent of days abstinent from alcohol, drinks per drinking day, and percent heavy 
drinking days and to assess cigarette and other non-alcohol substance use frequency. 
Time required for administration: The initial assessment requires 10-15 minutes; subsequent weekly 
administration takes 5 minutes. Frequency of administration: Baseline and weekly during weeks 1-8 and week 
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D.4.d.2 OBSESSIVE COMPULSIVE DRINKING SCALE (OCDS)  
The Obsessive Compulsive Drinking Scale (OCDS) assesses obsessive thoughts and compulsions associated 
with alcohol craving using a 14-item self-report scale171. The OCDS is a modification of the Yale-Brown 
Obsessive Compulsive Scale (Y-BOCS) and is designed to measure these thought patterns and behaviors in 
heavy drinkers. Each question has five possible answers scored on a scale of 0-4. A higher score indicates a 
greater level of obsessive compulsive drinking. The 14 items will be divided into 4 empirically derived factors172 
The first factor, Drinking Obsessions is composed of 4 variables (items 1-4) that address obsessive thoughts 
related to drinking. The second factor, Alcohol Consumption, consists of 2 items (items 7 and 8) which 
evaluate the quantity and frequency of alcohol consumption. The third factor, Automaticity of Drinking contains 
5 variables (items 5, 6, 12, 13 and 14) which assess the extent to which drinking was controlled or 
uncontrolled. The fourth factor, Interference, is comprised of 3 items (items 9, 10 and 11) which evaluate the 
extent to which drinking interferes with work and social functioning, and the degree to which being prevented 
from drinking is distressing. The same 14 items will also be summed to produce a total score, an Obsessive 
Thoughts subscale score, and a Compulsive Drinking subscale score. It takes approximately 5 minutes to 
complete the OCDS.  Purpose: To provide data for descriptive purposes and a secondary outcome relating to 
drinking and as an exploratory measure that assesses thoughts and compulsions associated with alcohol 
craving. Time required for administration:  5 minutes. Frequency of administration: The OCDS will be 
administered at baseline screening and weeks 4, 8, and 12.
D.4.d.3. BREATH ALCOHOL CONCENTRATION (BrAC)
The breath alcohol concentration (BrAC) will be measured at each session to detect recent alcohol use.  The 
Intoximeters Alco-Sensor IV instrument will be used to measure breath alcohol at each visit to ensure that 
participants are not acutely intoxicated. This instrument is approved by the US Department of Transportation 
for evidential use; it meets and exceeds the federal model specification for traffic enforcement and Omnibus 
Breath Alcohol Testing138.
It must be determined that the participant has a BrAC of 0.00% in order to sign the informed consent. 
At subsequent visits, if the participant’s BrAC is greater than 0.025%,  study clinician will assess whether or 
not the participant may complete the study visit.  The participant may be asked to wait until the breathalyzer 
test is lower, or he/she may be asked to complete the visit at another time.  If the participant is unwilling or 
unable to remain at the site until their BrAC returns to 0.025%, study medication will be dispensed but 
additional study procedures will not be completed. Breath Alcohol Concentration (BrAC) –will be measured 
weekly. Study visits that include neurocognitive testing require complete sobriety (0.00%).  If a participant’s 
BrAC is greater than 0.00% the participant will wait until BrAC returns to normal or complete the visit on 
another day.   Purpose:  To ensure that the participant is sober enough to perform the required study 
activities.  Time required for administration:  1 minute. Frequency of administration:  This test will be 
administered at each weekly visit.
D.4.d.4. URINE DRUG SCREEN (UDS)
Urine Drug Screen (UDS): Urine drug testing for opioids, cocaine, cannabis (THC), and 
amphetamine/methamphetamine at baseline.  The test will be performed by the SF VAMC Clinical Laboratory.
Purpose:  To provide data for descriptive purposes, and provide data for exploratory outcomes on substance 
use other than alcohol.  Time required for administration:  Collecting the urine sample should take less than 5 
minutes.  Analysis may take 1 to 3 days (estimate).  Frequency of administration:  The urine drug screens are 
conductet at baseline screening and weeks 4, 8, and 12.  
D.4.d.5. ETHYL GLUCURONIDE (EtG)
Ethyl Glucuronide (EtG), is a non-volatile, water-soluble, stable, direct metabolite of ethanol that is currently 
used in clinical research for alcohol treatment to detect recent alcohol use, up to approximately 80 hours post 
consumption140.   EtG is considered a sensitive and specific marker that enables detection of small amounts of 
alcohol in cases where neither traditional biological state markers of alcohol intake nor clinical impression gave 
an indication for lapse or relapse173. EtG also validates self-report measures such as TLFB and AUDIT.   
Purpose:  To provide an objective biological measure that detects recent alcohol consumption and verifies 
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sample, packing, storing, and shipping should take less than 15 minutes.  Once 20 samples have been 
collected they will be sent to a remote processing center. Test results 
will be received 1 to 2 weeks from the shipment date (estimate).   Frequency of administration: The EtG will be 
conducted at baseline screening and weekly.  
D.4.d.6. GAMMA GLUTAMYL TRANSPEPTIDASE (GGT)
GGT is currently the most widely used marker for alcohol consumption.  GGT has been found to be elevated 
in patients with chronic heavy alcohol consumption and in a variety of liver conditions unrelated to drinking and 
therefore is not specific to alcohol consumption.  GGT levels generally rise after heavy alcohol intake that has 
continued for several weeks.  50-72% of elevated GGT levels can be explained by excessive alcohol 
consumption (Sillanaukee, 1996).  We will measure GGT on a Vitros 950 with a normal range for males of 15-
73 U/l and for females of 12-43 U/l.   Purpose: To provide an objective biological measure as a secondary 
measure of alcohol use.   Time required for administration: Collecting blood sample should take 5-10 minutes.  
Lab analysis will take 1-3 days.  Frequency of administration: At baseline screening and weeks 4, 8, and 12.
D.4.d.7. PHOSPHATIDYLETHANOL (PEth)
According to a combination of research, analysis demonstrates good efficiency of PEth for detecting chronic 
heavy drinking174. It is considered a mid to long-term alcohol biomarker, and a positive result is an indication of 
alcohol exposure the 2-3 weeks prior to sample collection. During a series of processes, Phosphatidylethanol 
(PEth) accumulates in human red blood cells when the body is exposed to ethanol. Since it is formed only 
when the body is exposed to ethanol it is called a direct alcohol biomarker. The accumulation in red blood cells 
make it easy to test by collecting blood specimens. Purpose: : To provide an objective biological measure as a 
secondary measure of alcohol use the 2-3 weeks prior to the test. Time required for administration: 5 minutes 
Frequency of administration: At Week 12
D.4.d.8. PENN ALCOHOL CRAVING SCALE (PACS)
The Penn Alcohol Craving Scale (PACS) is a self-report measure that is used to assess alcohol craving, 
without directly asking about craving’s aversive quality or incentive properties 175.  Number of items: 5 items. 
Time required for administration: 3 minutes. Frequency of administration: Weeks 0, 4, 8, 12.
 
