Zonisamide Treatment of Alcohol Use Disorder: an Evaluation of Efficacy and Mechanism of Action
Phase: PHASE3
Conditions: Alcohol Use Disorder
Sponsor: Virginia Commonwealth University

 
 
Title: Zonisamide Treatment of Alcohol Use Disorder: an Evaluation of Efficacy and Mechanism of Action 
 
NCT #: NCT02900352 
 
Document date: June 5, 2020 
 
Document Type: Protocol and Statistical Analysis Plan 
 
 
 

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1.  Principal Investigator: Albert Arias, M.D., M.S.  
 
2. Project Title: 
 “Zonisamide treatment of Alcohol Use Disorder: an evaluation of efficacy and 
mechanism of action” 
 
3.  Purpose, hypothesis and key questions 
 
Purpose: To comprehensively evaluate the efficacy of an anticonvulsant medication 
zonisamide (ZNS) for the treatment of alcohol dependence in civilians. We want to see if the 
medication works to reduce harmful drinking patterns, and try to determine whether medication 
response can be predicted by a few key factors such as genotype, the age of onset of 
alcoholism (early vs. late), or stress-reactivity. This protocol also contains translational sub-
studies that will help elucidate the mechanism of action of the medication and determine subject 
characteristics that predict preferential response.  
 
SPECIFIC AIMS: Zonisamide (ZNS) is an anticonvulsant medication for which evidence of 
efficacy in treating alcohol use disorders (AUDs) was obtained in two small placebo-controlled 
pilot studies. We propose to 1) add a civilian arm (N=160) to complement the existing 
VA/CSR&D study comparing ZNS to placebo over 16 weeks of treatment; 2) add important 
mechanistic and translational components to both trials (potential N=320) to elucidate the 
mechanism of action of ZNS and enhance our understanding of how anticonvulsant treatments 
reduce drinking. Importantly, there is no overlap between the VA/CSR&D funding, and the 
proposed NIH funding. So we will evaluate efficacy, safety, and mechanism of action of 
zonisamide in treating alcoholism.  
Specific Aim 1) To evaluate fully the efficacy of and scope of effectiveness for ZNS in treating 
AUDs by adding a civilian arm (N=160 randomized, 80 on ZNS and 80 on placebo) to the 
CSR&D-funded study in veterans, using the same primary outcome (drinks per week) and 
secondary measures of drinking behavior as the veteran arm [i.e., heavy drinking days/week, 
percentage of subjects with no heavy drinking days (PSNHDD), craving, reductions in GGT]. 
Subjects will meet criteria for an AUD (DSM-5) and be heavy drinkers similar to the participants 
in the VA study. We hypothesize that ZNS will produce a significantly greater reduction in drinks 
per week than placebo (primary outcome alpha = .05). We also hypothesize that ZNS will 
significantly improve secondary measures of drinking (corrected for multiple comparisons). We 
will recruit civilians from the University of Connecticut Health Center (UCHC) and VCU’s 
Institute for Drug and Alcohol Studies (IDAS) 
Specific Aim 2) To use telephone-based daily process data collection to elucidate the 
mechanism of action of ZNS as it relates to changes in craving, anxiety, and genetic variation. 
This method has been shown to elucidate the mechanism of action of topiramate, as well as its 
pharmacogenetic interactions. We hypothesize that ZNS’ effects will be moderated by genetic 
variation, craving, and anxiety, but mediated through changes in self-efficacy to reduce heavy 
drinking.  
Exploratory Aim 1) To study genetic variation as a predictor of treatment response to ZNS 
using a convergent functional pharmacogenomics approach. This will be based largely on 
information gleaned from genomic analysis that has already been performed, although we will 
also perform a meta-analysis on data and samples on hand from previous clinical trials that are 
already completed. Those samples from previous studies will be genotyped using genome-wide 
assay, and merged with de-identified clinical trial data, consisting of items such as responses to 
assessments, demographics and other data collected during study visits (See section 6.E 
through 6.K for information on study visits) which may be pertinent to the overall study (all data 
and samples are de-identified) at Yale University. That data will be analyzed (in de-identified 
fashion) at both VCU and at Yale. VCU will host their own version of REDCap which may be 
used to store the data. Those findings will be used to generate methods of predicting outcomes 
and medication response in the ZNS trial data. All the ZNS trial subjects will be genotyped with 

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a genome-wide assay. We hypothesize that we can predict the response to medication based 
largely on a genetic risk prediction score (GRPS) generated from an empirically derived set of 
polymorphisms in genes known to be involved in the pathophysiology of AUDs and a stress-
reactive endophenotype. We hypothesize that the ZNS treatment effect compared with placebo 
will be greater for subjects with higher GRPS in terms of reduced drinking. We will develop and 
refine this method in an available discovery samples from clinical trials of AUD via meta-
analysis before testing it in the ZNS samples.  
Exploratory Aim 2) To compare ZNS and placebo-treated subjects on pre- and post-treatment 
changes in measures of stress-reactivity (i.e., stress-induced anxiety, alcohol craving, 
autonomic nervous system activity), cue-elicited craving, and impulsivity. We hypothesize that 
ZNS will attenuate stress-reactivity, cue-elicited craving, and impulsivity more than placebo in a 
stress laboratory paradigm, and that attenuation of those measures will be associated with 
reduction in drinking. 
4.  BACKGROUND: 
4. A.  Alcohol Use Disorders Background. 
 
Alcohol use disorders (AUDs) continue to be highly prevalent in the U.S. (lifetime prevalence 
estimated to be >30% in the U.S. general population, and >40% in military veterans) and have a 
large detrimental impact on society [[1-3], also unpublished data from the VA National Center for 
PTSD]. Because the FDA-approved medication treatments for alcoholism (naltrexone, 
acamprosate, disulfiram) have modest effects, there is a need for more efficacious 
pharmacologic treatments [4]. Anticonvulsants have shown evidence of efficacy in treating 
alcoholism. Zonisamide (ZNS) is an anticonvulsant and a promising potential treatment for 
AUDs.  ZNS appears to have a number of advantages over existing pharmacologic treatments 
for alcohol dependence (AD), which include its easy once-a-day dosing and simple titration 
schedule, a favorable side effect profile, and efficacy in reducing weight/overeating. ZNS 
reduces anxiety and craving in patients with AUD. 
 
4.A.1. Further study of ZNS advances the development of pharmacologic treatments for 
AUDs: Despite a recommendation from the NIAAA to offer medication as a first line treatment 
for AUDs, their use has not been widely adopted by physicians. Many people with an AUD that 
might benefit from a pharmacologic treatment never receive it [5, 6]. A study of barriers to the 
use of medications found that side effects were thought to present a significant barrier to use, 
based not only on patients’ reports, but the reports of physicians [6]. ZNS appears to be better 
tolerated than some other available treatments for reducing drinking such as disulfiram or 
topiramate. ZNS’s beneficial effects on weight and overeating behavior offer an additional 
incentive to many patients to use the medication, and may facilitate adherence compared to that 
with naltrexone (NTX) or gabapentin [7, 8]. The study by Mark et al. [6] showed that a perceived 
lack of research into medication efficacy was a barrier to medication use in practice. Thus, there 
is a great need for research evaluating the efficacy of new medications. The research proposed 
here will help to address that need by testing ZNS’s efficacy in a well-powered study of regularly 
heavy drinking subjects with DSM-5 AUD.  
4.A.2. ZNS to treat AUD/The Pharmacology of ZNS: 
4.A.2.a. Treating AUDs with Anticonvulsants:   
The potential utility of anticonvulsants to reduce the risk or severity of relapse was 
demonstrated initially in studies by Mueller et al. [9] and by Brady et al. [10] showing some 
benefits compared to PLC treatment. Johnson et al. [11] demonstrated the efficacy of 
topiramate for AD in a double blind, randomized, placebo-controlled trial. In a follow-up, larger 
(N=371), multi-center, randomized placebo-controlled trial, topiramate was again found superior 
to PLC with a moderate effect size [12]. A more conservative analysis of the topiramate data, 
which assumed a return to baseline drinking levels for dropouts, reduced the effect on heavy 
drinking by about half. Critics have brought attention to the frequency and severity of side 
effects from topiramate, which limit its effectiveness [12-14]. A recent study showed a moderate 
dose of topiramate to be fairly well tolerated and efficacious [15]. A placebo-controlled trial of 