D.4.d.9. ALCOHOL USE DISORDERS IDENTIFICATION TEST (AUDIT)
The Alcohol Use Disorders Identification Test (AUDIT) has been developed from a six-country WHO 
collaborative project as a screening instrument for hazardous and harmful alcohol consumption.  It covers the 
domains of alcohol consumption, drinking behavior, and alcohol-related problems. It provides a simple method 
of early detection of hazardous and harmful alcohol use in primary health care settings 176. Number of items: 
10 items Time required for administration: 5 minutes Frequency of administration: Weeks 0, 4, 8, 12.
D.4.d.10. SHORT INDEX OF PROBLEMS (SIP 2-R)
The Short Index of Problems is an alternate short version of the 45-item assessment Drinker Inventory of 
Consequences (DrInC). These items were chosen to represent lifetime consequences of alcohol use. 177 
Number of items: 15 items Time required for administration: 5 minutes Frequency of administration: Weeks 0, 
4, 8, 12.
D.4.d.11. CLINICAL INSTITUTE WITHDRAWAL  ASSESSMENT FOR ALCOHOL (CIWA-AD)
The Clinical Institute Withdrawal Assessment for Alcohol is for clinical quantitation of the severity of the 
alcohol withdrawal syndrome.  The scale is administered by trained study staff 178. Number of items: 10 items 
Time required for administration: 3 minutes Frequency of administration: The CIWA will be conducted at 
baseline and at the beginning of every weekly visit.
D.4.d.12. FAMILY TREE QUESTIONNAIRE (FTQ)
This brief, self-report questionnaire is used to assess the family history of drinking problems. The 
questionnaire was designed to provide participants with a consistent set of cues for identifying relatives with 
drinking problems 179. Number of items: At least 6, asked to identify drinking history of maternal and paternal 
grandparents, parents, and brothers and sisters. Time required for administration: 3 minutes Frequency of 
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D.4.d.13. THOUGHTS ABOUT ABSTINENCE (TAA)
The Thoughts About Abstinence is designed to assess the participant’s thoughts related to alcohol. It 
measures the desire to quit, expected success in quitting and estimated difficulty in avoiding relapse. It also 
assesses the participant’s goal for use raning from no goal to complete abstinence for life 180. Number of 
items:4 items Time required for administration: 5 minutes Frequency of administration: Week 0
D.4.d.14. READINESS TO CHANGE RULER (RTC)
The Readiness to Change Ruler is a quick, self-report measure that asks the participant to identify where they 
are on the continuum of motivation readiness to change their drinking behavior 181. Number of items: 1 item. 
Time required for administration: 1 minute Frequency of administration: Week 0
D.4.d.15. SUBJECTIVE HIGH ASSESSMENT SCALE (SHAS)
A self-rated adjective checklist to assess the effects of alcohol on mood and levels of intoxication. The items 
includes questions aobut the positive effects of alcohol and the negative aspects of intoxication 182.  Number of 
items:38 items Time required for administration: 10 minutes Frequency of administration: Weeks 0, 4, 8, 12.
D.4.d.16. ALCOHOL PURCHASE TASK (APT)
The Alcohol Purchase Task presents a scenario and asks participants how many drinks they would purchase 
and consume at different prices.  The measure  aims to assess the relative value of alcohol and measure of 
risk for alcohol problems 183. Number of items 27 items  Time required for administration: 3 minutes Frequency 
of administration: Weeks 0, 4, 8, 12.
D.4.e.TBI Measures
D.4.e.1. NEUROBEHAVIORAL SYMPTOM INVENTORY (NSI)
In accordance with the recommendation of the Review Committee, we are specifying the inclusion of the 
Neurobehavioral Symptom Inventory (NSI) as a measure to quantify symptoms associated with mild traumatic 
brain injury.  The NSI evaluates common complaints associated with mild TBI and post-concussive syndrome. 
The NSI asks patients to rate how much various symptoms have disturbed them in the last two weeks.  While 
it is not a diagnostic test, the constellation of symptoms has been validated for mild TBI, and the NSI is useful 
in developing a clinical profile (Cicerone & Kalmar, 1995; Meterko et al., 2012). Cicerone and Kalmar 
developed this 22-item self-report inventory of symptoms commonly observed among patients with mild TBI.  
The NSI, based on the Cicerone and Kalmar tool, is utilized by the Veterans Administration in the evaluation of 
returning OEF/OIF veterans. The 22 items of the NSI are embedded within the VA's Secondary TBI Evaluation 
that is conducted for all veterans entering the VA who have not been previously diagnosed with TBI, but who 
screen positive for possible TBI.
We will analyze the results to detect both within-group changes in the Topiramate arm of the study as well as 
between-groups differences between the Topiramate and Placebo groups over the course of the study.   
Purpose: To quantify symptoms associated with mild traumatic brain injury.   Time Required for administration: 
5-10 minutes.   Frequency of administration: The NSI will be administered at baseline and weeks 4, 8, and 12.
D.4.f. PTSD Measures
D.4.f.1. PTSD CHECKLIST (PCL)
The PCL (Weathers et al., 1994) is a 17-item self-report questionnaire that prompts informants to endorse
the level of distress that has co-occurred with each reported PTSD symptom over the prior 30 days. A five 
point scale is used for informant responding (1 = not at all, 5 =extremely)185.  The PCL has been demonstrated 
to possess good internal consistency, test-retest reliability, convergent validity, and discriminant validity 
(Ruggiero, 2003).  The short administration time also makes it useful in settings where it might need to be 
administered multiple times.  Purpose:  To assess PTSD symptom severity. Time required for administration:  
Approximately 5 minutes (Ruggiero, 2003).  Frequency of administration:  at baseline screening and weeks 4, 
8, and 12.
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D.4.g.1. STRUCTURED CLINICAL INTERVIEW FOR DSM-IV-TR, PATIENT  EDITION (SCID-I/P)  
Alcohol and other substance use disorder diagnoses will be established by administering the Substance Use 
Disorders (SUDs) diagnostic module of the SCID I/P (First et al., 2001) combined with a review of clinical 
records, information from the primary therapist and/or psychiatrist.  The SCID-I/P is a clinician-administered, 
semi-structured interview for use with psychiatric patients.  The SCID-I/P is the standard SCID-I designed for 
research participants identified as psychiatric patients (Ventura, 1998). The interview begins with an overview 
section that obtains demographic information, work history, chief complaint and past periods of psychiatric 
illness, treatment history, and assessments of current functioning with open ended questions to elicit response 
in the participant’s own words. The interview provides required probe questions and suggested follow-up 
questions. Liberal use of skip-out directions are employed when a participant fails to meet a critical criterion 
required for a particular disorder.  Purpose:  To identify eligible potential participants.  Time required for 
administration:  The SUDs module of the SCID-I/P takes approximately 30 minutes to complete.  Frequency of 
administration:  This test will be administered at the screening visit.
D.4.g.2. BECK DEPRESSION INVENTORY (BDI)
Depression will be measured with the Beck Depression Inventory (Beck et al., 1961). The BDI is a 21-item, 
self-report questionnaire that provides a measurement of depression severity.  Each item is rated on a four-
point scale (absent, mild, moderate, or severe).  It has demonstrated high internal consistency and good 
concurrent validity with other measures of depression (Beck et al, 2000)   Purpose: To assess participant 
depression severity before, during, and after topiramate or placebo treatment.  Time required for 
administration: 5-10 minutes.  Frequency of administration: at baseline screening and weeks 4, 8, and 12.
D.4.g.3. BECK ANXIETY INVENTORY (BAI) 
The BAI is a 21-item self-report questionnaire designed to evaluate symptoms such as nervousness and 
inability to relax using a 4-point likert scale (Beck et al., 1988).  The BAI has been proven to be a reliable and 
well-validated measure of anxiety symptoms and is well suited for monitoring change with treatment (Beck, 
1988).  Purpose:  To assess participant anxiety severity before, during, and after topiramate or placebo 
treatment.  Time required for administration: 5 minutes.  Frequency of administration:  at baseline screening 
and weeks 4, 8, and 12.
D.4.g.4. DIFFICULTIES IN EMOTION REGULATION SCALE (DERS)
The Difficulties in Emotion Regulation Scale (DERS) is a brief, self-report questionnaire designed to assess 
multiple aspects of emotion regulation. The measure yields a total score as well as scores on six scales 
derived through factor analysis: nonacceptance, goals, impulse, awareness, strategies, clarity188. Number of 
items: 36 items Time required for administration: 8 minutes Frequency of administration: Weeks 0, 4, 8, 12.
D.4.g.5. DISTRESS TOLERANCE SCALE (DTS)
The Distress Tolerance Scale is a self-report measure of emotional distress tolerance189. Number of items: 15 
items Time required for administration: 5 minutes Frequency of administration: Weeks 0, 4, 8, 12.
D.4.g.6. INSOMNIA SEVERITY INDEX (ISI)
The Insomnia Severity Index is a brief screening measure of insomnia. Number of items: 7 items Time 
required for administration: 3 minutes Frequency of administration: Weeks 0, 4, 8, 12.
D.4.g.7. PITTSBURGH SLEEP QUALITY INDEX (PSQI)
The Pittsburgh Sleep Quality Index is a self-rated questionnaire which asses sleep quality and disturbances 
over a 1-month time interval 190.  Number of items: 19 items Time required for administration: 5 minutes 
Frequency of administration: Weeks 0, 4, 8, 12.
D.4.g.8. PROFILE OF MOOD STATES (POMS)
The Profile of Mood States instrument is used to assess the mood states of individuals. Scales include anger-
hostility, confusion-bewilderment, depression-dejection, fatigue-inertia, tension-anxiety, vigor-activity, and 
friendliness 191 192.Number of items:65 items Time required for administration: 15 minutes Frequency of 
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D.4.h. Neuropsychological Assessment
The neuropsychological battery tt will be used in this study was developed to assess performance in the 
cognitive domains commonly affected by mild TBI and alcohol abuse. 
The overall battery of neuropsychological tests will take approximately 1.5 hours, with allowances for breaks.
All neuropsychological test data will be scored based on standardized age and when available educational and 
repeated administration norms, and transformed into z scores for consistency.  To assess the impact of 
training on targeted cognitive domains, and reduce the variability and number of multiple comparisons, z 
scores of individual neuropsychological tests will be averaged into the Cognitive Domain Scores. 
To minimize adverse practice affects, whenever feasible, alternative test forms for  repeated testing will be 
used for repeated administrations.
D.4.h.1. DECISION-MAKING ASSESSMENTS
D.4.h.1.a. IOWA GAMBLING TASK (IGT)
The Iowa Gambling Task (IGT)203 is a measure of decision making, considered to be a behavioral 
manifestation of executive functioning.  Participants are presented with 4 decks of cards on a computer screen 
and are told that they can win money by picking cards from the most advantageous deck.  After each deck 
selection, participants are provided feedback as to whether their selection resulted in a “win” or a “loss” and 
the dollar amount of the win/loss.  Its validity has been established in a number of studies examining decision-
making abilities with a variety of populations, including substance users. The test generates a continuous 
score representing the dollar amount that the participant has at the end of the task.   Purpose: To test 
decision-making processes so as to track how it changes over the course of the study and/or examine how it 
relates to topiramate/placebo, alcohol use and mild TBI.  Number of items: Participants will choose a single 
card from 4 decks of cards. This process is repeated approximately 100 times.  Time required for 
administration: 15 to 20 minutes.  Frequency of administration: This test will be administered at baseline 
screening and weeks 4, 8, and 12.
D.4.h.1.b. DELAY DISCOUNTING (DD)
The second behavioral measure of impulsivity will be a delay discounting task of the type used in a number of 
previous experiments (Baker, Johnson, & Bickel, 2003; Bickel et al., 1999; Coffey et al., 2003; Kirby et al., 
1999), using hypothetical rewards.  In this task, participants will be asked to choose between a smaller 
immediate monetary reward and a larger delayed monetary reward. The behavioral principles guiding this task 
suggest that a pattern of choosing more immediate, smaller rewards over delayed, larger rewards indicates 
impulsivity (e.g., choice of $25 today over $100 in one month). Following a study conducted in Bickel’s 
laboratory (Baker et al., 2003), the monetary rewards will be in $2 increments between $2 and $100. Delays 
for the later reward option will be 1 day, 1 week, 1 month, 6 months, 1 year, 5 years, and 25 years. On a 
computer screen, the participant will be shown, one at a time, hypothetical amounts that could be received 
immediately, while the hypothetical $100 reward will be displayed continuously. The “delay duration” will 
indicate the waiting period for the $100 delayed reward. The computer will randomly present each immediate 
reward amount, one at a time and respondents are asked to choose between each immediate reward or the 
delayed $100. Immediate reward amounts will be presented randomly. The computer will calculate the 
indifference point, the point at which delayed and immediate rewards are equally valuable to the participant. 
The same procedure will be repeated for each of the delay periods. Multiple studies have found that 
participants do not respond in a systematically different way to real and hypothetical rewards 193 194. Purpose:  
To measure risk-taking as an exploratory outcome variable.  Time needed:  10 minutes.  Frequency of 
administration: This test will be administered at baseline screening and weeks 4, 8, and 12.
D.4.h.2. RISK-TAKING ASSESSMENTS