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gabapentin in patients with AD showed significant benefit with the medication, although the 
dropout rate was high [16].  
4.A.2.b. The Rationale For ZNS Treatment Of AUDs: 
ZNS is FDA approved for the adjunctive treatment of partial seizures in adults with epilepsy, 
and widely available as a cheap generic medication. Strong support is available from animal 
models for the use of ZNS to treat AUDs. Rats chronically administered topiramate or ZNS 
showed reduced consumption of an ethanol-sucrose solution [17]. Four small clinical trials have 
examined ZNS effects on alcohol consumption in humans, one of which was the placebo-
controlled pilot study that we recently completed showing significantly greater improvement 
with ZNS [18]. Two other clinical trials were open-label [19, 20] and reported findings that 
agreed with those of our placebo-controlled trial by showing reduced drinking and craving with 
the medication, plus a favorable safety profile. A small human clinical study of alcohol self-
administration and a one-time dose of ZNS in risky drinkers showed a reduction in craving and 
in the amount of alcohol consumed with ZNS compared to PLC [21]. A trial comparing ZNS to 
diazepam in treating the alcohol withdrawal syndrome found ZNS more effective, and ZNS 
treated subjects had less craving, less anxiety, and less sedation [22]. In these studies, ZNS 
was well tolerated, and few participants dropped out.  
Most recently, a small (n=19 subjects on ZNS) placebo-controlled study of ZNS for AUDs 
was completed at Boston University as part of a larger trial comparing levitiracetam, topiramate, 
ZNS, and PLC [23]. In this 16-week study, ZNS 400mg daily was found to significantly reduce 
percent drinking and percent heavy drinking days more than PLC, with effect sizes similar to 
topiramate. In general, side effects were less with ZNS than topiramate. ZNS was well tolerated 
in that study with some caveats. ZNS did have some cognitive side effects, though not across 
as many domains as topiramate, and to a lesser extent. One subject on topiramate developed 
metabolic acidosis, and none in the ZNS group did. 17% of topiramate subjects reported 
paresthesias, though none of the ZNS subjects did. One serious adverse reaction (suicide 
attempt) was reported in the ZNS group, though it was rated as “only remotely related to ZNS”. 
Anticonvulsants as a class are thought to carry an increased risk of suicidal ideation and 
behavior. The observed benefits of ZNS as a treatment for AUD suggest it should be studied 
further.  
4.A.2.c. ZNS Acts On The Major Neurotransmitter Pathways Involved In Alcoholism:  
ZNS has a unique and multifaceted pharmacological profile causing facilitation of 
dopaminergic, serotonergic, and GABAergic neurotransmission, while attenuating glutamatergic 
transmission. The most unique actions of ZNS are its effects on the GABA reuptake transporter 
GAT-1, and its reversible Monoamine Oxidase-B (MAO-B) inhibition. ZNS blocks sodium 
channels, and inhibits carbonic anhydrase [24]. ZNS blocks T-type calcium channels [24]. ZNS 
indirectly facilitates GABA and indirectly reduces glutamate neurotransmission, unlike the direct 
effects exerted by topiramate on GABA-A, AMPA, and kainate receptors [25, 26]. ZNS effects 
on GABAergic neurotransmission are highly complex, but ZNS facilitates GABAergic inhibitory 
neurotransmission overall while reducing glutamate release from neurons [26]. ZNS also acts 
on Excitatory Amino Acid Transporters (EAATs), which are membrane bound glutamate 
transporters thought to play a role in the pathophysiology of AUDs [27]. In the hippocampal and 
frontal brain areas of rats, ZNS up-regulated and enhanced the function of the glutamate 
transporter EAAT3/EAAC1 and down-regulated the GABA reuptake transporter GAT-1 [25]. By 
this mechanism, ZNS increases glutamate clearance and potentiates GABAergic transmission 
by increasing tissue and synaptic GABA levels. ZNS’s effects on GABA may explain its 
anxiolytic properties in patients with AUD and patients with refractory anxiety [22, 28, 29]. 
ZNS causes reversible MAO-B inhibition, an effect that is not associated with the side 
effects attributed to irreversible MAO inhibitors, so hypertensive crises or dietary restrictions are 
not concerns [30, 31]. ZNS has direct effects on serotonergic and on dopaminergic 
neurotransmission [32, 33]. ZNS increases serotonergic and dopaminergic output over time, an 
effect that is biphasic in terms of dose relationship; thus at a certain point, output of these 
neurotransmitters plateau, although output remains elevated relative to baseline.  
4.A.2.d. ZNS Pharmacokinetics: Hepatic metabolism of the drug occurs with acetylation of 
ZNS to N-acetyl ZNS and CYP3A4 mediated reduction to 2-sulfamoylacetyl phenol. The plasma 
elimination half-life is about 63 hours [34, 35]. ZNS penetrates the blood-brain barrier and the 

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ratio of cerebrospinal fluid ZNS to plasma ZNS is .76.  Metabolism and clearance of ZNS is 
increased in subjects taking enzyme-inducing medications. ZNS does not appear to be an 
inducer or substantial inhibitor of P450 microsomal enzymes. Steady state levels are achieved 
within 14 days from achieving a stable target dose. Patients with significant renal or hepatic 
disease may require dosage adjustment but such subjects will not be included in this study (see 
exclusion criteria).  
4.A.2.e. ZNS Dosing Rationale for AUD treatment: ZNS is typically used efficaciously in the 
range of 400-600 mg/day in adults with seizure disorders [36]. Similarly, clinical trials for weight 
reduction in obesity, and for treatment of binge eating disorder have employed ZNS target 
doses in the range of 400-600 mg/day [7, 8, 37, 38]. For our pilot study of ZNS, the target dose 
was determined based on extrapolation from the aforementioned studies, and a comparison to 
the efficacious dosing of topiramate in studies for the treatment of alcoholism and weight 
reduction. Topiramate appears to be efficacious in reducing weight, binge eating, and drinking in 
the range of 200-300 mg/day, though significant weight loss can occur at lower doses [11, 12, 
39-42]. In our pilot study, a target dose of 500 mg/day was selected based on ZNS’s general 
clinical behavioral similarity to topiramate at an approximate analogous 2:1 dosing equivalency 
between the two drugs with regard to appetitive behaviors. The mean maximal dose of ZNS in 
the pilot study was 430 mg/day. The data from our ZNS pilot study suggest that a slightly higher 
dose of 600mg daily may optimize effects on reducing drinking, and should be well tolerated. 
Titration rates of 50-100 mg every 1-2 weeks have been used safely [43, 44]. 
4.A.3. Using a micro-longitudinal approach to examine a medication’s mechanism of 
action and pharmacogenetic interactions: 
Using this method, they demonstrated an interesting and complex pharmacogenetic 
interaction with topiramate and a GRIK1 single nucleotide polymorphism (SNP, rs2832407) [45]. 
GRIK1 is the gene that encodes the GluK1 kainate receptor subunit, and rs2832407 (C/T) is an 
intronic SNP that has been associated to the risk of developing AUD, with the C allele being the 
risk allele. They performed a mediation analysis using the daily micro-longitudinal data 
investigating the role of “self-efficacy” in changes of drinking behavior. They found that 
topiramate’s effects on drinking level were moderated by rs2832407, such that C-allele 
homozygotes treated with the active medication showed the greatest increases in self-efficacy 
across the 12-week trial.  Further, the effect on self-efficacy (measured in the early evening) 
fully mediated the reduction by topiramate of nighttime drinking level.  This is important because 
the mediation analysis points to causal factors. 
 
4.A.4. Pharmacogenomics 2.0: Pharmacogenetic studies of alcoholism treatment have yielded 
promising findings, yet translating this information into clinical practice remains difficult because 
of many conflicting results. Thus, the current state of applied pharmacogenetics for treating 
AUDs is very limited, and is lagging behind other fields. We are developing a new method for 
pharmacogenomic optimization of medication response in alcoholism treatment. This method 
seeks to identify and prioritize the most succinct list of clinically relevant genetic loci for 
predicting a given phenotype. This “Convergent Functional Pharmacogenomics” approach 
converts data from that succinct set of highly relevant variants into an averaged or total score 
referred to as the “genetic risk prediction score” (GRPS), which can be used in statistical 
analyses as a continuous single variable, thus eliminating the need to perform multiple 
comparisons. In order to do that appropriately, the approach needs to be informed by previous 
behavioral genetic and pharmacogenetic research, developed in discovery samples, and 
validated in replication studies. Much of this work for predicting risk of developing alcohol 
dependence has been done, and Drs. Gelernter (co-investigator) and Kranzler (consultant) 
made significant contributions to this work [46]. A similar but more limited approach has been 
applied in smoking cessation treatment research, though not yet in alcoholism treatment trials.  
 
5.  Significance: 
AUDs are highly prevalent in civilians and in veterans, and the prevalence may be 
increasing over time, at least for civilians. ZNS is an extremely promising medicine for treating 
AUDs and managing other clinical problems including psychiatric disorders. ZNS is an 
affordable, generic anticonvulsant with unique actions on the major neurotransmitter systems 

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involved in alcoholism, and it has neuroprotective effects. We completed a randomized, 
placebo-controlled pilot study of ZNS in treating AD that showed significant reductions in heavy 
drinking, overall drinking, and alcohol craving. ZNS was very well tolerated in this study. In this 
application, we propose a larger (N = 160), 16-week, randomized, double-blind, placebo-
controlled, efficacy study of ZNS in reducing drinking and improving outcomes in a 
representative population of heavy-drinking civilians with AUD.  
 
 
6.  RESEARCH PLAN/EXPERIMENTAL METHODS: 
 
6.A. CLINICAL TRIAL METHODS OVERVIEW: Overall trial design: ZNS treatment of 
civilians with AUD: The proposed study, which is registered on clinicaltrials.gov 
(NCT02900352), will be a two-arm, parallel-groups comparison of ZNS and PLC on outcomes of 
reducing and eliminating heavy drinking in subjects with AUD. We will conduct a 16 week, 
randomized, double-blind, placebo-controlled study in N=160 regularly heavy drinking subjects 
with DSM-5 AUD. We will enroll patients whose goal is to reduce their drinking to safe levels or 
to stop drinking.  At each visit, all patients will receive Medical Management [47], which was 
developed for the COMBINE Trial and which we modified to be relevant for both reducing heavy 
drinking and promoting abstinence.  Random assignment to treatment group and double-blind 
conditions will be maintained throughout the study.  Raters will be trained in the reliable use of 
all assessments.  We will use serum GGTP, Phosphatidyl Ethanol (PEth), Ethyl Glucuronide, 
and Ethyl Sulfate (EtS) to validate patient reports.  Following a 1-2 week pre-treatment 
assessment period, patients will receive 16 weeks of treatment.  Daily reports obtained using 
IVR will be used to identify subjective correlates of medication effects (e.g., craving) and to 
monitor medication use.  A half-day long “stress response” laboratory session based on that 
developed by Sinha [48] will be performed with subjects after screening but before starting 
medication (baseline stress/impulsivity), and then a second lab will be performed between 
weeks 9-16.  
 
The target dosage for ZNS is 500mg/day, which will be titrated up over the first 7 weeks 
of treatment, with dosage increases based on tolerability. The titration schedule will start with 
100mg daily, increased to 200mg/day after the first week, and then increased by 100mg/day 
every 2 weeks to the target dose of 500mg/day. Subjects will then begin 9 weeks at the target 
dose with the option to increase to 600mg daily after two weeks at target if treatment response 
is suboptimal and there are no significant side effects (no current moderate to severe AE’s with 
500mg daily, which will be assessed at visits as described in Section 6.F.2 “Counseling”). 
Dosing will remain flexible with respect to the time of day that the medication is administered, in 
order to maximize compliance and minimize the impact of adverse effects.  The dosage will be 
held or reduced based on the appearance of moderate-to-severe adverse effects. Following 
the seven week titration phase, subjects will begin the 9 week period of active treatment 
on the target dose, followed by up to 2 weeks of tapering and discontinuation of the 
medicine, and a return for follow-up at three months post-treatment. The dosing is also 
flexible in that it will allow subjects to continue on at less than the target dose based on 
tolerability, but subjects must be able to tolerate at least 200mg/day (two pills). Also, if 
subjects are not having moderate to severe side effects during the treatment phase, and 
have not yet reached 600mg/day, they may be increased by up to 100mg every 2 weeks if 
it is felt that they may benefit further from it. This will allow maximum flexibility and 
optimal dosing. 
 
6.B.  Subjects and recruitment:  The clinical trial portion of this study is being conducted at 
two sites; (1) VCU’s Institute for Drug and Alcohol Studies (IDAS) and (2) the University of 
Connecticut Health Center (UCHC) in Farmington CT, which also has its own NIAAA-funded 
Alcohol Research Center. This Project will benefit from the expertise and resources for 
conducting clinical trials at both centers. Both sites recruit from different catchment areas and 
have good records of subject recruitment. N= 160 subjects will be randomly assigned to receive 

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either ZNS (80 subjects) or PLC (80 subjects).  Note that the translational sub-studies (genetics, 
and stress reactivity lab) will be performed on both the civilians and veterans, so they will occur 
at all 4 total sites for both the civilian and veterans studies: VA Connecticut (the West Haven 
VAMC), UCONN Health Center, VCU IDAS, and the RichmondVAMC. We anticipate an upper 
limit of enrollment to be N=200, however for the study we have a participant target goal of 
N=160.For the sake of simplicity, we describe those procedures here written for the civilians 
only, but they will be added separately to the veterans study protocol also. The funding for the 
translational sub-studies will come from NIAAA. We would like to reserve the right to enroll 
veterans here at VCU IDAS for the translational components of the study only, if that is easier 
logistically than running the translational components at the Richmond VAMC. The Richmond 
VAMC will recruit veterans for the study, using their specialized protocol and these participants 
will be given the option of coming to VCU for the add-on stress lab and IVR components.  
 
6.C. Clinical Trial Inclusion and Exclusion Criteria:  
Participants: N=160 men and women civilians from the greater Richmond area are being 
recruited through radio, bus, and print advertising, online advertising, study web sites, referrals, 
and flyers at VCU facilities and community areas (i.e., coffee shops, grocery stores, etc.), as 
well as surrounding area clinics. We will also utilize HM20000294 in which participants indicated 
if they would like to be contacted for future studies in order to identify and contact potential 
participants 
  
Inclusion Criteria (each subject must meet all of the following to participate): a) age 21-70 
years, inclusive; b) regular heavy drinkers as defined by averaging ≥ 2 heavy drinking days per 
week over the 90 days baseline pre-treatment timeline follow-back (TLFB), and current DSM-5 
AUD that recognize a need to reduce or stop drinking; c) willingness to provide written, informed 
consent to participate in the study; and d) for women of child-bearing potential (i.e., no 
hysterectomy, bilateral oophorectomy, or tubal ligation or <2 years postmenopausal), must be 
non-lactating, practicing a reliable method of birth control, and have a negative serum 
pregnancy test prior to initiation of treatment. Section 6.I reviews medications allowed and not 
allowed during study.  
Exclusion criteria are: a) a current, clinically significant physical disease [i.e., neurologic, 
renal, rheumatologic, gastrointestinal, hematologic, pulmonary, endocrine, cardiovascular, 
hepatic, or autoimmune disease] on the basis of medical history, physical examination, or 
routine laboratory evaluation that, in the context of the study would represent a risk to the 
subject, or significant laboratory abnormalities related to hepatic function such as marked 
elevations of hepatic aminotransferase levels (i.e., AST and ALT) or direct bilirubin. Other 
specific exclusionary disorders include; b) history of clinically significant renal calculi or renal 
failure; renal compromise (defined by an elevation of serum creatinine above our laboratory’s 
limit of normal);c) history of hypersensitivity to ZNS, or any sulfonamide, Stevens-Johnson 
Syndrome, or history of any severe drug allergic reaction; d) current clinically significant blood 
dyscrasia, e) history of seizure disorder; f) use of any of a number of medications that might 
prominently influence drinking patterns or cause risk of harm or injury (e.g., FDA approved 
medications to treat AUD, chronic use of opioid pain medication or benzodiazepines, tramadol); 
g) schizophrenia, bipolar disorder, or substantial suicide or violence risk on the basis of history 
or psychiatric examination; h) currently dependent on opioids or benzodiazepines; i) are 
considered to be unsuitable candidates for receipt of an investigational drug; j) patients who 
report having 5 or more standard drinks within 24 hours of urine ETG sample collection at 
screening will be excluded if their ETG levels are negative. 
6.D.Temporal Sequence of Study Procedures: Following telephone screening to determine 
initial eligibility, patients will be invited to the clinical site for an in-person visit.  At the first in-
person visit, informed consent will be obtained and patients will undergo a screening interview 

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to assess inclusion and exclusion criteria.  Patients excluded at any point in the recruitment 
process will be referred for appropriate treatment based upon consultation with the study 
physician (See Section 6.I “Other Treatments Allowed During the Study” for a more detailed 
explanation). If subjects are unable to complete the entire screening procedures in 1 visit due to 
their schedule, they may be allowed to return for additional visits if needed prior to baseline.  
6.E.  Schedule of Visits: 
6.E.1.  Visit 1 (Screening Visit):  At the screening visit (visit 1), patients will be asked to 
provide informed consent. The PI and/or the study Nurse Practioner (NP) will obtain a medical 
and psychiatric history, and perform a physical exam.  Substance use data for the 90 days prior 
to the screening visit will be collected via the Timeline Follow-Back (TLFB) Method. Blood or 
saliva  and urine samples will be taken for routine clinical laboratory evaluations (including 
GGTP, ETG/ETS, and PEth), drug screening, pregnancy testing (in females of reproductive 
potential), and DNA extraction. All projected amounts will be discussed in the consent form, we 
estimate the total amount of blood drawn to be approximately 10 TBSP for the entire study, but 
additional labs may need to be repeated at the discretion of the PI to ensure participant health 
and safety. Additional blood will only be drawn if determined medically necessary. Screening will 
last about 3-4 hours total. 
 
6.E.2.  Visit 2a (Baseline Visit): After the screening visit, eligible patients will undergo the 
baseline visit prior to randomization.  They will complete a packet of questionnaires and the 
research assistant will train them to record data on alcohol consumption, medication 
administration and other daily variables using IVR, which is a self-reported assessment of 
mood, drinking habits and attitudes towards alcohol. Baseline impulsivity will also be measured 
before imagery using the Barrett Impulsivity Scale [51]. The subject begins a 7-week titration 
phase, during which the ZNS (or matching PLC) dosage will be titrated up as indicated below in 
Table 1, to a maximum of 600mg/day. Subjects will receive compensation for all visits, including 
follow-up visits (see Table 4). Compensation will not be prorated. Participants will be offered 
transportation assistance if needed to return home from study visits in the form of bus tickets or 
taxi rides, as long as these trips are within a 20 mile radius or are on the bus lines. Study staff 
will work with the participant at individual study visits to determine which mode of 
transportation is most feasible for the participant. 
 
TABLE 1: Medication Titration Schedule 
Week 
Placebo 
Zonisamide dose 
1 
One capsule daily 
100mg QHS 
2 
Two capsules daily  
200mg QHS 
3 
Two capsules daily  
200mg QHS 
4 
Three capsules daily 
300mg QHS 
5 
Three capsules daily  
300mg QHS 
6 
Four capsules daily  
400mg QHS 
7 
Four capsules daily  
400mg QHS 
8-9 
Five capsules daily  
500mg QHS (Target dose) 
10-16 
Five or Six capsules daily, 7 weeks 
duration  
 
Continue 500mg daily or optional increase 
to 600mg QHS,    
7 weeks duration          
17-18 
TAPER: Decrease capsules by one 
a day every 3 days, over a period of 
up to 15 days 
TAPER: Decrease dose 100mg  
every 3 days, over a period of up to 15 days 
Table 1 notes: 7 weeks of titration to the 500mg daily target dose. 9 weeks at the target dose 
with the option to increase to 600mg daily after two weeks at target if treatment response is 
suboptimal and there are no significant side effects (no current moderate to severe AE’s with 
500mg daily).  

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8 
6.E.3. Visit 2b (Baseline Stress response lab): THIS LAB SESSION IS DESCRIBED IN FULL 
DETAIL BELOW IN SECTION 6.J. Subjects will be scheduled for this ~ 4-6-hour session to 
occur after being screened and giving informed consent. This paradigm is based on that 
developed by Dr. Rajita Sinha which uses mental imagery techniques to examine the response 
to stress, though we have condensed it into a one lab session. Staff will help subjects to 
develop six 5 minute long scripts that will be read and audiotaped; two describe a very stressful 
event in the person’s life, two describe a neutral event, and two describe a pleasant alcohol-
related event. Then subjects sit in an isolation booth and listen to the audiotapes sequentially 
while psychological measures of craving and anxiety are recorded.   Impulsivity/risk-taking [via 
the Balloon Analogue Risk Task (BART)] will be recorded at the start of each lab session [50]. 
Subjects are taught to relax for ten minutes between each audio tape script listening session, 
and measures are repeated identically for each of the three tapes. This entire lab session will be 
repeated again with an additional visit (10b) occurring between weeks 9-16 of being on the 
medication. All subjects enrolled at the VCU IDAS site will have their lab sessions at the IDAS 
facility where we have successfully run a similar protocol. Note that we will try to have all 
participants undergo the stress labs, however, if it is too burdensome due to the subject’s 
schedule, we will still allow them to participate in the clinical trial without completing the stress 
lab. We anticipate that we will still be able to evaluate primary and secondary outcomes and 
having stress lab data for less than N=160 will not impact our overall results in a significant 
manner.l   
6.E.4.  Visits 2c-11 (Treatment and End-of-Treatment Visits):  Patients will first receive 
counseling and study medication during a treatment session (visit 2c) scheduled on the same 
day as the baseline assessment.  Patients will be given study medication consisting of ZNS or 
matching PLC and titrated up to a maximum of 600 mg/day of ZNS (see Table 1). We will use 
blocked stratified randomization with treatment site (Yale versus UCHC) and use of 
antidepressants/psychotropic (yes/no) as the stratification variables, and block sizes of 4 in 
each stratum to achieve treatment balance throughout the randomization process. During the 
16-week treatment period, patients will come in for a visit within 1 week after starting the study 
medication (week 1).  They will then come in on weeks 3, 5, 7, 9, 11,13, and 16. After 
completing a two-week taper, patients will return on week 18. (Note: a research staff member 
will call the patient on weeks 2, 4, 6, 8, 10, 12, 14, 15, and 17. The purpose of this call will be to 
check in with the patient and make sure they do not have any questions and that they are 
tolerating the medication.)  At each visit, the patient's breath alcohol level (BAL), weight, and 
vital signs will be measured. Participants will be expected to have a BAL under the legal limit 
(.08) in order to participate in visits. At screening, all female subjects will have a blood 
pregnancy hCG quantitative titer drawn to detect pregnancy. Urine samples will be collected at 
each visit for drug screening and once monthly for female subject’s pregnancy testing. Samples 
for ETG (urine) and PEth (blood) will be collected as indicated in Table 2.   Patients will then 
complete questionnaires and be interviewed by the study nurse about their concomitant 
medications, adverse events, and protocol compliance.  At every treatment visit (i.e., for a total 
of 9 sessions), the nurse will deliver the MM intervention. At midpoint, Week 9, Baseline 
impulsivity will also be measured before imagery using the Barrett Impulsivity Scale [51]. At the 
end of treatment, the research assessment will be repeated, including a query of the patient’s 
belief as to their treatment condition (using the Medication Questionnaire; MED-Q).  Blood 
samples for measurement of serum GGTP will be obtained to assess the validity of self-reported 
drinking.  All patients will be asked to complete an end-of-treatment evaluation and to complete 
all scheduled assessments to facilitate intent-to-treat (ITT) analyses. Participants who 
discontinue the medication before the typical Endpoint will be given the option to participate in 
an abbreviated version of the visits starting at what would normally be the visit labeled Week 16 
onward. This will also allow us to monitor them for safety while tapering (if needed). 
6.E.5. Visit 10b (Stress Lab Session 2):   This visit will occur between weeks 9-16 of being on 
the study medication.  The session will use the same audiotapes created for the baseline stress 

V.6 05Jun2020 
 
9 
lab. The session will be identical to the baseline stress lab (assessments), with the exception of 
the randomized order of the presentation of the audiotapes.  
 