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D.4.h.2.a. BALLOON ANALOGUE RISK TASK (BART)
The Balloon Analogue Risk Task (BART; Lejuez et al., 2002, 2003), is a behavioral measure of impulsivity and 
risk taking developed by Carl Lejuez at the University of Maryland, College Park.  Dr. Lejuez’s research has 
shown that riskiness scores on the BART are positively related to self-reports of substance use and health and 
safety risk behaviors (Lejuez et al., 2002). The BART (Lejuez et al., 2002, 2003) was selected for its merits as 
a behavioral indicator of impulsivity and its simple, intuitive interface for lower-functioning participants. The 
BART displays a computer-generated balloon on the monitor of a desktop computer. The participant uses the 
click of a mouse to gradually inflate the balloon. Each click adds 5 cents to a temporary bank, the contents of 
which are not displayed. After each click, the participant has two options, 1) to continue to inflate the balloon at 
the risk of bursting it and losing all of the money from that balloon, or 2) saving the accumulated money to a 
permanent bank. Whenever a balloon bursts or the participant chooses to bank money, he or she starts with a 
new balloon. Participants respond to 30 balloons, each having a different bursting point. With each click, the 
participant must weigh the potential gain of collecting more money against the potential risk of losing all of the 
money accumulated with that balloon. The index of riskiness is based on the average number of clicks across 
balloons. The entire 30-trial task takes approximately 10 minutes to complete. 
The instructions to the participant will be as follows: “Throughout the task, you will be presented with 30 
balloons, one at a time. For each balloon you can click on the button labeled “Press This Button to Pump Up 
the Balloon” to increase the size of the balloon. You will accumulate 5 cents in a temporary bank for each 
pump. You will not be shown the amount you have accumulated in your temporary bank. At any point, you can 
stop pumping up the balloon and click on the button labeled “Collect $$$.” Clicking this button will start you on 
the next balloon and will transfer the accumulated money from your temporary bank to  your permanent bank 
labeled “Total Earned.” The amount you earned in the previous balloon is shown in the box labeled “Last 
Balloon.” It is your choice to determine how much to pump up the balloon, but be aware that at some point the 
balloon will explode. The explosion point varies across balloons, ranging from the first pump to enough pumps 
to make the balloon fill the entire computer screen. If the balloon explodes before you click on “Collect $$$,” 
then you move on to the next balloon and all money in your temporary bank is lost. Exploded balloons do not 
affect the money accumulated in your permanent bank. At the  end of the task, you will receive cash in the 
amount earned in your permanent bank.” (Lejuez, 2002, pp. 78-79).  Purpose: To measure risk-taking as an 
exploratory outcome variable. Number of Items: 30 balloons.  Time needed: The BART can be completed in 
approximately 15 minutes.  Frequency of administration: The BART will be given at baseline screening and 
weeks 4, 8, and 12.
D.4.h.2.b. EVALUATION OF RISKS (EVAR-B)
Used to assess risk-taking propensity in military samples. A series of risk-related statements are presented to 
the participant, who is asked to mark a point along the line that best represents his/her current sentiment for 
each risk-related statement195. Number of items: 24 items Time required for administration: 8 minutes 
Frequency of administration: Weeks 0, 4, 8, 12.
D.4.h.3. COGNITIVE FUNCTIONING ASSESSMENTS
D.4.h.3.a. WAIS-IV DIGIT SPAN
The WAIS-III Digit Span measures a person’s ability to concentrate while manipulating mental mathemateical 
problems 196.  Purpose: To  measure working memory in order to detect neurocognitive deficits that may 
accompany topiramate or placebo use, mild TBI, and alcohol use. Number of items:.  15 items Time required 
for administration: 10-15 minutes Frequency of administration: This test will be administered at baseline 
screening and weeks 4, 8, and 12.
D.4.h.3.b. WAIS-IV ARITHMETIC
The WAIS-III Arithmetic measures a person’s attention, concentration and mental control196.  Purpose: To  
measure working memory in order to detect neurocognitive deficits that may accompany topiramate or 
placebo use, mild TBI, and alcohol use. Number of items: 20 items Time required for administration: 10-13  
minutes Frequency of administration: This test will be administered at baseline screening and weeks 4, 8, and 
12.
D.4.h.3.c. CONTROLLED ORAL WORD ASSOCIATION (COWA):
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attention and executive functioning; specifically, verbal fluency.  During the test the examinee is asked to 
generate words that begin with a specified letter for one minute (phonemic fluency); and to generate words 
that belong to a specified category (semantic fluency)160    Purpose: To measure verbal fluency in order to 
detect neurocognitive deficits that may accompany topiramate or placebo use, mild TBI, and alcohol use.  
Number of items: This test consists of three letter associations as well as two category associations.  Time 
required for administration: 10 minutes.  Frequency of administration: This test will be administered at baseline 
screening and weeks 4, 8, and 12.
D.4.h.3.d. HOPKINS VERBAL LEARNING TEST (HVLT)
Performance on Verbal and Visual Memory tests will be assessed with Hopkins Verbal Learning Test (HVLT-
R)164, requiring participants to learn 12 words after 3 learning trials and to recall them after 25 minutes.
The Hopkins Verbal Learning Test (Brandt, 1991) was developed to briefly assess verbal recall and 
recognition.  It consists of three learning/free-recall trials followed by a yes/no recognition trial 197. Test stimuli 
are 12 words, four from each of three semantic categories. In the recognition trial, the 12 target words are 
interspersed among 12 distractor words.  Six distractor items are high frequency exemplars of the same 
semantic categories as the target words, and six more are from other semantic categories. Because of these 
features the HVLT is well suited to repeated assessments (e.g., drug trials, tracking recovery from traumatic 
head injury or ECT) or where time constraints allow for only a brief assessment of new learning.  The domains 
tested by the Hopkins are verbal recall and recognition (memory).  Test–retest correlations of the HVLT are 
similar to other verbal memory tests, like the Logical Memory subtest of the Wechsler Memory Scale—
Revised and the California Verbal Learning Test 198. Other studies of the HVLT support its alternate form and 
test–retest reliability and its construct and content validity.  The HVLT’s reliability and validity has also been 
demonstrated in patients with head injury, schizophrenia, and dementia (Kuslansky, 2004).   Purpose:  To 
measure verbal memory and recall in order to detect neurocognitive deficits that may accompany topiramate 
or placebo use, mild TBI, and alcohol use.  Number of items:  12 words are shown to participant 3 times 
(learning trial / free recall).  This is followed by a recognition trial (Rasmusson, 1995).  Time needed:  10 
minutes or less (Rasmusson, 1995).  Frequency of administration:  This test will be administered at baseline 
screening and weeks 4, 8, and 12.
D.4.h.3.e. TRAIL MAKING TEST (TMT) PARTS A & B
The Trail Making Test, or TMT, was created as part of the Army Individual Test Battery 199.  Since then it has 
been widely used as an easily administered test of visual conceptual and visuomotor tracking 200.  Since it was 
developed by the U.S. Army, it is in the public domain and can be reproduced without permission.  The test is 
given in two parts, A and B.  The participant is first asked to draw lines connecting consecutively numbered 
circles on one work sheet (Part A), and then they are asked to connect the same number of consecutively 
numbered and lettered circles on a different worksheet, alternating between the two sequences (Part B).  The 
participant is asked to connect the circles as fast as they can, without lifting the pencil from the paper.  Scores 
are based on the amount of time the participant needs to complete the test.  The most common scoring 
method is the one created by Reitan 201 in which the examiner points out errors as they occur, so that the 
participant can complete the test without errors.  Then the score is based on time alone 202.  The domain 
tested by the TMT is tests complex visual scanning with a motor component 203.  Scores on the TMT are 
reliably sensitive to overall intelligence, neurological impairment, and age (Brown, 2006), and the TMT has 
been shown to be effective at discriminating between Vietnam combat veterans with and without PTSD 204.  It 
also has excellent interrater reliability (Brown, 2006).  Purpose:  To measure neurocognitive deficits that may 
accompany topiramate or placebo use, mild TBI, and alcohol use.  Number of items:  Participant connects 25 
encircled numbers in part A, and another 25 encircled numbers in part B.  Time needed:  A cutoff time of 300 
seconds is generally used to discontinue test administration and is therefore the typical maximum score 205. 
Frequency of administration:  Will be administered at baseline screening and weeks 4, 8, and 12.
D.4.h.3.f. WECHSLER TEST OF ADULT READING (WTAR):
Intellectual functions estimate will be assessed at baseline with Wechsler Test of Adult Reading- WTAR: The 
purpose of the WTAR is an estimation of pre-morbid intellectual ability. The examinee is asked to read a list of 
50 words that have a typical grapheme to phoneme translations. Reading recognition is relatively stable in the 
presence of cognitive decline associated with brain injury206.   Purpose: To gain a baseline estimation of 
intellectual functioning in order to examine how it relates to topiramate or placebo, mild TBI, and/or alcohol 
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pronunciations and tallied for a total score of words read correctly.  Time required for administration: 5 to 10 
minutes  Frequency of administration: The test will be administered at baseline screening and weeks 4, 8, and 
12.
D.4.h.4. IMPULSIVITY ASSESSMENTS
D.4.h.4.a STROOP INHIBITION
The Stroop Inhibition160 is another assessment used to measure the performance of complex attention and 
executive functioning; specifically, inhibition of automatic responding.  The Stroop Inhibition (time and error 
score)160  in which words are printed in dissonant ink color, and participants are instructed to name the color of 
the ink instead of the automatic response of reading the word.   Purpose: To measure inhibition of automatic 
responding, an executive functioning task that is thought to be affected by alcohol use and mild TBI.   Number 
of items: There are three, single page forms that participants will be instructed to read from. These sheets 
consists of a Word Page with color words printed in black ink, a Color Page with ‘Xs’ printed in color, and a 
color-Word Page with words from the first page printed in colors from the second page (the color and the word 
do not match).Time required for administration: 5 minutes.  Frequency of administration: This test will be 
administered at baseline screening and weeks 4, 8, and 12.
D.4.h.4.b. STOP-SIGNAL TASK (SST)
The Stop Signal Task is a test designed to provide a measure of an individual’s ability to inhibit an impulse. 
During the test, participants are instructed to respond as fast as they can to symbols such as letters or arrows 
presented on a computer screen. An auditory tone, which indicates to the participant that they are to withhold 
their response, accompanies a portion of these symbols. The tone occurs at various latencies after the 
appearance of the symbol on the computer and is randomized for each participant. 
The SSRT, stop signal reaction time, is an estimation of the time an individual needs to stop their usual 
behavior (Striking a key every time they see the corresponding symbol) in response to the stop signal.
Purpose: To measure the ability of a participant to inhibit thought and action over the course of the study in 
order to examine how inhibition relates to topiramate or placebo, alcohol use and mild TBI.  Time required for 
administration: 20 minutes.  Frequency of administration: This test will be administered at baseline, as well as 
weeks 6, 12, and 16.
D.4.h.4.c. BARRETT IMPULSIVITY SCALE (BIS-11)
Barratt Impulsiveness Scale is a questionnaire designed to assess the personality/behavioral construct of 
impulsiveness 207. It is the most widely cited instrument for the assessment of impulsiveness and has been 
used to advance our understanding of this construct and its relationship to other clinical phenomena. The 
items of the measure describe common impulsive and non-impulsive behaviors and preferences.  The 
measure was created with the vision that impulsivity is a multifaceted construct and this multi-dimensionality is 
reflected in the structure of the measure. Number of items: 30 items Time required for administration: 5 
minutes Frequency of administration: Weeks 0, 4, 8, 12.
D.4.h.5. ALCOHOL APPROACH BIAS ASSESSMENT
D.4.h.5.a. ALCOHOL APPROACH TASK
A non-training version of the Alcohol-AAT will measure automatic approach tendency toward alcohol at 
baseline and Week-4. This differs from our training AABM in that every picture will be presented in both 
formats (push landscape, pull portrait). The task starts with 10 practice trials showing neutral objects, followed 
by 80 test trials. A standardized d-score is calculated which represents differences in reaction time for pushing 
vs. pulling209. Negative values indicate less attentional bias209. Number of items:90 Time required for 
administration: 20 minutes  Frequency of administration: Weeks 0, 4, 8, 12.
D.5. WEEKLY VISIT SCHEDULE
D.5.a. Screening Phase: Prescreening, Consent, Screening and Baseline Assessments
Each participant’s participation in the study begins with the Screening Phase, consisting of approximately 3 
visits over roughly 1 week, during which participants are evaluated for entry into the study. After the participant 


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passes the brief Prescreening Questionnaire (done in person or over the telephone), a consent form will be 
given to the participant to read and an oral explanation of the procedures will be given allowing the participant 
time to ask questions and consider study participation. Once the participant has agreed to participate in the 
study, a signed and dated informed consent will be obtained before any study-related procedures are 
performed. Each participant will be provided a copy of his/her signed and dated informed consent.
PRESCREENING
CPRS Prescreen
Phone Prescreen
CONSENT
Informed Consent
HIPAA
Research Subject’s Bill of Rights
Patient Locator
SCREENING PHASE – BASELINE MEASURES + PROCEDURES
The following baseline measures and procedures will occur during approximately 3 visits over roughly 1 
week and take approximately 4.5 to 7 hours to complete.  
Measures
Eligibility Form
Review of Medical History
TLFB - Timeline Followback
Concurrent Medications Form
Concurrent Treatments Form
AE Spontaneous Form
AE Checklist Form
SCID – Structured Clinical Interview for DSM-5 (Patient Edition)
Demographics 
TBI Evaluation
CIWA – Clinical Institute Withdrawal Assessment for Alcohol, DSM-IV Version (CIWA-AD)
Suicide Risk Assessment
NSI – Neurobehavioral Symptom Inventory
AUDIT – Alcohol Use Disorders Identification Test
SIP-2R – Short Index of Problems
OCDS – Obsessive Compulsive Drinking Scales
PACS – Penn Alcohol Craving Scale
FTQ – Family Tree Questionnaire
TAA – Thoughts About Abstinence
RTC – Readiness to Change Ruler
SHAS – Subjective High Assessment Scale
EVAR-B – Evaluation of Risks Scale
PCL – PTSD Checklist
POMS – Profile of Mood States
BDI-II – Beck Depression Inventory
BAI – Beck Anxiety Inventory
BIS-11 – Barratt Impulsivity Scale
PSQI – Pittsburgh Sleep Quality Index
ISI – Insomnia Severity Index
DERS – Difficulties in Emotion Regulation Scale
DTS – Distress Tolerance Scale
APT – Alcohol Purchase Task
WTAR -  Wechsler Test of Adult Reading
HVLT-R – Hopkins Verbal Learning Test


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TMT A + B – Trail Making Test A & B
WAIS 4 – Arithmetic 
WAIS 4 – Digit Span
Stroop Inhibition
COWA – Controlled Oral Word Association
BART – Balloon Analogue Risk Task 
IGT – Iowa Gambling Task
SST – Stop Signal Task
AAT – Alcohol Approach Task
Medication Dispensing Form
Procedures
Breath Alcohol Concentration (BrAC)
Physical Exam
Clinical Labs – renal panel, hepatic panel and GGT
Ethyl Glucuronide (EtG)
Urine Drug Screen
Blood draw for genetics (optional)
Vitals (Blood pressure, heart rate, temperature)
Weight
Medical Management
Assess birth control method and perform urine pregnancy test (women only)
Review Medical Event Monitoring System (MEMS)
Drug Accountability
Dispense Medication
Following completion of Screening Phase: Lab Manager will review inclusion/exclusion criteria. If eligible, the 
participant will proceed to the Treatment Phase.
Randomization assignment occurs at the end of Screening Phase.
D.5.b. Treatment Phase
TREATMENT PHASE – WEEKS 1, 2, 3, 5, 6, 7, 9, 10, 11
The measures and procedures collected and performed at these visits requires approximately 1 to 1.5 
hours, the shortest amount of time relative to other visits.  
Measures
TLFB – Timeline Followback
Concurrent Medications Form
AE Spontaneous Form
AE Checklist Form
CIWA – Clinical Institute Withdrawal Assessment for Alcohol, DSM-IV Version (CIWA-AD)
Medication Dispensing Form
Procedures
Breath Alcohol Concentration (BrAC)
Ethyl Glucuronide (EtG)
Vitals (Blood pressure, heart rate, temperature)
Weight
Medical Management
Review Medical Event Monitoring System (MEMS)
Drug Accountability
Dispense Medication
TREATMENT PHASE – WEEKS 4, 8
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originally collected at baseline/screening to ensure safety and allow for subsequent points of 
comparison.  These visits are estimated to take between 3 – 3.5 hours to complete.
Measures
TLFB – Timeline Followback
Concurrent Medications Form
Concurrent Treatments Form
AE Spontaneous Form
AE Checklist Form
CIWA – Clinical Institute Withdrawal Assessment for Alcohol, DSM-IV Version (CIWA-AD)
NSI – Neurobehavioral Symptom Inventory
AUDIT – Alcohol Use Disorders Identification Test
SIP-2R – Short Index of Problems
OCDS – Obsessive Compulsive Drinking Scales
PACS – Penn Alcohol Craving Scale
SHAS – Subjective High Assessment Scale
EVAR-B – Evaluation of Risks Scale
POMS – Profile of Mood States
BDI-II – Beck Depression Inventory
BAI – Beck Anxiety Inventory
BIS-11 – Barratt Impulsivity Scale
PSQI – Pittsburgh Sleep Quality Index
ISI – Insomnia Severity Index
DERS – Difficulties in Emotion Regulation Scale
DTS – Distress Tolerance Scale
APT – Alcohol Purchase Task
HVLT-R – Hopkins Verbal Learning Test
TMT A + B – Trail Making Test A & B
WAIS 4 – Arithmetic 
WAIS 4 – Digit Span
Stroop Inhibition
COWA – Controlled Oral Word Association
BART – Balloon Analogue Risk Task 
IGT – Iowa Gambling Task
SST – Stop Signal Task
AAT – Alcohol Approach Task 
Medication Dispensing Form
Procedures
Breath Alcohol Concentration (BrAC)
Clinical Labs – renal panel, hepatic panel and GGT
Ethyl Glucuronide (EtG)
Urine Drug Screen
Vitals (Blood pressure, heart rate, temperature)
Weight
Medical Management
Assess birth control method and perform urine pregnancy test (women only)
Review Medical Event Monitoring System (MEMS)
Drug Accountability
Dispense Medication
D.5.c. Follow-up Phase
FOLLOW-UP PHASE
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Measures
Concurrent Medications Form
Concurrent Treatments Form
AE Spontaneous Form
AE Checklist Form
TLFB – Timeline Followback
Demographics 
CIWA – Clinical Institute Withdrawal Assessment for Alcohol, DSM-IV Version (CIWA-AD)
NSI – Neurobehavioral Symptom Inventory
AUDIT – Alcohol Use Disorders Identification Test
SIP-2R – Short Index of Problems
OCDS – Obsessive Compulsive Drinking Scales
PACS – Penn Alcohol Craving Scale
SHAS – Subjective High Assessment Scale
EVAR-B – Evaluation of Risks Scale
PCL – PTSD Checklist
POMS – Profile of Mood States
BDI-II – Beck Depression Inventory
BAI – Beck Anxiety Inventory
BIS-11 – Barrett Impulsivity Scale
PSQI – Pittsburgh Sleep Quality Index
ISI – Insomnia Severity Index
DERS – Difficulties in Emotion Regulation Scale
DTS – Distress Tolerance Scale
APT – Alcohol Purchase Task
WTAR -  Wechsler Test of Adult Reading
HVLT-R – Hopkins Verbal Learning Test
TMT A + B – Trail Making Test A & B
WAIS 4 – Arithmetic 
WAIS 4 – Digit Span
Stroop Inhibition
COWA – Controlled Oral Word Association
BART – Balloon Analogue Risk Task 
IGT – Iowa Gambling Task
SST – Stop Signal Task
AAT – Alcohol Approach Task
End of Study Completion Questionnaire
Procedures
Breath Alcohol Concentration (BrAC)
Clinical Labs – renal panel, hepatic panel and GGT
Ethyl Glucuronide (EtG)
Urine Drug Screen
Phosphatidylethanol (PEth)
Vitals (Blood pressure, heart rate, temperature)
Weight
Assess birth control method and perform urine pregnancy test (women only)
Drug Accountability
Dispense Medication
D.6. DATA ANALYSIS 
The proposed study has primary, secondary, and exploratory outcomes.  
D.6.a. Primary Outcome Measure


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The primary outcome measure will be the change in number of drinking days from baseline to end of study, 
associated with NAC treatment.
1) Primary Hypothesis 
The Primary hypotheses are that NAC treatment will be more efficacious than placebo in reducing PHDDs and 
TBI symptom severity (NSI).
2) Data Analytic Technique for the Primary Outcome 
Percent Heavy Drinking Days (PHDD): Negative binomial regression accommodates over dispersion and 
derives as an alternative to Poisson regression (most natural for analyzing count data). Heavy percent drinking 
days is often over-dispersed, positively skewed count data. Therefore, we will use random-intercept zero-
inflated negative binomial model, modeling week (week 1 - week 8) as a continuous variable to analyze group 
differences in PHDD. Neurobehavioral Symptom Inventory (NSI):  We will use random-intercept linear mixed 
models to explore the efficacy for NAC related reduction in TBI symptom severity measured by the NSI. Time 
period will be treated as a repeated effect, with correlations between time periods within participants modeled 
by an unstructured correlation matrix where appropriate. Model assumptions will be tested and required 
modifications will be performed. Both models will included fixed effect for week, treatment group (NAC and 
placebo), and the interaction between treatment group and week. Baseline alcohol consumption and NSI 
means will be used as respective covariates in group comparisons to control for pre-study and study 
enrollment effects. 
3) Power Analyses for the Primary Outcome 
We conducted a power analysis on our current pilot study of topiramate treatment of alcohol dependence in 
veterans with PTSD (see Section C.2.b.). For the outcome measure of percent drinking days (PDD), the effect 
size from the pilot data comparing week 12 to baseline within the topiramate group is d = 1.87.  Because the 
proposed project is focused on veterans with TBI who have hazardous as well as harmful alcohol use, rather 
than just harmful use (alcohol dependence), we assume that the participants may start at a lower baseline 
level of DD in the proposed study than in the pilot study.  This may not allow us to show as much improvement 
in the proposed study as in the completed pilot study of PTSD and alcohol dependence.  Therefore, it would 
seem reasonable to target an effect size approximately half of  what we found in our pilot study, i.e. d=0.9.  A 
sample size of 16 for the topiramate arm of our proposed placebo-controlled pilot will allow us to detect a 
within-subjects effect size of d = 0.9, with 80% power at alpha = .05. 
D.6.b. Exploratory outcomes/exploratory hypotheses
1) Exploratory Hypotheses
Our exploratory hypotheses are that NAC treatment will be more efficacious than placebo in reducing other 
measures of alcohol use (see section H.4.b), producing significant improvement in cognitive performance (see 
section H.4.e), and will be moderated by rs6465084. 
2) Data Analytic Technique for the Exploratory Aims
Exploratory hypotheses will be analyzed in a parallel fashion noted in H.5.a., with separate negative binomial 
models applied to non-normally distributed count data and mixed linear models used for the remaining 
normally distributed outcome measures. Assumptions of each model will be tested and any required 
modifications will be performed. To investigate the potential moderating effect of rs6465084, we will use linear 
mixed models crossing treatment group with a two-level genotype group (C-allele vs. non C-allele 
carriers)110,121, looking for a treatment group-by-genotype interaction on PHDD, and other secondary 
exploratory outcome measures of alcohol use.
D.7. TIME SEQUENCE 
The study is expected to last 24 months.  The first 2 months leading up to the start of the project through the 
second month of Year 01 will be devoted to start-up activities including hiring and training the research and 
clinical personnel, establishing the procedures and logistical aspects of conducting the clinical trial in the five 


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sites, obtaining all UCSF IRB, DoD, VA, and other regulatory approvals, and identifying the first study 
participants.  Participant recruitment and randomization will begin in Month 3 of Year 01.  At an average rate of 
about 2 participants per month, recruitment will take approximately 17 months. Delivery of intervention will 
begin in Month 3 of Year 01 and end in Month 19.  The last of the follow-up appointments will be finished by 
the end of Month 23.  In the final month of Year 02, we will concentrate on data cleaning, data analysis and 
preparation presentations and publications.
E. HUMAN PARTICIPANTS RESEARCH CONCERNS
E.1. PROTECTION OF HUMAN PARTICIPANTS 
The PI will be responsible for following adverse event reporting requirements as outlined below in the protocol.  
These responsibilities include reviewing the accuracy and completeness of all adverse events reported; 
compliance with IRB policies for reporting adverse events and serious adverse events; reporting any safety 
issues to the IRB; and closely monitoring research volunteers at each study visit and telephone contact for any 
new Adverse Events (AEs) or Serious Adverse Events (SAEs).
E.1.a. Risks to Participants
E.1.a.1. Sources of Materials
The research material collected from participants includes: a) biological specimens (i.e., blood, urine, and 
breath alcohol samples); b) review of medical and psychiatric records; and c) self-report on medical and 
psychiatric history, alcohol and drug use, and current psychiatric status. The study physician will collect 
information regarding medical and psychiatric history. Research staff trained in phlebotomy and biological 
specimen processing will collect blood, urine, and breath alcohol samples. Trained research staff will conduct 
neuropsychological assessment, administer self-report questionnaires, and conduct semi-structured  
interviews. 
Information regarding specimens and data collected will be recorded on research forms, which will be coded 
with a unique identifying number. A master list linking this unique identifying number with the participant’s 
name will be maintained together with original copies of the consent forms in a locked file cabinet in a locked 
research room. Specimens and data collected during research visits will be used only for the proposed 
research project. Research staff working on this specific project will be the only individuals with access to this 
information with the following exception: if information obtained during the study indicates the possibility of 
danger to the participant or others, the information may be shared with clinical care providers for that 
participant, in order to ensure safety.
E.1.a.2. NAC Medication Risks
Adverse effects:
NAC is generally a safe and tolerable medication that is available in the oral form as a non-prescription dietary 
supplement in many health food stores. Its clinical use by prescription is for a variety of FDA-approved 
indications including acetaminophen overdose, cystic fibrosis. Such use is generally in the intravenous, 
nebulized liquid, or oral liquid forms and is used at much higher doses than those proposed in this project (for 
example as much as 40 grams per day orally for acetaminophen overdose as compared to the 2400 mg per 
day in the proposed study). Adverse effects using the above routes of administration at the high doses utilized 
have included stomatitis, nausea, vomiting, fever, rhinorrhea, drowsiness, clamminess, chest tightness, and 
bronchoconstriction. Clinically overt acetylcysteine induced bronchospasm occurs infrequently. Acquired 
sensitization to acetylcysteine has been reported rarely. Most of the following adverse effects are derived from 
studies employing the intravenous form of NAC, not the oral form that is to be used in the proposed project. 
NAC in its oral form has low toxicity and few known clinically significant adverse effects observed in doses up 
to 8000 mg/day (Arkury, 2007; Hoffer 2013), which covers the dose range to be used in the proposed study.
Frequency of adverse effects170,208:
Common
•
Dermatologic