6.E.6. Visit 12 (Follow-up): A follow-up visit will occur approximately 3 months after the patient 
completes the 16 weeks of the study medication.  This visit will last approximately 1-2 hours and 
the patient will be asked to complete the same surveys they had completed during the 
weekly/biweekly visits. 
 
6.F.  Study Treatments:  Throughout the study, we will maintain double-blind conditions 
regarding medication condition.   We will break the blind in the event of a severe adverse event 
wherein knowledge of the identity of the study drug received by the participant is necessary for 
effective emergency treatment of the event. MM will be delivered by a study nurse who is 
experienced in its use in alcohol pharmacotherapy trials.  The PI will meet with the patient at the 
beginning of treatment and discuss clinical management with the nurse weekly.  The PI will 
evaluate the patient for severe or persistent adverse effects.  At each visit, the nurse will 
dispense study medications prescribed by the physician.   
6.F.1.  Medication Condition: The maximal dosage of ZNS to be used in the present study is 
600 mg/day. We will use a seven-week titration period. The dosage of medication will be 
increased only as tolerated and patients experiencing intolerable adverse effects will have their 
dosage decreased gradually to the highest tolerated dosage. The study nurse (in consultation 
with the PI) and the PI will provide guidance for patients as they increase their medication 
dosage, per the titration schedule.  ZNS will be purchased commercially and formulated by the 
VCU and UCHC research pharmacies respectively; PLC capsules will be formulated to match 
the active medication, so that inspection of the capsules cannot allow them to be differentiated. 
6.F.2.  Counseling: At each treatment visit, all patients will receive MM, a medically oriented 
intervention that supports the use of pharmacotherapy and maximizes medication adherence in 
AUD treatment [47].  Clinicians with minimal specialty training but who are knowledgeable about 
AUD can deliver this brief and effective intervention, which has been widely used.  In MM, the 
clinician highlights the patient’s AUD symptoms and need for treatment.  The patient is advised 
to reduce or stop drinking, is educated about AUD, is provided a rationale to take medication for 
its treatment, and is instructed on the importance of daily medication adherence.  The clinician 
and patient jointly develop an individualized medication adherence plan; and the patient is given 
information on the medications.  MM enhances adherence, providing treatment comparable to 
what is feasible in most medical settings. It is unlikely to obscure a medication effect on drinking 
outcomes. 
The first MM session will last 30 minutes and subsequent sessions 20 minutes.  During all 
sessions, the study nurse will check the patient’s BAL, vital signs and weight, adverse effects, 
medication adherence, and concurrent medications; perform a brief assessment of the patient’s 
drinking and general functioning; and make recommendations for the patient to follow until the 
next visit.  Patients with severe psychological symptoms (e.g., suicidal thoughts) will be 
withdrawn from treatment and referred for appropriate clinical care.   
6.F.2.a.  Ensuring Adherence to MM Content and Procedures: Our study nurse will undergo 
training from the study nurse at UCHC which will entail a review of the protocol and MM manual, 
role-play, practice of initial and follow-up sessions, and review of taped practice sessions until 
adequate performance is achieved.  Our study nurse will also monitor the MM for this study (i.e., 
by listening to 10% of recorded visits, evaluating adherence to MM principles, recording the total 
time in the treatment session, assessing the therapeutic relationship, reviewing the achievement 
of reduced drinking goals and clinical improvement during treatment, and providing individual 
feedback).  One session from each subject will be reviewed with equal frequency for each of the 
10 different MM sessions. Monthly protocol adherence meetings will be held with the nurse to 
assure protocol adherence.   

V.6 05Jun2020 
 
10
6.G.  Assessments:  We include measures from different sources (see Table 2) to cover the 
various domains in which alcohol treatment may exert an effect and to corroborate self-reported 
treatment effects.  
Study data will be collected and managed using REDCap electronic data capture tools hosted at 
VCU. REDCap (Research Electronic Data Capture) is a secure, web-based application 
designed to support data capture for research studies, providing 1) an intuitive interface for 
validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) 
automated export procedures for seamless data downloads to common statistical packages; 
and 4) procedures for importing data from external sources [52]. 
6.G.1.  Laboratory/Medical Assessments:  These assessments serve to:  1) screen patients 
for medical exclusion criteria, 2) assess potential adverse effects of ZNS, and 3) corroborate 
self-reported drinking.  Prior to entrance into the study, each patient will receive a physical 
exam, urinalysis and urine toxicology, CBC, a chemistry panel [which includes electrolytes, liver 
enzymes (ASAT, ALAT, GGTP), bilirubin, uric acid, BUN, and creatinine], and pregnancy 
testing.  Bicarbonate levels will be every 4 weeks because ZNS can cause metabolic acidosis; 
pregnancy testing and a CBC will also be repeated at the midpoint, which is planned to be week 
9 but may be adjusted per patient visit needs.  If a patient reports being pregnant or tests 
positive, she will immediately be excluded or withdrawn from treatment with medication, referred 
for obstetric evaluation, and advised to discontinue all drinking.  At the midpoint (week 9) and 
endpoint (week 16), GGTP will be repeated to corroborate self-reported alcohol consumption. 
The patient will be in the downward titration phase of the medication at this point (See Table 1: 
Medication Titration Schedule). We will also obtain Ethyl Glucuronide (EtG), Ethyl Sulfate (EtS), 
and Phosphatidyl Ethanol (PEth) as biomarkers to verify subjective claims of drinking during the 
study.  
6.G.2. Psychological/Behavioral Assessments: ZNS is hypothesized to have its greatest 
influence on alcohol consumption.  The assessments listed below measure multiple outcome 
criteria, because a reduction in drinking may not result in improvement in other domains.  
Table 2:  Schedule of Assessments 
 
 
 
Study Week 
 
SC 
BL 
1 
3 
5 
7 
9 
11 
13 
16 
18 
28 
Surveys/Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Overview and Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
Locator Information 
x 
 
 
 
 
 
 
 
 
 
 
 
SCID-V 
x 
 
 
 
 
 
 
 
 
 
 
 
Medical History/ 
Physical/Psych Exam 
x 
 
 
 
 
 
 
 
 
 
 
 
FHAM 
x 
 
 
 
 
 
 
 
 
 
 
 
Table 2 Continued 
 
 
Study Week 
 
SC 
BL 
1 
3 
5 
7 
9 
11 
13 
16 
18 
28 
Neurocognitive panel (Trail 
making test A & B; Verbal 
Fluency (FAS); RAVLT; Brown 
Visual Learning Test (BLT) 
 
x 
 
 
 
 
x 
 
 
x 
 
x 
AUQ 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Barrent Impulsivity Scale 
 
x 
 
 
 
 
x 
 
 
 
 
 
CIWA 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 

V.6 05Jun2020 
 
11
Table 2 Notes:  
(1) Week 9 is the study midpoint; (2) TLFB data will be collected at each visit to cover the period since the last visit 
(baseline will be 90 days prior to randomization); (3) IVR calls will be made daily and will measure drinking behavior, 
craving, anxiety, and medication usage over the preceding 24-hour period. (4) Abbreviations: SC: screening; BL: 
baseline; TIPI: Ten-Item Personality Inventory; all other abbreviations can be found under the assessments sections 
of the project description. (5) Urine pregnancy testing will be performed at each visit for females of childbearing 
potential and a serum pregnancy test will be performed monthly, as needed, to rule out early pregnancy. 
6.G.3. Areas assessed only at intake: 
a.  Sociodemographic/general patient information: During screening, an assessment of 
medical history, personal and family history of alcoholism, marital status, educational and 
C-SSRS 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PCL-5 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PHQ-9 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SAFTEE 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
STAI 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
TLFB/measures of treatment 
received 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
MM 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
IVR Daily Reports 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
AADUD 
x 
 
 
 
 
 
 
 
 
x 
 
x 
AEQ 
 
x 
 
 
 
 
x 
 
 
x 
 
x 
CAPS-5 
 
x 
 
 
 
 
x 
 
 
x 
 
x 
CGI-I 
 
 
 
 
x 
 
x 
 
x 
x 
x 
 
CGI-S 
 
x 
 
 
 
 
 
 
 
 
 
x 
DMQ 
 
x 
 
 
 
 
x 
 
 
x 
 
x 
LSCR 
x 
 
 
 
 
 
 
 
 
 
 
 
PSS 
 
x 
 
 
x 
 
x 
 
x 
x 
 
x 
Q-LES-Q 
 
x 
 
 
 
 
 
 
 
x 
x 
x 
RAND SF-12 
 
x 
 
 
 
 
 
 
 
x 
 
x 
SCID Section E 
 
 
 
 
 
 
 
 
 
x 
 
x 
SCID-II (antisocial) 
 
x 
 
 
 
 
 
 
 
 
 
 
SIP 
 
x 
 
 
 
 
 
 
 
x 
 
x 
SLEI 
 
x 
 
 
x 
 
x 
 
 
x 
 
x 
SORT 
x 
 
 
 
 
 
 
 
 
 
 
 
SRE 
 
x 
 
 
 
 
 
 
 
x 
 
x 
TIPI 
 
x 
 
 
 
 
 
 
 
 
 
 
Early Termination Form 
 
 
 
 
 
 
 
 
 
x 
 
 
Endpoint Rating Form 
 
 
 
 
 
 
 
 
 
x 
 
 
Med-Q 
 
 
 
 
 
 
 
 
 
x 
 
 
Laboratory/Medical 
 
 
 
 
 
 
 
 
 
 
 
 
Screening/Monitoring Labs 
x 
 
 
 
x 
 
x 
 
 
x 
 
 
DNA 
x 
 
 
 
 
 
 
 
 
 
 
 
PEth 
x 
 
 
 
 
 
x 
 
x 
x 
 
 
ETG (urine) 
x 
 
 
 
x 
 
x 
 
x 
x 
 
 
Urine/blood pregnancy test 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Breathalyzer/Vitals/Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine drug screen 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 

V.6 05Jun2020 
 
12
occupational information and substance abuse treatment history will be obtained, along with the 
individual’s self-identified ancestry.   
b.  Locator information:  At the time of enrollment in the study, the research coordinator 
will select patient locators on the basis of relationship to the patient, duration and current status 
of relationship, frequency of contact with the patient, and willingness to participate.  Locators are 
contacted when efforts to reach a patient are unsuccessful, which enhances retention of 
patients in treatment and data collection.   
c.  Psychiatric diagnosis:  The Structured Clinical Interview for DSM-5 (SCID) will be used 
to classify patients according to the presence or absence of standard psychiatric disorders 
according to DSM-5 criteria.  The clinical trials version is now available [53]. We may opt to use 
an online version for ease and clarity.   
d.  Family history of alcohol dependence: The Family History Assessment Module [54] 
systematically queries the patient about the presence of an alcohol use disorder (AUD) in 
relatives.  The patient will provide information concerning parents’ and siblings’ history of 
alcohol use without their being identified.   
 
e. History of stressful events and trauma: The Life Stressor Checklist (Revised), a 30-
item lifetime inventory of very stressful or traumatic events.  
 