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o
Pruritus: 1% - 3%
o
Rash: 4% - 5%
o
Urticaria: 6.1%
o
Flushing: 2% - 4%
•
Gastrointestinal
o
Diarrhea: 2% - 7%
o
Vomiting: 9% - 12%
o
Nausea: 2% - 7%
•
Cardiovascular
o
Edema: 1.2% - 1.6%
o
Hypotension: 0.1%
o
Tachycardia: 3% - 5%
•
Immunologic
o
Anaphylactoid reaction: Incidence unclear
•
Other
o
Angioedema: Incidence unclear
E.1.a.2.a Reproductive/Pregnancy risks: 
Pregnancy: Teratogenic Effects: Pregnancy Category B: 
NAC is classified as pregnancy Category B,  “Either animal-reproduction studies have not demonstrated a 
fetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown 
adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 
first trimester (and there is no evidence of a risk in later trimesters).”
Animal studies have generally not shown teratogenic effects. They also have revealed no evidence of impaired 
fertility or harm to the fetus due to acetylcysteine. There are, however, no adequate and well-controlled studies 
in pregnant women. Because animal reproduction studies may not always be predictive of human responses, 
this drug should be used during pregnancy only if clearly needed for clinical care. Therefore pregnant women 
will be excluded from the study.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are 
excreted in human milk, caution should be exercised when acetylcysteine is administered to a nursing woman. 
Therefore nursing women will be excluded from the study.
E.1.a.3. Blood Drawing (Venipuncture) Risks
Participation in the study requires participants to have their blood drawn 3 different times over the course of 8 
weeks.  Having blood drawn may cause pain (common), fainting/passing out (not very often), a bruise where 
the needle goes in (not very often), and infection at the same place (rare).
E.1.a.4. Risk to Privacy/Confidentiality
Participation in the study presents a risk to the participant of loss of privacy and confidentiality regarding 
research material, particularly with respect to potentially embarrassing or harmful personal health information, 
particularly related to mental health and alcohol and substance use. This includes detailed and sensitive 
information regarding alcohol and drug use, and psychiatric symptoms.  For example, urine drug testing will be 
conducted. Potential release of information regarding drug use, in particular, could have serious  implications if 
made known, for example legal ramifications, jeopardizing insurability or employability.  
In order to ensure the safety of the participant and others, information may be shared between research staff 
and the clinical team only under the following circumstances: 1) If in the judgment of the study physician, the 
participant has a psychiatric or medical condition that requires urgent attention to protect the safety of the 
participant or others; and 2) If a participant has missed several study appointments, and research staff needs 
to verify the participant's whereabouts and/or verify the participant's safety.  These above circumstances will 
be clearly outlined in the informed consent form, and be discussed and clarified with prospective participants 
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E.1.a.5. Randomized risks
Participants will be assigned to a treatment program by chance, and the treatment received may prove to be 
less effective or to have more side effects than other available treatments.
E.1.a.6. Risk of relapse or increased alcohol use 
Participants may face the risk of relapse or to increased alcohol use. This risk may be greater if they are 
assigned to receive placebo as compared to NAC, although the exact nature of this risk is unknown.
E.1.b. Adequacy of Protection Against Risks
E.1.b.1. Informed Consent
Participants will be educated of the risks attendant to study participation through the informed consent 
process.
E.1.b.2. Protection Against NAC Medication Risks
To protect against this risk, we will do the following:
a.) Protection Against Adverse Effects
1.
IND: We have informed the FDA and asked for guidance regarding the possible need for an 
IND.
2.
We will provide participants with a complete list of adverse effects and other medication risks at 
the time of obtaining informed consent, and we will also inform participants of the following:
Possible Side Effects While Using This Medicine:
Call your doctor right away if you notice any of these side effects:
-
Allergic reaction: Itching or hives, swelling in your face or hands, swelling or tingling in 
your mouth or throat, chest tightness, trouble breathing
-
Chest pain
-
Facial flushing or rash
-
Swelling in your hands, ankles, or feet
If you notice these less serious side effects, talk with your doctor:
-
Clammy skin
-
Drowsiness
-
Nausea or vomiting
-
Sore mouth
E.1.b.2.a. Protection Against Reproductive/Pregnancy Risks 
To protect against these risks, we will do the following: 
1) Birth Control/ Pregnancy Assessment will be done at baseline/screening, weeks 4, 8, and 12. Any 
participant who becomes pregnant during participation in the study will be withdrawn.  The results will 
be recorded on a Birth Control/Pregnancy Assessment Form. 
2) In the informed consent form, participants are instructed: “You should not become pregnant while on 
this study because NAC may harm the fetus.  Women of  child bearing potential will be asked to use 
birth control. Acceptable methods include condom, spermicide, diaphragm, or not having sex. 
Pregnancy tests will be done monthly throughout your participation in the study to assure that you are 
not pregnant. If you become pregnant during the study, study treatment will be discontinued and one of 
your alternative treatment plans may be implemented. If you are practicing abstinence, you must agree 
to continue abstinence or use an acceptable method of contraception should sexual activity 
commence. 
E.1.b.3. Protection Against Blood Drawing/Venipuncture risks
To protect against this risk, we will do the following:
1) Professionally trained phlebotomists at the SFVAMC Clinical laboratory will perform all phlebotomies. 
E.1.b.4. Protection Against Risks to Privacy/Confidentiality 
To protect against this risk, we will do the following:
1) In the informed consent form, participants are instructed: “Participation in research may involve a loss 


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of privacy, but information about you will be handled as confidentially as possible. If you do not already 
have a medical record at the VA Medical Center, San Francisco, one will be created because of your 
participation in this study.”
2)  HIPAA regulations will be followed throughout this study. 
3)  Several methods will be used to decrease the risk of loss of confidentiality to participants. First, all study 
forms will be labeled with a unique, identifying code number, and maintained in a locked cabinet.  Those that 
contain the names of participants or other identifying information will be stored in a locked cabinet, separate 
from other study forms. Second, research material will not be shared between the research team and clinical 
staff - with the exception of information to be shared only to ensure the safety of the participant and others. 
Third, no names will be used in any published reports about this study. We anticipate that the above 
procedures will be highly effective in decreasing the likelihood of loss of privacy or confidentiality to 
participants in the proposed research project.
E.1.b.5. Protection Against Randomization Risks
To protect against this risk, we will do the following:
1) During the informed consent process, key personnel will explain the definition of randomization and its 
associated risks.
2) In the informed consent form, participants are instructed, “You will be assigned to a treatment program 
by chance, and the treatment you receive may prove to be less effective or to have more side effects 
than other available treatments.”
E.1.b.6.  Protection Against Risk of Relapse or Increased Alcohol Use
To protect against this risk, we will do the following:
1) We will closely monitor alcohol use at each weekly visit.
2) Participants will be withdrawn from the study if, in the opinion of the PI or the DSMB, there is: sustained 
clinically significant worsening in the primary outcome measure of alcohol use, unacceptable adverse 
events judged to be related to study interventions, or any other clinically significant medical, 
psychiatric, or substance use related poor outcome that makes continued study participation unsafe.
E.1.b.7. Reporting Unanticipated Problems  Involving Risk to Participants or Others
All unanticipated problems involving risk to participants or others, serious adverse events related to 
participation in the study and participant deaths related to participation in the study should be promptly 
reported by phone (301-619-2165), by email (hsrrb@det.amedd.army.mil), or by facsimile (301-619-7803) to 
the USAMRMC, Office of Research Protections, Human Research Protection Office.  A complete written 
report will follow the initial notification.  In addition to the methods above, the complete report will be sent to 
the U.S. Army Medical Research and Materiel Command, ATTN: MCMR-ZB-PH, 504 Scott Street, Fort 
Detrick, Maryland 21702-5012.
E.1.c. Adverse Event Reporting
E.1.c.1. Introduction
The PI will be responsible for following adverse event reporting requirements as outlined below in the protocol. 
These responsibilities include reviewing the accuracy and completeness of all adverse events reported; 
compliance with IRB policies for reporting adverse events and serious adverse events; reporting any safety 
issues to the IRB; and closely monitoring research volunteers at each study visit and telephone contact for any 
new Adverse Events (AEs) or Serious Adverse Events (SAEs).
E.1.c.2. Adverse event definition
Adverse Events (AEs) will be collected using the definition of the UCSF IRB and International Conference on 
Harmonization (ICH) for Clinical Safety Data Management (ICH-E2A), according to which an adverse event is 
“any untoward medical occurrence in a patient or clinical investigation participant administered a 
pharmacological product which does not necessarily have to have a causal relationship with this treatment.”  
An AE can therefore be any unfavorable or unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporarily associated with the study intervention. This includes any occurrence that is 
new in onset or aggravated in severity or frequency from the baseline condition, or abnormal results of 


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diagnostic procedures including laboratory test abnormalities. 
E.1.c.3. Serious adverse event definition
Research staff will immediately notify the study physician in the event of a serious adverse event (SAE).  In the 
event of one that is life-threatening or requires hospitalization, the participant's medical status will be 
monitored and the decision of whether to withdraw the participant from the study will be made on an individual 
basis by the study physician based on severity and nature of the medical problem.  For all adverse reactions 
that are serious, life-threatening, or require hospitalization, the principal investigator and research coordinator 
will notify the UCSF IRB and the Federal Drug Administration (FDA) using the standard procedures provided 
by each agency. An FDA adverse reaction form will be completed at that time.
E.1.d. Participant Withdrawal
Participants will be withdrawn from the study if:
-
in the clinical judgment of the investigator, the participant requires acute detoxification from alcohol, 
-
in the clinical judgment of the investigator, the participant’s clinical condition worsens substantially (for 
example, if weekly alcohol use increases 25% or more over baseline) and it is felt to be in the 
participant’s best interest to obtain alternative treatment including, but not limited to, additional 
psychotherapy,  pharmacotherapy, hospitalization, etc. 
-
the participant becomes pregnant. Should a participant become pregnant at any time during the study 
the participant will immediately discontinue study medication. Study medication will not be tapered. 
E.2. DATA AND SAFETY MONITORING
E.2.a. Plan to Monitor Study Progress and Safety: The Data and Safety Monitoring Plan (DSMP)
The DSMP for this project consists of:
-
a Data and Safety Monitoring Board (DSMB)
-
a schedule of DSMB meetings to review study data and events
-
a list of study data and event items to be reviewed by the DSMB
-
procedures for communicating DSMB findings to the UCSF IRB, and other appropriate entities
-
a plan for conducting and reporting interim analysis
-
stopping rules
-
rules for withdrawing study participants from the study interventions
Note: These elements of the DSMP are described below:
E.2.b. The Data and Safety Monitoring Board (DSMB)
The Data and Safety Monitoring Board (DSMB) is a group of 3 physicians who are clinicians as well as clinical 
researchers, and who are not study investigators. They have expertise in the areas of clinical psychiatry, 
clinical psychopharmacology, neurocognitive functioning, traumatic brain injury and substance use disorders. 
The composition of the DSMB is:  Anne Richards, M.D., M.P.H., Staff Psychiatrist, SFVAMC; Steven Lieske, 
M.D., Staff Psychiatrist, SFVAMC; and William Wolfe, M.D., SFVAMC.
The DSMB will meet quarterly to review data reports prepared by the PI regarding the progress of the study 
and will monitor patient enrollment, retention, outcomes, adverse events, and other issues related to patient 
safety. The DSMB will make recommendations to the PI as to whether the study should continue or be 
modified or terminated. The DSMB can consider patient safety or other circumstances as grounds for early 
termination. Any member of the DSMB can ask for a meeting of the group if he/she feels that it is necessary, 
based upon the data.
During the course of the study, reports will be prepared and distributed to the Data and Safety Monitoring 
Board on a quarterly basis. In order for the Data and Safety Monitoring Board to discharge their duties for 
overseeing the study and the rights of the patients, they will receive analyses of the primary outcome 
measures and the important exploratory measures on a quarterly basis. The DSMB will receive reports of 
serious adverse events (SAEs) within 72 hours of their occurrence. DSMB Minutes will be prepared by the 
Study Coordinator within 5 working days after each quarterly DSMB meeting.