6.G.4. Areas assessed only at treatment endpoint: 
a.  Overall condition at the end of treatment (for early withdrawal from the study):  The 
Early Termination Form, indicating the patient’s level of functioning at termination, will be 
completed by the study nurse for any patients that leave treatment prematurely.  The form is 
used to identify the reasons for early termination (e.g., symptomatic failure, adverse effects) and 
other relevant circumstances.   
b.  Integrity of the double blind: The Medication Questionnaire (MED-Q) was developed to 
evaluate the masking procedure and will be completed by the patient at the midpoint (week 9) 
and end of treatment.  Patients who are unable to return for the endpoint and are willing to 
complete the assessments will be mailed questionnaires (with a stamped envelope to facilitate 
their timely return) and then be interviewed by telephone to collect all information.  Such 
subjects will be paid the same amount as if they actually attended the endpoint visit to complete 
those endpoint assessments.  
6.G.5. Areas assessed at intake, end of treatment, monthly, or at each visit:  
a.  Alcohol use patterns:  The Timeline Follow-back (TLFB) [55] will be used to estimate 
past 90-day drinking at intake and at every treatment visit going back in time from the last 
assessment.  This interview procedure will provide quantity/frequency of alcohol consumption 
data for each day during the period prior to the interview.  The TLFB is reliable and valid when 
used by trained interviewers.  However, it is less useful than daily measures for detecting 
patterns of alcohol consumption that vary on a day-to-day basis [56, 57]. The Clinical Global 
Impression scale (CGI) will be used to assess progress in treatment monthly. The Clinical 
Institute Withdrawal Assessment (CIWA-Ar) will be used to facilitate assessment of withdrawal, 
and decisions regarding appropriateness for study entry and continuation with respect to 
physical dependence will be made based on the judgment of the PI.  
 
b. Alcohol craving; will be assessed at each treatment visit with the Alcohol Urge 
Questionnaire (AUQ), [58].  
c.  Alcohol-related problems:  The Short Index of Problems (SIP). The SIP, a 15-item 
instrument that is a subset of the 50-item DrInC [59], measures alcohol dependence symptoms 

V.6 05Jun2020 
 
13
and medical, psychological, social, occupational, and legal problems.  To reduce respondent 
burden, we chose to use the SIP which, like the DrInC, measures a single factor of alcohol-
related problems (61).  The Quality of life enjoyment and satisfaction survey (Q-LES-Q)[60] 
(REF) will be used to assess quality of life in subjects. 
d.  Drinking motives and expected alcohol effects:  1) Drinking Motives: Drinking motives 
will be measured with the Drinking Motives Questionnaire [DMQ;[61, 62] to explore potential 
changes as a result of treatment in drinking motives. This instrument contains 20 items with 4 
subscales, drink to a) cope motives (e.g., “Because it helps when you are feeling nervous or 
depressed”), b) conformity motives (e.g., “Because it helps me fit in”), c) enhancement motives 
(e.g., “Because it’s fun”), and d) social motives (e.g., “Because it makes a social occasion more 
enjoyable”).  The DMQ will be administered at baseline and for those subjects who continue to 
drink again at midpoint, end of treatment and at the 3-month follow-up visit.  2) Alcohol 
expectancies will be assessed with 24 items from the Alcohol Effects Questionnaire [AEQ;[63] 
probing 4 positive expectancy subscales (social and physical pleasure, aggression and power, 
social expressiveness, and relaxation and tension reduction) and 1 negative subscales 
(cognitive/physical impairment) to explore potential changes as a result of treatment with 
zonisamide.  The AEQ will be administered at baseline and for those subjects who continue to 
drink again at midpoint, end of treatment and 3-month follow-up visit. 3) Self Rating of Effects of 
Alcohol (SRE) [64] is a widely used measure of number of drinks subjects report are needed to 
produce typical alcohol effects (alcohol sensitivity) during the first use of alcohol period in one’s 
life, the past 3 months or period of heaviest use. The SRE will be administered at baseline and 
for those subjects who continue to drink again at end of treatment and 3-month follow-up visit. 
 
e.  Psychological symptoms:  1) The Physician’s Health Questionnaire (PHQ-9), a 
validated 9-item self-report measure of depressive symptoms with a total score of 0-27 [65, 66] 
will be administered at each visit.  2) The State-Trait Anxiety Inventory will be used to measure 
anxiety symptoms at each visit [67]. 3) The Columbia Suicide Severity Rating Scale, C-SSRS 
[68] evaluates suicidal risk. A study nurse or research team member will administer the C-SSRS 
at each study visit and, if rated 4 or 5 (i.e., clinically significant suicidal ideation), the PI will be 
consulted to decide on the appropriate clinical management.  4) The RAND 12-Item Health 
Survey (SF-12)[66] (64), a self-report measure of life functioning in various domains, will be 
completed at study baseline, endpoint (week 18) and follow-up. We will focus on the mental 
health component of the SF-12. 4) Monthly Stressful Life Event Inventory: This is a 34-item 
questionnaire asking subjects to report and any stressful events in the interim period (SLEI). 6) 
Perceived Stress Scale, a ten item scale measuring perceived stress [69].   PTSD symptoms 
will be measured by the Clinician-Administered PTSD Scale for DSM-V (CAPS-5) and the PTSD 
Checklist for DSM-V (PCL-5)[70, 71].  CAPS-5 will be conducted at baseline, week 9, week 16, 
and follow-up; PCL-5 will be conducted at baseline, each treatment visit and follow-up. 
f. Neurocognitive measures: To evaluate the potential cognitive side effects of zonisamide 
in subjects with alcohol use disorder, we will use a panel of brief neuropsychological tests 
covering multiple cognitive domains at baseline, midpoint, endpoint and 3 month follow up visit.  
1) Psychomotor / visual motor tracking Trail Making Test A, subjects are instructed to draw a 
line connecting sequentially 25 numbers distributed on a sheet of paper, time in seconds 
required to complete the task recorded. 2) Executive Function Trail Making Test B.  In this test 
subjects are instructed to draw a continuous line connecting numbers and letters distributed on 
a sheet of paper  in alternating fashion (e.g., 1, A, 2, B, 3, C, etc.). The score is the time in 
seconds required to complete the task.  3) Verbal Fluency  Phonetic fluency – FAS letter 
fluency/word naming, participants are instructed to verbally generate words that begin with the 
letters F, A, and S in three separate, 1-min trials. Proper nouns and multiple words using the 
same stem with different suffix (e.g., friend, friends, friendly) were scored as incorrect. Total 
words for the three trials are summed.  Semantic category fluency – animal naming.  For the 
category fluency task, participants are instructed to say “the names of as many animals that 
they could think of” in a 1-minute period.  4) Verbal learning and memory: Rey auditory verbal 
learning test (RAVLT) measures short-term verbal memory and rate of learning.  In this test 
subjects are read a list of 15 unrelated words repeated over 5 trials and asked to repeat the list 
after each trial.  Words may be recalled in any order.  The number of words recalled during each 

V.6 05Jun2020 
 
14
trial is summed.  5) Visual learning and memory: The Brown Location Test (BLT) is a visual 
learning task independent of verbal, global intellectual, fine motor or drawing skills that consists 
of five recall learning trials, an interference trial, and a short delay recall.  In this task, presented 
on a computer screen, subjects are shown a series of 12 images for 4 seconds each that 
contain one red dot in different locations on a common field of 56 non-symmetrically placed 
circles.  Subjects are then presented a page with the 56 non-symmetrically placed circles and 
instructed to place 12 red dots at the positions in which they appeared in the prior presentations.  
Following five red dot learning trials an interference trial is presented using one trial of 12 
images with black dots in different locations on the circle array and asked to indicate the 
locations of the black dots.  A final blank 56 circle array is provided and subjects asked to 
indicate the positions of the red dots learned in trials 1-5.  Total correct for trials 1-5 sum, 
interference and delayed recall are scored.  Normative data are available for each of these 
neuropsychological tasks[72-76].  
g. Medication adverse effects:  Patients will provide subjective reports of side effects at 
each study visit using the Systematic Assessment for Treatment Emergent Effects (SAFTEE) 
interview [77], a widely used measure of adverse events.  A standardized approach was 
developed for use in alcohol treatment trials [78].  
h. Measures of treatment received:  Records of medication taken will be kept and patients 
will be asked to return the unused portion of study medication at each visit.  The nurse will also 
record the number of contact hours patients have been exposed to any alcohol treatment 
outside of the study.  
6.G.6. Areas assessed daily: We will use IVR to collect daily ratings of alcohol-related 
expectancies, craving, anxiety/tension, feelings of self-efficacy to reduce drinking, drinking, and 
medication usage.  These are the same procedures used to examine genetic moderation of 
medication effects in the studies by Kranzler et al. [45, 79, 80].  Patients will be trained to use 
the IVR with a wallet-sized, follow-along sheet detailing each question in the IVR phone call, 
including answer options as a guide; this will be given to patients to assist them with the first few 
IVR calls.  A research assistant will monitor calls to ensure that they are made daily and that 
any problems and questions are addressed immediately (to enhance accuracy and adherence).  
Patients who fail to call in during the allotted time receive a computerized reminder call [which 
has been found to increase the response rate by nearly 10% [81]].  Patients are paid $2 for 
each telephone call completed and an additional $6 for each week in which they complete 6 or 
more of the calls (i.e., up to $20 per week for 16 weeks or a maximum of $320).  The use of a 
modest incentive helped achieve a call completion rate of 81.6% in a study of NTX [79] and 
83.5% in a study of topiramate [15].  
a.  Daily subjective measures assessed with IVR: These include 4 items assessing 
anticipated positive outcomes for drinking later that day. The items, adapted from existing 
expectancy scales (67-69), correspond to the commonly identified expectancy domains of 
general pleasure, tension reduction, social expressiveness, and enhanced sexuality. Responses 
will be made on a 4-point scale (0=not at all to 4=extremely likely). Similarly, subjects will report 
on their craving, self-efficacy for controlling drinking, and anxiety levels.  
b. Daily drinking diary:  Every evening, as part of the daily diary measuring subjective 
measures and medication usage, patients will record their alcohol consumption.  The patient will 
report the number of standard drinks of beer, wine, liquor and "other" category. To capture all 
drinking during the preceding 24-hour period, patients are asked to report separately drinking 
from yesterday (in total), and any drinking during the current day, up until the time of the IVR 
report.  This will allow us to examine lagged associations (44, 65).  The time of the calls (5-8 
PM) was chosen to minimize the potential for patients to have begun drinking heavily prior to 
making the calls.  Patients are taught to complete the telephone interview, which requires less 
than 5 minutes/day.  Daily measures of alcohol consumption obtained via IVR will enable us to 
examine co-variation of anxiety and drinking behavior to test for moderator effects. The IVR 
system is run centrally from UCHC, but will be implemented at all three sites. Cellphones or 

V.6 05Jun2020 
 
15
prepaid phone cards will be provided to subjects without a reliable phone during the study. Staff 
will determine participant’s needs and work with them to determine a feasible option. 
c. Daily medication usage: Using IVR, patients will report daily their use of medication that 
day, which correlated highly (r=0.91) with electronic monitoring (i.e., MEMS cap) [82].  
6.H. Exploratory Pharmacogenomic Analysis: DNA samples will be prepared on site at each 
site. Genotyping will be carried out either in the VCU Psychiatry genetics laboratories, or the 
Yale affiliated Laboratory of Psychiatric Genetics with the Illumina genomewide microarrays and 
GenomeStudio software, using standard quality control measures.  Using PLINK software, we 
will obtain genotypes for 66 SNPs in the 11 genes identified by Levey et al. [46] using a CFG 
method as being predictive of AUD risk, and which are also thought to be associated to an 
endophenotype of stress-driven drinking. We will genotype data from ancestry informative 
markers (AIMs) contained in the HumanCore24 array to derive ancestry proportions to be used 
in the analyses to adjust for population genetic structure [83]. This 11 gene panel of key 
alcoholism related genes includes that encoding the alpha-synuclein protein (SNCA), for which 
variants have been shown to influence alcohol cue reactivity and brain activity in humans [84], 
as well as the AD risk-associated DRD2 gene encoding the dopamine D2 receptor. We will 
augment this panel with SNPs in several other genes that have been shown to have 
pharmacogenetic treatment interactions with ethanol or medications to treat AUDs such as the 
GABRA2 gene, OPRM1, DBH, and GRIK1. In each subject we will calculate a GRPS using the 
sum of the number of risk alleles (0,1,2) for each polymorphism in the panel. This genetic 
loading score can be used as a variable in the statistical models of treatment outcome. Before 
applying this in the ZNS samples, we will first explore and refine this approach in available 
“discovery” samples of over 1000 de-identified clinical trial subjects. Because the SNCA 
rs17015888 risk allele (G) has a relatively high frequency in both EAs and African Americans 
(AAs) (~.5 for both), we should be able to apply this method in a combined sample using AIMS 
to control for population genetic structure. Sensitivity analysis in EAs only (a separate analysis) 
will be performed. We expect that ~75% of our sample (240 of 320) will be of EA descent. 
Originally, for the first phase of the work we had planned to genotype subjects using a genome-
wide chip in order to explore the use of these CFG derived GRPS to predict treatment outcomes 
and medication response in two available clinical trial samples of medication treatments for AUD 
(a sertraline and a topiramate trial) via patient level meta-analysis. However, a number of other 
available trials have been found to be available for genotyping, and since a larger study sample 
and particularly a larger available sample of naltrexone treated subjects are available, we have 
expanded the plan to include these additional samples. We anticipate having upwards of 900-
1000 naltrexone (versus placebo) treated subjects with DNA samples and clinical trial data. 
Having this large core of naltrexone treated subjects should substantially increase our power to 
find naltrexone specific pharmacogenetic predictors. Additionally we can genotype other 
available samples including the zonisamide samples (currently about halfway thru trial) and the 
previously mentioned samples (topiramate, sertraline) and also those from trials of 
mecamylamine and Dutasteride, totaling about 1400 total DNA samples. We will explore using 
functional genomics methods, the ability to predict outcomes and medication response based 
on genotype and the use of combined genome-wide data. A similar but much more rudimentary 
method combinatory multi-gene approach has recently been used to improve response and 
remission rates in the treatment of major depression with antidepressants in a large (N~1200) 
prospective clinical trial. We will use multiple exploratory methods of data analysis to compare 
different algorithms and methods of predicting outcomes which will include more traditional 
methods of data analysis such as longitudinal mixed models, multilevel modeling, as well as 
newer approaches such as machine learning. The algorithms and methods of predicting 
response derived from these exploratory analyses can be further tested for predictive validity 
when the ongoing zonisamide trials (and potentially other ongoing medication clinical trials) are 
completed.  
 

V.6 05Jun2020 
 
16
6.I. Other Treatments Allowed During the Study: Subjects will be allowed to continue to 
receive, or will be referred for, additional psychiatric care as needed. This is similar to what has 
been done in previous studies in this population. They can receive antidepressants and other 
medications, as long as the medication is not on the list of those excluded. The type and 
amount of services received will be collected as data. Subjects will be allowed to participate in 
twelve step programs, group psychotherapy, day treatment programs etc.  
 
6.J. STRESS REACTIVITY LAB PROCEDURES: 
(Visit 2b) 
Intake: Qualified staff will meet with eligible subjects to explain all study procedures and 
risk/benefits and obtain informed consent.  Next, scripts for the imagery procedures will be 
developed and audio recorded on the day of the lab, or after screening but before the day of the 
lab. The stress reactivity lab session is performed twice, the first stress reactivity lab session 
occurs after screening but prior to starting medication. The second stress reactivity lab session 
occurs after being on the target dose for at least 2 weeks (i.e. between weeks 9-16) Each stress 
reactivity lab takes place on one day, and is approximately 4 hours long. A description of the 
procedure is provided in Table 3.   
 
6.J.1. Imagery Script Development: First, scripts for the guided imagery induction will be 
developed. The stress imagery script will be based on subjects’ description of a recent personal 
stressful event that is self-rated as an 8 or above on a 10-point Likert scale, where 1 = “not at all 
stressful” and 10 = “the most stress I have recently felt in my life”. Examples of acceptable stressful 
situations include breakup with significant other, a verbal argument with a significant other or family 
member or unemployment-related stress, such as being fired or laid off from work.  A neutral-
relaxing script will be developed from the subjects’ commonly experienced neutral-relaxing 
situations. Neutral-relaxing events that involve nicotine or alcohol/drugs will not be allowed.  An 
alcohol craving cue imagery script will be based on subjects’ description of a recent event in 
which alcohol was consumed.  Stressful situations will not be acceptable for these latter two types 
of scripts. 
 
A ‘script’ or description of each situation will be developed using Scene Development 
Questionnaires which obtain specific stimulus and response details, including specific physical and 
interpersonal context details, verbal/cognitive attributions regarding the people involved, and 
physiological and bodily sensations experienced for the situation being described. The six scripts 
for each subject (2 for each condition: stress, neutral, and alcohol) will then be recorded on an 
audiotape (or similar technology) for guided imagery in the laboratory sessions. The order of stress, 
alcohol-cue, and neutral scripts will be assigned randomly, and counterbalanced across subjects. 
Detailed procedures are outlined in the imagery development procedures manual.[86]  Audiotapes 
will be destroyed after review.  Due to the length of this appointment (4-6 hours), we will provide 
food for participants for the script development appointment. 
 
6.J.2. Manipulation Check for Script Development: All six scripts will be rated on a Likert scale from 
1 to 10 on a standard rating form (Independent Rating Scale) by two objective independent raters 
for stressful and emotional content. If a script scores below a rating of 8 for stressful content on a 
five-point rating scale the subject will be asked to develop a new script prior to the laboratory 
sessions. These procedures ensure that the stress scripts of all subjects are equated in intensity 
and content. It further ensures that differences in stress reactivity are not due to differences in 
intensity and emotional content of the stressor. The procedures for development of imagery scripts, 
rating of scripts for content and physiological activation are similar to those used by Miller et al.,[87] 
and have been successfully used in previous work by co-investigators. 
 
6.J.3. Imagery & Relaxation Training: subjects will be introduced to all self-report measures and 
instructed how to complete them.  In order to minimize baseline imagery variability participant 
will be given relaxation and imagery training, as described in the imagery training procedures 
manual.[86] Relaxation training will be approximately 10 minutes and will consist of progressive 

V.6 05Jun2020 
 
17
muscle relaxation technique.  The imagery training will consist of two types of visualizations.  
First, participants will be asked to visualize an unemotional scene, such as reading a magazine.  
Second, they will be presented with an unemotional but physically arousing scene, such as 
exercising in a gym.  Here, the emphasis will be placed on assuring that participants are aware 
of physiological changes, increased heart rate, or breathing.  Subjects will be given instructions 
throughout the imagery exercises regarding the process of imagining the scenes and 
maintaining the visualization for an extended period of time.   
 
The order and content of the imagery conditions will not be revealed to the subject or 
to the research staff conducting the sessions. The neutral script will always occur in between 
the stress script and alcohol-cue script, the both of which will be randomized to occur 
before or after the neutral script. In the imagery task, the subjects will be asked to imagine the 
situation being described vividly, 'as if' he/she is in the specific situation, until asked to stop. The 
imagery script will be played to the subject over headphones and the subject will be required to 
imagine the situation for 5 minutes.  Participants will listen to one imagery recording for each 
condition (stress, neutral, and alcohol) at each lab. Each imagery recording will only be heard one 
time (the stress, neutral, and alcohol cues played during lab 1 will not be played during lab 2). 
 