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E.2.c. Research Monitor
Anne Richards, MD, MPH, is an Assistant Clinical Professor at UCSF and Staff Psychiatrist at the SFVAMC. 
Her clinical and research interests are in the area of traumatic stress.  Dr. Richards will serve as Research 
Monitor.  At a minimum, the research monitor: (1) may discuss the research protocol with the investigators, 
interview human subjects, and consult with others outside of the study about the research; (2) shall have 
authority to stop a research protocol in progress, remove individual human subjects from a research protocol, 
and take whatever steps are necessary to protect the safety and well-being of human subjects until the UCSF 
CHR can assess the monitor’s report; (3) shall have the responsibility to promptly report their observations and 
findings to the IRB or other designated official.  As Research Monitor, Dr. Richards will review all unanticipated 
problems involving risk to subjects or others, serious adverse events and all subject deaths associated with 
the protocol and provide an unbiased written report of the event.  The medical monitor will comment on the 
outcomes of the event of problem and in case of a serious adverse event or death, comment on the 
relationship to participation in the study.  The Research Monitor will also indicate whether he/she concurs with 
the details of the report provided by the principal investigator.  Reports for events determined by either the 
investigator or medical monitor to be possibly or definitely related to participation and reports of events 
resulting in death will be promptly forwarded to the USAMRMC ORP HRPO. 
E.2.d. Schedule of DSMB Meetings 
The DSMB will meet semi-annually.
E.2.e. List of Study Data and Event Items to be Reviewed by the DSMB 
Data reports prepared by the PI regarding the progress of the study will include patient enrollment, retention, 
analyses of the primary outcome measures (alcohol use, brain injury symptom severity, and cognitive 
performance) and important exploratory outcome measures (other alcohol use measures), adverse events, 
serious adverse events, and other items related to patient safety.  
E.2.f. Procedures for Communicating DSMB Findings to Appropriate Regulatory Bodies 
The PI will communicate DSMB findings in the form of copies of the minutes of each quarterly DSMB meeting, 
within 10 working days following each meeting.  Reports will be sent to the UCSF IRB, and SFVAMC Human 
Research Protection Program (HRPP).
E.2.g. Stopping rules 
The study will be stopped if, in the judgment of the DSMB or the PI, there are sufficient safety concerns that 
arise during the conduct of the study that would indicate that participants are being harmed by study 
interventions. Examples of such safety concerns would be:
-
If, after the first 10 participants (33% of the planned enrollment) have completed their study treatment, the 
interim analysis reveals that more than 50% (i.e. 6 participants) have worsened to a clinically significant 
degree in the primary outcome measure of alcohol use from baseline to study end.
-
Other events that pose unacceptable risks to participants, e.g., multiple SAEs that are judged to be related 
to study interventions
E.2.h. Rules for Withdrawing Study Participants from the Study Interventions 
Participants will be withdrawn from the study if, in the opinion of the DSMB or the PI, there is: sustained 
clinically significant worsening in the primary outcome measure of alcohol use, unacceptable adverse events 
judged to be related to study interventions, or any other clinically significant medical, psychiatric, or substance 
use related poor outcome that makes continued study participation unsafe in the clinical judgment of the PI or 
DSMB members.
E.2.i. Rules for Breaking the Blind 
The blind will be broken for an individual in the study if, in the opinion of the PI or DSMB, there is an emergent 
clinical need to determine whether a participant is receiving NAC or placebo.
E.3. BENEFITS TO TAKING PART IN THE STUDY 
Participants may benefit from the extra physical examination, laboratory tests, and attention to and treatment 


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of alcohol use disorders. In the informed consent form, participants are instructed: “Taking part in this study 
may or may not make your health better. If you are in this study, you may benefit from the physical 
examinations, blood tests, and review of your symptoms. You may respond favorably to the treatment and 
reduce your drinking and brain injury symptoms, but there is no guarantee that this will happen. Others may 
benefit from the overall conclusions drawn from the results of this study.”
E.4. IMPORTANCE OF THE KNOWLEDGE TO BE GAINED 
Hazardous and harmful drinking (HHD) is a critical issue in the treatment of people with TBI.  HHD is much 
more common in this population and can cause much more harm than in the population at large. Existing 
treatments for these patients are inadequate. NAC also shows promise as a potential treatment for TBI related 
symptoms. Validating the efficacy of NAC could result in establishing a new treatment that effects a multi-
pronged reduction in alcohol consumption, TBI severity, and an increase in cognitive performance, all target 
treatment areas of this highly symptomatic and understudied population.
The potential knowledge to be gained in this study is judged to be highly significant. This research seeks to 
expand the knowledge base regarding the effectiveness of NAC in a particularly vulnerable and difficult-to-
treat population - i.e., patients with TBI who drink as hazardous and harmful levels. Because of the low risk 
profile of NAC and the close monitoring afforded by the study design, the level of risk for prospective 
participants is judged to be minimal, and therefore, is considered to be reasonable, in comparison with the 
potential knowledge to be gained.


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ICF_000.pdf: 
Official title: N‐acetylcysteine Treatment of Alcohol Use Disorder in Veterans with TBI 
NCT number: NCT02791945 
Document date: November 01, 2017 


9-25-17
Page 1 of 14 
                             NAC VAT ITN
VA 10-1086
Department of Veterans Affairs
INFORMED CONSENT FORM
Subject Name:  
Date:
Sponsor: Department of Defense/ Institute of Translational Neuroscience
Title of Study:  N-ACETYLCYSTEINE TREATMENT OF ALCOHOL USE DISORDER 
IN VETERANS WITH TBI
Principal Investigator:  Steven L. Batki, MD
San Francisco VAMC
CONSENT TO PARTICIPATE IN RESEARCH
This is a medical research study funded by the Department of Defense via the Institute of Translational 
Neuroscience. The principal investigator is Steven L. Batki, MD from the San Francisco VA Medical 
Center and UCSF Department of Psychiatry. The other researcher is David Pennington, PhD from the 
Addiction Research Program at the San Francisco VA Medical Center and UCSF Department of 
Psychiatry.  One of the study staff, supervised by these researchers, will explain the study to you.
1. What is an Informed Consent?
Medical research studies include only people who choose to take part. You are being asked to be in a 
research study.  The purpose of this form is to give you information about the study. Signing it will give 
your permission to take part in the study. The form describes the purpose, procedures, benefits, risks, 
discomforts and precautions of the study. You should take part in the study only if you want to. You 
may decide to not join the study. If you start the study, you may leave it at any time. There is no penalty 
for leaving and you will not lose any benefits to which you are otherwise entitled. You may decide to 
not join the study without penalty. Some risks of this study are known. Not all possible risks are known.
Please read this form carefully; you can take as much time as you need. This consent form may 
contain words you do not understand. Please ask the study doctor or the study staff to explain words 
or procedures that you do not understand. Please ask as many questions as you need to. The study 
staff or study doctor can explain anything you do not understand. You should not sign this form if your 
questions have not been answered to your satisfaction.
You will be given a copy of this form to take home. You may want to talk with family or friends before 
deciding if you will participate in this study. The decision to join the study is entirely yours to make; 
participating is strictly voluntary
2. Why am I being asked to take part in this study? 
You are being invited to take part in this research study because you have a traumatic brain injury (TBI) 
and because you use alcohol in amounts that may pose a risk to your health. You have indicated a 
desire to stop drinking or reduce the amount of alcohol you drink with a possible long term goal to stop.  
3. Why is this study being done? 
The purpose of this study is to discover how a naturally occurring amino acid, n-acetylcysteine, 
affects a person’s use of alcohol and their TBI symptoms. N-acetylcysteine (NAC) is a compound 
that may have the potential to regulate brain molecules associated with impulse control but this is not yet 
known.
IRB NUMBER: 16-20123
IRB APPROVAL DATE: 11/01/2017
IRB EXPIRATION DATE: 08/09/2018


9-25-17
Page 2 of 14 
                             NAC VAT ITN
VA 10-1086
NAC has been shown to help reduce cocaine use, cannabis use, nicotine use, pathological gambling and 
other habits marked by impulsivity/compulsivity. There is some preliminary evidence that suggests it 
might help reduce alcohol use, too. Additionally, NAC is a neuroprotective (protects the nerves), anti-
inflammatory (reduces inflammation) compound which results in anti-oxidative (protect cells from 
damage) benefits which may also result in improved neurobiological recovery from traumatic brain injury.  
NAC has not been proven safe or helpful by the US Food and Drug Administration (FDA) for your 
conditions. NAC in the injection form has been approved by the FDA to treat acetaminophen overdose 
and cystic fibrosis.  It is being studied in several other illnesses.
This study is being funded by the Department of Defense and the Institute for Translational Neuroscience 
at UCSF.  The investigators in this study do not have any financial interest in the company that 
manufactures n-acetylcysteine (NAC).
4. How many people will take part in this study? 
About 30 veterans will be enrolled in the study. All participants will receive study capsules (NAC or 
inactive substance (Placebo). It is important to know that one-half of the study participants will receive 
the active study capsules (NAC) and the other one-half will receive the inactive study capsules 
(Placebo). You will be randomly assigned to a group, which means that there is a 50/50 chance that you 
will receive the active compound (NAC). Once you are assigned a group at the beginning on the study, 
you will stay in that group for the remainder of the study.  Neither you nor your doctor will choose the 
group you will be in; only the research pharmacist will know to which group you have been assigned.  
You will have an equal chance (50/50) of being placed in either of the two groups.
o
If you are in group 1 you will be given NAC.  

The study will last for 13 weeks.

You will be asked to take NAC every day for the 8 week duration of the main phase.  

You will continue to receive all of your usual treatments for TBI and substance use in addition to 
NAC.
o
If you are in group 2 you will be given Placebo. 

The study will last for 13 weeks.

You will be asked to take the placebo every day for the 8 week duration of the main phase.  

You will continue to receive all of your usual treatments for TBI and substance use in addition to 
the placebo.
5. Are there some people who should not be in this study?
The study doctor or a member of the study staff will talk with you about the requirements to be in this 
study. It is important that you are truthful with them about your history. You should not be in this study 
if you do not meet all the qualifications.
You should not be in this study if:

You are currently receiving NAC or other medication for alcohol dependence, including disulfiram 
(Antabuse), naltrexone (Depade, Revia, or Vivitrol), or acamprosate (Campral).

You are younger than 18 years of age or older than 69 years of age.

You are already in another alcohol treatment study or study involving a medication as a 
treatment. 

You have had a previous allergic reaction to n-acetylcysteine.

For women:  If you are pregnant or breast feeding, you will not be able to participate in this study 
because we do not know how NAC will affect your child. 
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6. How long will I be in the study?
In total, you could be asked to commit approximately 23 to 33 hours of your time over the course of 12 
weeks. 
7. What will happen if I take part in this study?
After completing the screening phase, if you are eligible to participate, you will begin the main phase. 
Over a period of 8 weeks, you will take NAC or Placebo, attend weekly research visits, and receive 
weekly alcohol counseling. 
The study can be divided into the following 3 phases:
Screening Phase: 3-5 visits over approximately 1 week
Main Phase: 8 visits over 8 weeks
Follow-up Phase: 1 visit at week 12, 4 weeks after the end of the Main Phase
a. Screening Phase: 3 visits over approximately 1 week 
To see if you are eligible to participate in the study, the following will take place during the Screening 
Phase. Information will be kept confidential (as detailed later in this Consent Form). 

The study will be discussed with you, and you will be asked to sign this consent form. 

First, a breath alcohol (“breathalyzer”) test will be done. If you have ANY alcohol on your breath 
as measured by the breathalyzer, you will be asked to wait until you have no alcohol on your 
breath or complete your visit at another time.
o
You can also be referred to other treatment if you wish.
o
If you are legally intoxicated, you will be offered transportation home.

You will be asked to provide your contact information, names and phone numbers to be called 
in case you miss a study appointment. Research staff will confirm your personal contact 
information, as well as that of your alternate contact, before you can continue in the study.

Medical History and Physical exam: A study doctor will take your medical history and review 
the medications you use. You will also have a physical examination, all procedures similar to 
those done for regular medical care. 

Medical chart review: Your medical chart will be reviewed by the study doctors.

Blood drawing (venipuncture): You will be asked to give a blood sample for routine laboratory 
tests to check your health. Approximately 3 teaspoons of blood will be drawn by inserting a 
needle into a vein in your arm for these tests. Blood will be taken for routine medical tests, and for 
looking at the possible genetic effects on your response to NAC. The results of these tests are for 
the purpose of this research study only and will be kept strictly confidential.

Genetic Testing: Some of this blood will be used to determine variants of several of your genes 
that may influence the development of alcohol use disorders. We will look at a specific gene, 
called rs6465084, that has been associated with the development of alcohol use disorders and 
investigate their association with NAC treatment if that is the arm of the study to which you are 
assigned. Since the medical and neuropsychological significance of this genotype is not known at 
this time, the results will not be given to you. All blood samples will be kept up to 50 years. If you 
decide later that you do not want your blood samples to be used for future research, you will 
notify the Principal Investigator and any remaining identifiable samples will be destroyed. If you 
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do not want your blood sample used for genetic testing, you will indicate so on the last page of 
this document. Your sample will be stored at a VA, clearly labeled with a numerical code. No 
personally identifiable information will be linked with this sample in any way. Material from your 
sample will be sent for specific genetic testing to a genetics laboratory at UCSF’s facilities. 

You will be asked to give a urine sample. The urine sample will be tested for drug use, 
including illegal drug use and alcohol. 