 
After the imagery period, relaxation instructions will be provided to ameliorate any residual 
effects of imagining stressful situations. In addition to reducing anxiety, relaxation instructions have 
been found to be effective in reducing alcohol cue-induced craving in the laboratory.[86, 88] 
Following the scheduled assessments, subjects will remain on the unit until subjective and 
physiological measures return to baseline levels. Subjects will continue to be supervised by a 
psychologist or psychiatrist until they feel safe.  Should subjects experience adverse psychological 
reactions to the procedure, immediate counseling and relaxation instructions will be provided.  
More severe reactions will be addressed pharmacologically by one of the study physicians.  Long-
term psychological effects are not expected because similar trauma exposure procedures are used 
in empirically-validated therapies for PTSD. 
 
6.J.4. Lab Session: After arrival on the research unit and before the start of the first laboratory 
session subjects will be instructed to relax for a few minutes by clearing their minds and 
focusing on deep breathing.  Subjects will be instructed that when situation is being read to 
them, they should try and imagine as though they are in the situation, and as though it is 
happening at that time.  They will be asked to imagine themselves in the situation until they are 
asked to stop.  The experimental procedure will follow the same format for each of the three 
conditions consisting of baseline relaxation, imaging scripts and recovery period for 10 min. the 
length of the appointment; we will provide participants with food at the start of each lab session. 
 
 
TABLE 3 Schedule for Stress Reactivity Laboratory Session Phase I, Day 4 
 
 
T  -20 
 
 
Subject arrives; urine, BrAC check (< 0.02), CIWA, psychophysiological 
setup; BIS, STAI, BART, brief 10 minute relaxation 
 
Stress script, or Alcohol Cue script, (Script #1) 
 
 
T      0 
 
T  +10 
T  +15 
T  +25 
T  +30 
T  +40 
Baseline, BP & HR recording, Craving and emotion ratings (VASA, 
VASC, DES-R,  AUQ, PANAS, STAI-6) 
Image period (administration), BP & HR recording,  
Craving & emotion ratings, BP & HR recording,  
Recovery period, BP & HR recording,  
Craving & emotion ratings, BP & HR recording 
10 minute relaxation period 
Neutral script (Script #2) 
 
T  +50 
Schedule of measurements same as above for Script #1 

V.6 05Jun2020 
 
18
 
 
Stress, or Alcohol Cue script, (Script #3) 
 
     T  +100 
Schedule of measurements same as above for Script #1 
 
     T + 150 
Craving and emotion ratings, subject assessed and cleared by 
study staff 
 
Table 3 Abbreviations: HR/BP: Heart rate/Blood pressure, BrAC: Breath Alcohol Concentration; 
 
 
 
6.J.5. Outcome Measures For The Stress Reactivity Lab: 
Positive and Negative Affect Schedule (PANAS ): PANAS is a 20-item scale that assesses both 
negative and positive affective states [89]. Subjects rate adjectives describing affective states 
on a scale of 1 to 5 using a specified time period (e.g., now, today, past week etc.). Scores are 
then added up to generate negative and positive scale scores. This scale is short, easy to 
administer and has good psychometric properties. 
Adverse Event Form (SAFTEE): In order to monitor adverse events from the study 
interventions, the SAFTEE will be administered before and after each session. This is a locally 
developed symptom checklist that includes possible side effects of study medications and/or 
procedures and has been used in our previous studies 
Visual Analog Scale - Anxiety (VASA). Anxiety levels will be measured using a self-report VASA.  
Participants will be asked to rate their level of anxiety, how “anxious, tense and/or jittery” they 
feel at that particular moment.  Their responses can range from 1=”not at all” to 10=”extremely 
high”. 
Visual Analog Scale - Craving (VASC). Current craving for alcohol will be measured using a 
self-report VASA.  Participants will be asked to rate their level of craving, “desire for a drink” 
they feel at that particular moment. Their responses can range from 0=”not at all” to 
10=”extremely high”. 
The Differential Emotions Scale-Revised short form (DES-R)[94] will be used as a measure of 
subjective emotional experience. The measure consists of a number of subscale and for the 
present study we will use five subscales: sadness, anger, joy, fear, and anxiety. Each subscale 
is made up of 5 adjectives describing the particular emotion state.  Participants rate on a 5-point 
scale the extent to which each word describes how they feel at the present moment. The DES 
shows good psychometric properties.[94] The DES has been used to examine subjective 
emotion following laboratory mood inductions.[88] 
 
Impulsivity will be assessed through the Balloon Analogue Risk Task (BART) [50]and Barrett 
Impulsivity Scale (BIS) [51].  The Go/No-Go Task will assess the ability to withhold responses to 
an infrequently occurring target (No-Go trials). A series of blue and green rectangular shapes 
are presented every 1150 ms and participants are instructed to press a spacebar every time the 
green rectangular shape appeared, and to give equal importance to speed and accuracy. The 
primary outcome is the number of errors on the No-Go trials[95, 96]. 
 
State-Trait Anxiety Inventory (STAI) will be used to assess anxiety symptoms; the full version 
will be used at the start of the lab session and the shorter version (STAI-6) will be used for all 
other indicated timepoints  [97]. 
 

V.6 05Jun2020 
 
19
6.J.6. Physiological Measures: BP and HR will be assessed using an automatic blood pressure 
cuff. 
 
6.K. Statistical Plan and Power Analysis:  
6.K.1. Procedures: Procedures for the monitoring and analysis of data were developed 
during previous clinical trials conducted at Yale and will be overseen by Drs. Ralevski and Arias. 
6.K.1.a. To Examine the Efficacy of ZNS (Specific Aim 1), Primary Outcome: We will 
use drinks per week as the primary outcome variable. This is also the primary outcome we are 
using for veteran ZNS study, and is one that can be readily applied when combining the 
samples. Recently the NIAAA and FDA Alcohol Clinical Trials Initiative (ACTIVE: a workgroup of 
experts in the field tasked with optimizing alcoholism clinical trials outcomes and methods) has 
suggested that for medication development trials and small to medium size trials, continuous 
outcome variables such as drinks/week or heavy drinking days per week are optimal as 
opposed to categorical outcomes. We will use a mixed models approach to examine for a 
statistically significant difference in drinks per week and on continuous secondary outcome 
variables. The model will include fixed effects for medication group, week, and the interaction 
between medication and week. We will include pre-treatment drinking behavior (past month 
HDD) as a covariate and will select the best-fitting variance-covariance structure based on 
Schwartz-Bayesian Information criterion (BIC). We will incorporate a grace period 
corresponding to the time it takes to titrate the medication to target dose into the models, and 
we will focus the primary analysis on the last 8 weeks of treatment at the target dose. All of 
these outcomes can be obtained from the TLFB data, and from the daily drinking data obtained 
from the IVR. 
An important initial consideration in considering efficacy will be to identify baseline 
differences between groups that may have occurred despite randomization. A successful 
outcome during the treatment trial will be defined in terms of a statistically significant difference 
on the primary outcome measure: drinks per week, compared during the 8 weeks of active 
treatment at the target dose, allowing for an 8 week grace period for the medication titration. For 
all analyses, heavy drinking days will be defined as follows; for men > 4 drinks in a day and for 
women > 3 drinks in a day. Patients will be followed irrespective of whether they continue to 
receive medication treatment, so that analysis will include all data available for the 8-week 
treatment period. All analyses will be intent-to-treat. The α will be set at .05 for the primary 
outcome variable. Between site differences will be explored. We will test interaction effects of 
GRPS in the regression models for the primary/secondary outcomes (Exploratory Aim 1), 
testing the hypothesis that ZNS’s effect on drinking is greater in those with higher GRPS.  
6.K.2 Secondary outcome measures: We will use a mixed models approach to examine 
for a statistically significant difference on heavy drinking days (HDD) per week, changes in 
GGTP level, measures of alcohol urge/craving (AUQ), and alcohol-related problems (as 
measured on the SIP). For each of these outcome measures, the model will include fixed effects 
for medication group, week, and the interaction between medication and week. We will include 
pre-treatment drinking behavior (past month HDD) as a covariate and will select the best-fitting 
variance-covariance structure based on Schwartz-Bayesian Information criterion (BIC). We will 
incorporate a grace period corresponding to the time it takes to titrate the medication to target 
dose into the models, and we will focus the primary analysis on the 8 weeks of treatment at the 
target dose. We will use the Hommel’s correction for multiple comparisons on the secondary 
outcomes to guard against chance findings. With last secondary outcome measure percentage 
of subjects with no heavy drinking days (PSNHDD), we will use a logistic regression analysis 
with PSNHDD as a categorical dependent variable. Medication condition (PLC or ZNS) will be 
the main independent variable, and we will include the variables of civilian or veteran status, 
and sex as covariates. We will also examine the use of biomarkers (GGT, PEth) to verify and 
adjust subjective drinking data as these biomarkers can detect occult harmful drinking when a 
subject is not forthcoming.  
6. K. 3. Dropouts and missing data: For the analysis of PSNHDD using logistic regression, 
all dropouts will be counted as relapsed. For all repeated measures analysis, we will use all 

V.6 05Jun2020 
 
20
available data on individuals and thus dropouts provide data until the point of dropout. We will 
compare dropout patterns between groups and if there are concerns of informative dropout 
and/or informative intermittent missing data, we will use pattern mixture models [98] to perform 
sensitivity analyses to our main analyses. Adherence to the medication will be evaluated and 
controlled for in secondary analyses. We will evaluate and compare both medication conditions 
(PLC, ZNS) for percentage of prescribed pills taken. 
6. K. 4. To use telephone-based daily process data collection to elucidate the 
mechanism of action of ZNS as it relates to changes in craving, anxiety, self-efficacy, and 
genetic variation (Specific Aim 2, Exploratory Aim 1):  Multilevel models will be used to 
evaluate the associations between craving, self-efficacy, anxiety, and daily drinking and how 
these associations vary as a function of medication group and GRPS.  Similar to Kranzler et al. 
[79], we will focus on predicting nighttime drinking (i.e., drinks consumed after the early evening 
report), but here we will use psychological measures reported during the early evening in the 
daily survey.  Nighttime drinking levels will be determined by subtracting the number of drinks 
consumed during the current day from the total number of drinks consumed for that day 
(reported the following day).  We will follow the general analysis scheme used by Kranzler et al. 
[79], but will use mixed effects/multilevel models, rather than generalized estimating equations 
(GEE) models [99] because mixed models give unbiased estimates under less restrictive 
assumptions about missing data.  We will examine the number of drinks consumed (using a 
Poisson model or negative binomial model if there is overdispersion).  We will use the HGLM 
module of the HLM7 program, as it is more flexible for some of our models than PROC 
GLIMMIX in SAS.  Analysis will focus on the last eight weeks of treatment, consistent with the 
analyses of outcomes in Aim 1.  We will test the hypothesis that ZNS reduces nighttime 
drinking and that craving, anxiety, and GRPS act as moderators of this effect. We anticipate 
greater ZNS effect in subjects with greater anxiety, craving and genetic loading (greater GPRS). 
We will examine whether ZNS’s effect on drinking is mediated by self-efficacy using the 
approach of Kraemer et al. [100, 101], such that self-efficacy is significantly affected by ZNS 
treatment, and has a main or interaction effect on nighttime drinking in the model containing 
both treatment and the potential mediator as predictors.  
6. K. 5. Stress Reactivity Lab (Exploratory Aim 2): We will compare pre- and post-
treatment changes in levels of anxiety, craving, and impulsivity measures induced by stressful 
and alcohol-cue imagery in the lab. We will test if the mean induced changes are attenuated by 
ZNS more than placebo using ANCOVA. The amount of reactivity pre-treatment will be explored 
as a covariate in secondary outcome models.  
6.K. 6. Safety: Safety will be analyzed using categorical outcomes, defined by the type and 
severity of adverse effects.  Summary measures of adverse events will be developed by organ 
system from the SAFTEE [77, 78] and will be compared for patients receiving ZNS or PLC using 
2 analysis or Fisher’s exact tests, with an emphasis on moderate-to-severe adverse events.   
6. K. 7. Sample Size And Power Estimate (Specific Aim 1): For continuous outcomes, 
based on the effect sizes from our pilot study of ZNS (showing a moderate effect size on 
drinks/week d=0.5, and .27 HDD/week), we estimated that a study with N=128 subjects (a 20% 
drop out rate) would be well powered (>.80) to detect a medium effect size difference on the 
secondary outcomes HDD per week and total drinks per week for the main effect of group 
assuming alpha level of 0.05. Based on past trials we are expecting a dropout rate < 30%. We 
will quantitatively examine the veteran and civilian populations for differences in variance and 
treatment response, and combine them (if valid) in a patient-level pooled analysis, further 
increasing power on all outcomes. If substantial differences are observed between the veteran 
and civilian samples, we will meta-analyze them. For PSNHDD, from the pilot study, in the ZNS 
group, 12 of 20 subjects did not relapse in the 28 days of the study, compared to 7 of 20 PLC 
subjects. Using this effect size, the proposed sample size of 80 subjects per group has >89% 
power to detect such a difference in the rates of no heavy drinking (i.e. 60% vs. 35%), assuming 
a two-sided alpha level of 0.05. We can also detect slightly smaller differences (60% vs. 38%, 
35% vs. 57%) with 80% power under the same assumptions. Both in the estimation of effect 

V.6 05Jun2020 
 
21
size from the pilot data and in the sample size analysis, dropouts are counted as relapsed to 
heavy drinking. 
6 K. 8. Pharmacogenomic and Micro-longitudinal analyses power estimate (Aim 2, 
exploratory aims): There is little ZNS-specific data by which we could reasonably estimate 
effect sizes for these analyses. Three recent treatment studies by our group showed significant 
pharmacogenetic effects with samples of about 110-150 in each [15, 85, 102]. By using a mixed 
models approach on drinking variables, and HLM for the micro-longitudinal analyses, we will be 
adequately powered to detect medium-to-large effects in these analyses.  
6.L. Economic Considerations: Participants will be paid a nominal but fair amount of money 
for their time and participation, up to $1110 (i.e., enough money to fairly compensate and 
encourage follow-up without being coercive or encouraging risk taking).  The payment schedule 
is outlined in detail below (SEE TABLE 4).   
Additionally, participants can earn up to $320 for completing the IVR phone calls ($2 per 
completed phone call plus $6 for each week where 6 or more calls are completed (up to 
$20/week for 16 weeks)).  If they do not have a cell phone to complete the calls we will give 
them one to borrow during the study which must be returned when they complete the study. 
By participating in the stress labs, subjects can also earn $40 for the script development, $100 
for each of the two stress labs ($200 total), and up to $40 for the computer tasks during the 
stress labs (up to $20 per lab session). 
If all parts of this study are completed, participants have the potential to earn up to $1110 (this 
does not include the additional travel compensation mentioned earlier). This payment is for the 
time and effort associated with study assessments and procedures.  All payments will be in the 
form of cash, check, gift card or clin card, upon completion of each appointment. 
 
 
TABLE 4: Subject visit and payment overview: 
Visit title 
VISIT # 
Weeks of 
completed 
medication 
Payment ($) 
Screening 
1 
 
50 
Baseline 
2 
0 
65 
Weekly treatment visit 
3 
1 
25 
Biweekly treatment visit 
4 
3 
40 
Biweekly treatment visit  
5 
5 
40 
Biweekly treatment visit    
TARGET DOSE achieved (500mg)  
6 
7 
40 
Biweekly treatment visit- midpoint 
assessments. Subjects eligible to 
go to 600mg daily.  
7 
9 
45 
Biweekly treatment visit 
8 
11 
40 
Biweekly treatment visit 
9 
13 
40 
Endpoint visit  
10 
16 
80 
Two weeks post endpoint visit follow 
up (end of medication taper) 
11 
 
15 
3 month follow up visit 
12 
 
30 
Total 
12 
 
510 

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22
 
 
 
 
Additional compensation 
 
 
 
Stress script session 
 
 
40 
Stress lab 1 
 
 
100 
Stress lab 2  
 
 
100 
Computer tasks 
 
 
Up to 40 
IVR phone calls 
 
 
Up to 320 ($2 per 
completed phone call plus 
$6 for each week where 6 
or more calls are 
completed (up to 
$20/week for 16 weeks)) 
Maximum Total compensation for 
all visits, labs, and phone calls 
 
 
1110 
FOR ADDITIONAL DETAILS OF SAFETY AND HUMAN SUBJECTS PROTECTION, PLEASE REFER 
TO THE ATTACHED “HUMAN SUBJECTS” APPENDIX FROM THE GRANT. ALSO, WE HAVE 
ATTACHED THE CORRESPONDING GRANT APPLICATION FOR MORE INFORMATION.  
7. Data and Safety Monitoring Board 
The DSMB is composed of persons not otherwise affiliated with the clinical trial who are 
experienced in various aspects of the conduct of clinical trials for the treatment of addictive 
disorders. The DSMB for this study had been composed of three investigators located in 
Connecticut (at Yale) who are not directly involved in this trial – Declan Berry, M.D., Ph.D., 
Sherry McKee, Ph.D., and David Fiellin, M.D., as the membership of the DSMB. These three 
clinicians have appropriate expertise in substance abuse and psychopharmacology for this 
study. None of three are directly involved with this proposed trial and consequently should not 
pose a conflict of interest. All are faculty at Yale. DSMB members have been transitioned to a 
VCU faculty composed board and members include Drs. Yifrah Kaminer, Megan S. Lemay and 
Gaurav Gupta, who are not directly involved in this trail.  These clinicians have appropriate 
expertise in clinical trials and with expertise in substance abuse and psychopharmacology.    
Review will occur every 6 months. The DSMB will review any serious and unanticipated events, 
also severe adverse events and patterns. Additional items may be review like issues with 
dropouts or early terminations, data issues. 
 
 

V.6 05Jun2020 
 
23
TABLE 5: Abbreviations: 
AADUD 
Alcohol Dependence Use Disorder – Measures effects of alcohol on life using DSM V 
criteria 
AEQ 
Alcohol Expectations Questionnaire - Measure of number of drinks subjects report 
are needed to produce typical alcohol effects (alcohol sensitivity) 
AUQ 
Alcohol Urge Questionnaire – Assesses alcohol cravings 
BART 
Balloon Analogue Risk Task- Assesses reward vs loss to assess risk-taking behavior 
BIS 
Barratt Impulsiveness Scale -Impulsivity Scale-  self-reported measures of impulsive 
personality traits 
BLT 
Brown Location Test - Visual learning task independent of verbal, global intellectual, 
fine motor or drawing skills that consists of five recall learning trials, an interference 
trial, and a short delay recall  
CAPS-5 
Clinician Administered PTSD Scale for DSM-5 – Measures symptoms of PTSD 
CGI-I 
Clinical Global Impression – improvement – Assesses for improvement in baseline 
since initiation  
CGI-S 
Clinical Global Impression – severity – To rate severity of patient mental illness  
CIWA 
Clinical Institute Withdrawal Assessment  - Assesses for symptoms of withdrawal 
C-SSRS 
Columbia Suicide Severity Rating Scale – Suicidal ideation and behavior rating scale  
DMQ 
Drinking Motives Questionnaire – Assesses personal motives for drinking alcohol 
FHAM 
Family History Assessment Model – Assesses for psychiatric disorders among 
relatives of participant 
IVR 
Interactive Voice Response – A phone system used for self-reporting predetermined 
questions 
LSCR 
Lifetime Stressor Checklist – Revised - Self-report measure that assesses traumatic 
or stressful life events 
MM 
Medical Management- A method of conducting a patient visit based on a theoretical 
paradigm to evaluate adherence to medications and adherence to treatment 
MED-Q 
Medication Questionnaire- Assesses the participant’s belief as to their treatment 
condition 
PCL-5 
PTSD Checklist for DSM 5 – Assesses for presence of PTSD symptoms 
PHQ-9 
Physician’s Health Questionnaire - 9-item self-report measure of depressive 
symptoms with a total score of 0-27 
PSS 
Perceived Stress Scale - Ten item scale measuring perceived stress 
Q-LES-Q 
Quality of Life Enjoyment and Satsfaction Questionnaire - Assesses quality of life in 
subjects 
RAND SF-12 
RAND (Research AND development) 12 Item Short Form Health Survey – Assesses 
personal habits and views on personal health 
SAFTEE 
Systematic Assessment for Treatment of Emergent Effects - Measure of adverse 
events 

V.6 05Jun2020 
 
24
SCID Section 
E 
Structured Clinical Interview  - Assesses for substance abuse disorders according to 
DSM V 
SCID-II 
(antisocial) 
Structured Clinical Interview - Assesses Conduct Disorder and Antisocial 
Personality Disorder Criteria 
SCID V 
Structured Clinical Interview - Classifies patients according to the presence or 
absence of standard psychiatric disorders according to DSM-5 criteria 
SIP 
Short Inventory of Problems – Evaluates experiences of drinkers over past 3 months 
SLEI 
Stressful Life Event Inventory – Evaluation of stressful life event occurrences over the 
past month 
SORT 
Slosson Oral Reading Test- evaluates English reading level 
SRE 
Self Rating Effects of Alcohol – Self-reported numeric responses to number of drinks 
needed to achieve certain effects 
STAI 
State-Trait anxiety Inventory - Measures state and anxiety level 
TIPI 
Ten item personality inventory – Assesses personality traits 
TLFB 
Timeline Follow-back- Estimates past 90-day drinking 
 
 
 
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