Women only: If you are a woman of child bearing potential, an additional urine sample will 
be taken for a pregnancy test. Because the effect of NAC upon a fetus is unknown, the 
pregnancy test must be negative for you to continue in the study. Additionally, you may not be 
breastfeeding. Pregnancy tests will be done monthly throughout your participation in the study to 
assure that you are not pregnant.

You will be evaluated for current and previous medical and psychiatric diagnoses.

You will be asked to report your use of alcohol and other substances (cigarettes, marijuana, 
cocaine, etc).

You will be asked to complete questionnaires about your military experience, education, 
work, and other aspects of your life.

You will also be asked questions about the type, frequency, and intensity of your TBI symptoms 
and about feelings of anxiety, depression, and suicidal thoughts.
The procedures and questionnaires listed above will be done over approximately 3 visits of the 
Screening Phase. Each of the 3 Screening visits takes approximately 1 ½ to 2 hours to complete (total 
time, approximately 6 ½ to 9 hours total over the 3 days). 
b. Main Phase – 8 visits over 8 Weeks (Titration and Maintenance Periods) 
After the Screening tests have been reviewed by the study doctor, if you continue to meet the eligibility 
requirements, you will enter the Main Phase of the study. You will be “randomly assigned” to receive 
NAC or Placebo. 
You will be asked to take NAC or Placebo for 8 weeks. The Main Phase is made up of 2 parts: 

Titration Period (1 week) – the number of NAC or Placebo capsules will be gradually increased 
(“titrated”) over the course of the first week. 

Maintenance Period (7 weeks) – the number of NAC or Placebo capsules will remain constant for 
the next 7 weeks. 
b.1 Titration Period (1 week) 
The Titration period of the study is one week. This means that every participant will begin taking the 
study capsules at 1200 mg per day- half of what previous studies have considered the effective dose- for 
3 days, and then continued at a dose of 1200 mg orally twice per day (2400 mg per day) for 4 days. 
 
Capsules will not be packaged in child-resistant bottles but in special research bottles. It is important that 
you follow your study doctor or his/her staff’s instructions on when and how to take the capsules. 
b.2 Maintenance Period (7 weeks) 
Starting at week 2, all participants will take study capsules at a dose of 3600 mg per day. If you 
experience unwanted side effects, the study doctor can lower the dose in 600 mg increments as needed. 
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c. Follow-Up Phase – 1 Visit
One month after your last visit of the main phase, you will return for one follow-up visit.
At each weekly visit and the follow-up visit, the following will take place: 

A breathalyzer test will be performed. If your breathalyzer test is above 0.025%, a study physician 
will assess whether or not you may complete the study visit.  You may be asked to wait until your 
breathalyzer test is lower, or you may be asked to complete your visit at another time.   Visits at 
Weeks 4, 8 and 12 have neurocognitive tests that require that you have no alcohol on your 
breath. This means that at Weeks 4, 8 and 12 if you have ANY alcohol on your breath as 
measured by the breathalyzer, you will be asked to wait until you have no alcohol on your breat h 
or complete your visit at another time.

In addition to the breathalyzer test, at each study visit you will be examined and asked questions 
about possible alcohol withdrawal symptoms. If your symptoms are severe enough, the study 
doctor will examine you further and make a decision about whether you need to go to the 
emergency room and also whether you need to stop your participation in the study. 

Your blood pressure, pulse, and temperature will be recorded. Your weight will be measured 
monthly. 

You will be asked how you are feeling and if you have started taking any new medications since 
your last visit. 

You must return all capsules and bottles whether they are empty, partially filled, or completely 
filled at each visit. Your unused capsules from the previous visit will be collected and counted and 
new capsules will be dispensed at every visit. 

During every visit, you will be asked about drinking and substance use, TBI symptoms, mood, 
and sleep. You will also be asked whether or not you currently feeling suicidal. The number of 
questionnaires will vary from visit to visit. 

If you are a female of childbearing potential, a urine pregnancy test will be performed on a 
monthly basis. The test must be negative to continue in the study. 

You will continue to receive all of your usual medicines and treatments for your medical illnesses 
and TBI. You may also continue all other psychotherapy and counseling for your alcohol use 
disorder. 

At the week 4, 8, and 12 visits a small sample of blood (about 1 teaspoon total) will be taken and 
used for routine medical tests to check your health. At the week 12 visit, 5 drops of blood will be 
collected, using the fingerstick method, to test for drug use. 

The study doctor or research staff will also ask for possible side effects. Your weekly dose of 
study capsules may be adjusted according to your status. 

You will also meet with a member of the study staff for alcohol counseling called “Medical 
Management,” to discuss your questions about the medication and your weekly goals with regard 
to your alcohol treatment. Medical Management is a 8-session, supportive therapy which has 
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been chosen as the counseling manual for this study. It is designed to increase problem 
recognition, enhance motivation to change drinking patterns, and further engage you in alcohol 
treatment. Additionally, it serves to promote medication adherence and track any negative side 
effects you may experience in this study. A Medical Management session lasts about 15 to 30 
minutes and will be administered by a medical professional. 
When you are finished taking the study medication: You may continue any treatments you are 
currently receiving, as well as resume any treatments you are being asked to discontinue due to study 
requirements. 
Study location: All study procedures will be done at the San Francisco VA Medical Center.
Table of Study Visits: The table below shows what will happen during your participation in the study.
Time
What you will do
Screening- 3 to 5 visits
Review consent form with study personnel, ask any questions you may have, and sign the 
form if you agree to participate.
Provide information about your medical history, current and past medication and 
treatments, your demographic information, and emergency contacts we can call.
Receive a physical examination, and measurements of your heart rate, blood 
pressure and body temperature (vitals).
Provide blood (about 3 teaspoons) and urine samples to assess your health. Women will 
be assessed for birth control and tested for pregnancy. Your urine sample will also be 
tested for substance use.
Take tests to determine your levels of decision-making, risk-taking, and impulsivity.
Participate in interviews and complete questionnaires about your drug/alcohol use and TBI 
and other mental health symptoms.
Learn about the study capsules and how to take them on a daily basis, then receive one 
week’s supply of study capsules.
These visits together should take approximately 6.5 to 9 hours to complete
Weeks 1, 2,
and 3
Let us know if your medication or other treatments have changed since we last saw you. 
Review NAC/Placebo intake and any changes you have noticed in the past week. 
Have your breath alcohol concentration and vital signs checked (temperature, heart rate, 
blood pressure). 
Provide a urine sample to be tested for alcohol use. 
Provide information about your sense of well-being and drug/alcohol use in the past week. 
Participate in a brief alcohol counseling session. 
Receive a week’s supply of capsules and return all extra capsules from previous week. 
These visits should each take approx. 1 to 1.5 hours to complete. 
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IRB EXPIRATION DATE: 08/09/2018


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Week 4
Let us know if your medication or other treatments have changed since we last saw you. 
Review NAC/Placebo intake and any changes you have noticed in the past week. 
Have your breath alcohol concentration and vital signs checked (temperature, heart rate, 
blood pressure). 
Provide a blood sample (about 1 teaspoon) to assess your health. 
Provide a urine sample to be tested for substance use. 
Provide information about your drug/alcohol use, TBI symptoms, and sense of well-being. 
Take tests to determine your levels of decision-making, risk-taking, and impulsivity. 
Participate in a brief alcohol counseling session. 
Receive a week’s supply of capsules and return all extra capsules from previous week. 

This visit should take approx. 3.5 to 5 hours to complete. 
Weeks 5,
6, and 7
Let us know if your medication or other treatments have changed since we last saw you. 
Review NAC/Placebo intake and any changes you have noticed in the past week. 
Have your breath alcohol concentration and vital signs checked (temperature, heart rate, 
blood pressure). 
Provide a urine sample to be tested for alcohol use. 
Provide information about your sense of well-being and drug/alcohol use in the past week. 
Participate in a brief alcohol counseling session. 
Receive a week’s supply of capsules and return all extra capsules from previous week. 
These visits should each take approx. 1 to 1.5 hours to complete. 
Week 8
Let us know if your medication or other treatments have changed since we last saw you. 
Review NAC/Placebo intake and any changes you have noticed in the past week. 
Have your breath alcohol concentration and vital signs checked (temperature, heart rate, 
blood pressure). 
Provide a blood sample (up to 3 teaspoons of blood). 
Provide a urine sample to be tested for substance use. 
Provide information about your drug/alcohol use, TBI symptoms, and sense of well-being. 
Take tests to determine your levels of decision-making, risk-taking, and impulsivity. 
Return all extra capsules from previous week. 

This visit should take approx. 3.5 to 5 hours to complete. 
Week 12
Let us know if your medication or other treatments have changed since we last saw you. 
Have your breath alcohol concentration and vital signs checked (temperature, heart rate, 
blood pressure). 
Provide a blood sample by blood draw (about 1 teaspoon) to assess your health. Provide 
5 drops, using the fingerstick method, to test for drug use.
Provide a urine sample to be tested for substance use. 
Provide information about your drug/alcohol use, TBI symptoms, and sense of well-being. 
Take tests to determine your levels of decision-making, risk-taking, and impulsivity. 

This visit should take approx. 3.5 to 5 hours to complete. 
8. Can I stop being in the study?
Yes. You can decide to stop participating in the study at any time. Study participation is entirely 
voluntary. There is no penalty for not participating, and there is no penalty for choosing to leave the study 
after you decide to participate.
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If you decide to leave the study, it is important that you tell the study staff and study doctor. The study 
doctor will tell you if there are any potential risks of leaving the study, and he or she will explain those 
risks to you. 
If you leave the study completely, you may be asked to return to the clinic for tests so that you can leave 
the study safely.
You may be withdrawn from the study at any time even if you do not wish to leave. The study physician 
may decide to withdraw you from the study at any point.  You may be withdrawn from the study for any of 
the following reasons (or other reasons not listed):

You tell the study doctor you do not want to be in the study.

It may be harmful for you to stay in the study.

You need to take or do take a drug or receive medical treatment that is not allowed in the study.

You do not follow study instructions.

You become pregnant.

You are no longer eligible for study participation.

The sponsor or the FDA stops the study for any reason.
It is important to know that you may be withdrawn from the study for other reasons not listed here. 
Please ask the study staff or doctor if you have any questions about something you think might result in 
your withdrawal from the study.  If you are withdrawn from the study, you will be asked to complete an 
end-of-study visit and a final follow-up visit. A physical exam and other tests at this final visit may be 
done to make sure it is safe for you to leave the study.
Please ask study staff or doctors any questions you have about leaving the study.
9. What are my responsibilities as a study participant?
As a participant in this study, your responsibilities are as follows:

Following the instructions given to you by the study staff and study doctor.

Attending all study visits as scheduled. 

Communicating with study staff if you will not be able to attend a study visit as scheduled.

Reporting any side effects, injuries, or other changes in your health to the study doctor.

Reporting all medicines, vitamins, recreational drugs, herbal products, supplements, or over-the-
counter products you use during the study.

Storing your study capsules as directed.

Reporting any lost or stolen study capsules to the study staff as soon as possible.

Bringing any remaining study capsules and the study capsule containers with you to study visits.

Speaking with the study doctor if you decide to stop taking the study capsules.

For women, using contraceptives to prevent pregnancy.
IMPORTANT: We request that you abstain from driving to the VA Medical Center for study visits if you 
have been drinking.  If you do drive and your breath alcohol is above a 0.08, then a clinician will assess 
your safety before you will be allowed to leave. This is a VA protocol established to ensure your safety.
NEW INFORMATION ABOUT THE STUDY DRUG
If important or new information about the study drug (good or bad) is learned while you are in the study, 
you will be told. You will be asked for your consent to continue in the study with the new information. You 
are free to leave the study at any time without penalty. 
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10. What side effects or other risks can I expect from being in the study? 
The study visits and procedures are designed to limit risks to your health and limit your discomfort as 
much as possible. These procedures closely monitor your safety throughout the study.
You may have side effects while in the study.  Everyone taking part in the study will be watched carefully 
for any side effects.  Side effects may be mild or moderate.  
Please report any side effects, illness, or other changes to your health that you notice.  It is important to 
report these changes even if you do not think they are related to the study drug.  If you have any serious 
or long-lasting side effects from the study drugs, the study doctor can remove you from the study.
NAC is not known to have any serious side effects.  Below, we have listed side effects that have been 
known to occur when NAC is administered orally up to 8000 mg. The max dose that you would receive in 
this study is 2400 mg:
Likely (occurs in greater than 20% or 1 out of every 5 people)

There are no known risks that occur in greater than 20% of people who take NAC.
Less Likely (occurs in less than or equal to 20% of people)

Flushing

Itching

Rash

Hives

Nausea

Vomiting

Upset stomach

Bloating

Low blood pressure

Rapid heart rate
Rare but Serious

Allergic reaction that is rapid in onset

Rapid swelling of skin
Randomization Risks: There is a risk that your condition may remain the same or worsen because 
you are getting a placebo or because NAC is not effective.  Participants will be assigned to a 
treatment program by chance, and the treatment received may prove to be less effective or to have 
more side effects than other available treatments.
Risk of Relapse or Increased Alcohol Use: You may face the risk of relapse or to increased alcohol 
use. This risk may be greater if you are assigned to receive Placebo as compared to NAC, although the 
exact nature of this risk is unknown.
Risk of Cessation of Current Alcohol Abuse Medication: You may face a risk if you decide to stop 
your current alcohol abuse medication to enroll in this study. This risk may be greater if you are 
assigned to receive Placebo as compared to NAC, although the exact nature of this risk is unknown.
Risk of Distress/Fatigue due to Psychiatric and Neurocognitive Assessments: Risks related to 
answering questions about your medical/psychiatric history, reporting of drug use, taking part in 
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neurocognitive assessment may include fatigue and distress. You are free to decline to answer any 
questions or to stop the assessments at any time. Neurocognitive assessment, interview sessions, and 
computer training will include breaks. In the event that you appear to be under undue strain, the session 
will be immediately discontinued.
Blood Drawing (Venipuncture) Risks:  Participation in the study requires you to have your blood drawn 
4 different times over the course of 12 weeks.  Having blood drawn may cause pain (common), 
fainting/passing out (not very often), a bruise where the needle goes in (not very often), and infection at 
the same place (rare).
Reproductive Risks: There are no adequate and well-controlled NAC studies in pregnant women. This 
drug should be used during pregnancy only if clearly needed for clinical care. Women of childbearing 
potential will be asked to use at least 2 forms of birth control.  Acceptable methods include condom 
AND spermicide, diaphragm AND spermicide, or not having sex.  
If you are of child-bearing potential, pregnancy tests will be done monthly throughout your participation in 
the study to assure that you are not pregnant.  If you become pregnant during the study, study treatment 
will be discontinued.  If you are practicing abstinence, you must agree to continue abstinence or use an 
acceptable method of birth control, should you become sexually active.
Unknown Risks: You may experience side effects that we do not know about yet. You should call the 
study doctor or research staff if you have any symptoms or reactions.  The researchers will let you know 
if they learn anything that might make you change your mind about participating in the study.  For more 
information about risks and side effects, ask the study doctor.
Contraindicated Medications: The following medications have been reported to have adverse drug-drug 
interactions with NAC and should not be taken while participating in the study – carbamazepine and 
nitroglycerin. 
11. Are there benefits to taking part in the study?  
Taking part in this study may or may not make your health better. You may respond favorably to the 
study capsules and reduce your drinking and TBI symptoms, but there is no guarantee that this will 
happen. Others may benefit from the overall conclusions drawn from the results of this study.
12. What other choices do I have if I do not take part in this study? 
You do not have to be in this study to be treated for traumatic brain injury (TBI) and/or alcohol use 
disorder. You can seek non-research treatment services if that is your choice. You have the right to 
continue with any ongoing treatment as long as it not an exclusion factor for this study. You may also 
choose to participate in another study targeting TBI and/or alcohol use disorders if you decide not to 
participate in this research study.
You can obtain FDA approved medications for alcohol use disorder through the clinical programs at the 
VA, the Addition Recovery Treatment Services (ARTS), as an alternative to study participation, or should 
you wish, after you complete study participation.  You have the option of requesting clinical treatment for 
alcohol use disorder instead of study participation. You also have the opportunity to participate in non-
medication forms of clinical addiction treatment alongside your participation in the study.  You are also 
free to seek treatment outside the context of the SFVAMC. You may also choose to seek no treatment 
for TBI and/or alcohol use disorder.
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13. Will my medical information be kept private?  
Participation in research involves some loss of privacy. We will do our best to make sure that information 
about you is kept confidential, but we cannot guarantee total privacy. Some information from your 
medical records will be collected and used for this study. If you do not have a San Francisco VA Medical 
Center medical record already, one will be created for you by the study staff. 
The information that will be collected includes demographic information (for example: name, address, 
age, date of birth, social security number) and health information (psychiatric information, alcohol and 
drug use, and medical information). By signing this form, you are giving the study staff permission to use 
the information collected about your health (TBI, mental health, alcohol and other substance abuse, and 
other medical information). This authorization to access and use the information will not expire. You have 
the right, at any time, to take back your authorization and end the study staff’s access to your personal 
information.
Every effort will be made to protect the confidential nature of your identifying information by assigning 
you a unique identification code during the study. All information and data collected by the study staff 
during this study will contain this identification code instead of any identifying personal information. This 
identification code will be stored in an electronic database on a password-protected, secure web server 
managed through the SFVAMC. The data manager will download study data from the server that will be 
needed for analysis and store it in a password-protected database, stored on a VA server behind a 
secure VA firewall at the SFAVMC. The written log that connects your identification code to the 
demographic information you give us will be kept in a file separate from the collected data. This log will 
have restricted access and will be stored in locked cabinets when not in use. Any data sent via email 
messages or delivery service will be encrypted and password-protected.
Your doctors and other providers in the VA health care system may become aware of your study 
participation. Hospital regulations require that all health care providers treat information in medical 
records confidentially. Also, people involved with your future care and insurance may become aware of 
your participation in the study and of any study-related information added to your medical record. 
Progress notes related to your participation in this study indicate that you have been in enrolled in a 
research study, any details that affect your clinical care, and the name and contact information for the 
investigator conducting the study. Details like urine drug test results, the study name or number will not 
be included in the progress notes. 
Study tests that are performed by non-VA research labs and information gathered directly from you by 
the study staff will be part of your research study records but will not be added to your medical record. 
Your personal information may be given out if required by law. If information from this study is published 
or presented at scientific meetings, your name and other personal information will not be used. 
There are a number of regulatory organizations that may look at and/or copy your research and medical 
records for research, quality assurance, and data analysis. These organizations include:

Members of the study’s Data and Safety and Monitoring Board and Medical Monitor

University of California

University of California, San Francisco Institutional Review Board (UCSF IRB)

The Food and Drug Administration (FDA)

Department of Defense (DoD)

Representatives of the U.S. Army Medical Research and Material Command

Department of Veterans Affairs 

Institute for Translational Neuroscience (ITN)
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
Office for Human Research Protections (OHRP)

Research Advisory Panel of California (RAPC)
Complete confidentiality cannot be promised, particularly for active military personnel, because 
information bearing on your health may be required to be reported to appropriate medical or command 
authorities. In this study, you will be asked questions about illegal drug use and your urine will be tested 
for illegal drugs. The researchers will keep information about you as confidential as possible, but 
complete confidentiality cannot be guaranteed. On rare occasions, research records have been 
subpoenaed by a court. 
14. What are the costs of taking part in this study? 
There will be no direct cost to you if you take part in this study. The study will pay for the study capsules 
and study procedures (for example: blood tests). Study participation will be free to you. You may need to 
pay an indirect cost of transportation to the San Francisco VA Medical Center in order to complete study 
visits. 
15. Will I be paid for taking part in this study?
You will be paid for completed study visits only via cash or check. (Please note that if you choose to be 
paid via check, you will need to provide your home address and social security number in order to 
receive payment.) You will be paid immediately after completing each study visit. You will not be paid for 
any missed visits. If you complete all study visits and procedures, you will be paid as follows:
Week
Attend study visit 
Return MEMS 
cap
Attend all 
study visits
Total per visit
Screening Visits
$85*
 
 
$85
Week 1
$20 
$5
 
$25 
Week 2
$20 
$5
 
$25 
Week 3
$20 
$5
 
$25 
Week 4
$35 
$5
 
$40 
Week 5
$20 
$5
 
$25 
Week 6
$20 
$5
 
$25 
Week 7
$20 
$5
 
$25 
Week 8
$35 
$5
 
$40 
Week 12
$40 
$50
$90
POTENTIAL TOTAL AMOUNT PAID
$405
*Payment for screening visits depends on the completion of tasks at each visit. You will earn up to $85 
total if you complete all screening measures. 
You will also be compensated an additional $5 at each study visit during weeks 1-8 for returning your 
medication cap and bottle. If you attend and complete all possible study visits, you will receive an end-of-
study bonus in the amount of $50. If you attend all possible study visits, return the medication cap 
and bottle each week, and receive the end-of-study bonus, you will receive the maximum 
possible payment of $405.
IRB NUMBER: 16-20123
IRB APPROVAL DATE: 11/01/2017
IRB EXPIRATION DATE: 08/09/2018


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16. What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, Dr. Batki, if you feel that you have been injured because of 
taking part in this study.  You can tell Dr. Batki in person or call him at 415-221-4810, ext. 23671.  In the 
case of an emergency, Dr. Batki can be reached 24 hours a day by pager at 415-313-6537. 
Treatment and Compensation for Injury:  If you are injured as a result of being in this study, VA will 
ensure that treatment is made available at a VA medical facility.  If you are eligible for veteran’s benefits, 
the costs of such treatment will be covered by the Department of Veterans Affairs.  If you are not eligible 
for veteran’s benefits, the costs of treatment may be billed to you or your insurer just like any other 
medical costs, or covered by the Department of Veterans’ Affairs or the University of California, 
depending on a number of factors.  The Department of Veterans Affairs and the University do not 
normally provide any other form of compensation for injury.  For further information about this, call the VA 
Regional Counsel at (415) 750-2288 or the office of the UCSF Committee on Human Research at (415) 
476-1814.
17. Clinical Trial Registry Data Bank 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by U.S. 
Law. This web site will not include information that can identify you. At most, the web site will include a 
summary of the results. You can search this web site at any time.
18. What are my rights if I take part in this study?
Taking part in this study is your choice. You may choose either to take part or not to take part in the 
study. If you decide to take part in this study, you may leave the study at any time. No matter what 
decision you make, there will be no penalty to you and you will not lose any of your regular benefits. 
Leaving the study will not affect your medical care.  You can still get your medical care from the 
Department of Veterans Affairs health care system.
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.
19. Who can answer my questions about the study?
You can talk to your study doctor about any questions or concerns you have about this study.  At San 
Francisco VA, please contact your study doctor Steven L. Batki, M.D. at 415-221-4810, ext 23671 or 
page him at 415-313-6537.
For questions about your rights while taking part in this study, call the office of the Committee on 
Human Research, UCSF's Institutional Review Board (a group of people who review the research to 
protect your rights) at 415-476-1814. 
IRB NUMBER: 16-20123
IRB APPROVAL DATE: 11/01/2017
IRB EXPIRATION DATE: 08/09/2018


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CONSENT OF RESEARCH PARTICIPANT
You have been given copies of this consent form and the Experimental Participant’s Bill of Rights to 
keep.
You will be asked to sign a separate form authorizing access, use, creation, or disclosure of health 
information about you.
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to 
participate or to withdraw at any point in this study without penalty or loss of benefits to which 
you are otherwise entitled.
Optional Procedures: Please indicate if you agree to participate in the following optional 
procedure by placing your initials on one of the lines below
-------------------------------------------------------------------------------------------------------------------------------------
________I agree to be contacted after this study is done and/or to be asked to be in other studies.
________I do not agree to be contacted after this study is done or to be asked to be in other studies.
----------------------------------------------------------------------------------------------------------------------------------------
________I do want my blood to be used for genetic testing.
________I do not want my blood to be used for genetic testing.
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If you wish to participate in this study, you should sign below.
Signature of Participant
Date
Printed Name of Participant
Signature of Person Obtaining Consent
Date
Printed Name of Person Obtaining Consent
IRB NUMBER: 16-20123
IRB APPROVAL DATE: 11/01/2017
IRB EXPIRATION DATE: 08/09/2018