Clinical trial NCT04249882
Conditions: Alcohol Use Disorder
Keywords: Alcohol Use Disorder Medications Development
Sponsor: University of California, Los Angeles
Start date: 2020-01-28; Completion date: 2022-06-28
Enrollment: 53 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study design consists of a randomized, double-blind, placebo-controlled, 3-arm, parallel-group study of naltrexone (50 mg QD) and varenicline (1 mg BID). A total of 108 men and women with current AUD (moderate or severe) and reporting intrinsic motivation to change their drinking, will be randomly assigned to receive naltrexone (50 mg QD), varenicline (1 mg BID) or matched placebo. Post-randomization, all participants will complete an alcohol cue-reactivity paradigm prior to the initial dose of study medication. After a week-long medication titration period, participants will be asked to complete a 7-day practice quit attempt, during which they will have daily virtual visits (phone and online) where they will report on their alcohol use. Additionally, a second cue-reactivity paradigm will be conducted 90 minutes following study drug administration on final day of the practice quit attempt (Day 14).

Detailed description:
Recruitment: Participants will be recruited from the community through online and newspaper advertisements. Campaigns in local buses and print publications (e.g., LA Weekly) will also be implemented. Targeted recruitment will also take place through a lab database of previous study participants who agreed to be contacted for future studies.

Telephone Screen: Individuals who call the lab (in response to flyers and advertisements) expressing interest in the study will receive detailed information about the study procedures, and if they remain interested they will complete a telephone screen performed by a trained research assistant for self-reported inclusion and exclusion criteria. Those who appear eligible will be invited to the laboratory for an initial in-person screening session.

Initial Screening: Prior to conducting any research related procedures, research staff will conduct the informed consent process, which details the procedures to take place during the screening visit. Informed consent will be a three-part process. First, participants will be asked to read and provide verbal consent for breathalyzer. If the breathalyzer is above 0.000, the visit will be stopped and the participant will not be compensated. The participant will be given an opportunity to reschedule the visit for another day. If the breathalyzer test is negative, the written informed consent form will be reviewed and signed by the participant and study staff outlining procedures for the initial screening visit. A second written consent form will be reviewed and signed in the presence of the study physician at the medical screening visit if the participant is found eligible to continue to that visit. At the initial screening visit, subjects will be asked to provide a urine sample to test for drugs of abuse and pregnancy (if female), and will complete a series of questionnaires and interviews (described in detail below) to determine initial eligibility. This visit will take approximately 1 hour. Following the initial in-person screening, the study coordinator will meet with the PI to determine if the participant is eligible to continue to the medical screening based on study inclusion/exclusion criteria.

Medical Screening: Those participants who appear to be eligible after the initial screening visit, will then be scheduled for a second screening visit. This visit will be conducted by the study physician and will start with a breathalyzer test. If the breathalyzer is above 0.000, the visit will be stopped and the participant will not be compensated. The participant will be given an opportunity to reschedule the visit for another day. If the breathalyzer test is negative, the physician will conduct the second written (experimental) consent; medical history interview and physical exam. In addition, a urine sample will be obtained for repeat drug screen and pregnancy tests. The participant will then be accompanied by research personnel to the CTRC for blood specimen collection including Comprehensive Metabolic Panel and Complete Blood Count to evaluate overall health; and EKG to screen for medical conditions that could make study participation medically unsafe. The study physician will review each participant's medical history, vital signs, weight, review of systems, and laboratory tests, including liver function tests (LFTs), drug screen, chemistry screen, and urine pregnancy screen to determine if it is medically safe for the participant to take the study medication. Any subject who is excluded from the study will be compensated for their time in the screening session and will be offered referrals for alcohol treatment in the community.

Randomization and Medication Titration: Participants who are eligible after the physical exam will be randomized to one of three treatment conditions (VAR, NTX, or PLA). Urn randomization will be used to balance the groups by gender, smoking status (as reported on question 1 of the Fagerstrom Test for Nicotine Dependence), and drinking status ('heavy' drinker defined as 28 or more drinks per week for males/14 or more drinks per week for females, or 'very heavy' drinker, defined as 35 or more drinks per week for males/28 or more drinks per week for females). The UCLA Research Pharmacy will manage the blind. The three treatment conditions will not be different in appearance or method of administration. All participants will undergo a week-long medication titration period prior to the onset of the practice quit attempt.

Practice-Quit Attempt: During the practice-quit attempt, participants will be instructed to abstain completely from drinking alcohol during a 7-day practice quit period. This period will begin on Day 8 of study medication dosing. During this period, participants will complete daily virtual visits to report on their drinking, mood and craving for alcohol during the previous day in a daily diary assessment (DDA).

Study Medication: On Day 1, participants will report to the laboratory to complete the alcohol cue-reactivity paradigm and receive their first medication dose under direct observation of study staff. They will receive a 7-day supply of study medication in blister packs with AM and PM dosing clearly distinguished for the titration procedure. After reaching full medication dose at the end of one week, participants will come to the laboratory on Day 8 to begin the practice quit attempt and to take AM dose of study medication daily in the lab under direct observation of study staff. Additionally, on the first day of the practice-quit attempt (Day 8), participants will receive a second 7-day supply of study medication. All study medication will be prepared by the UCLA Research Pharmacy and will be identically matched in appearance (opaque capsules with 50 mg of riboflavin to aid in medication compliance procedures) and the medication labels will not reveal the drug identity.

Alcohol Cue Reactivity Sessions (CR): Randomized participants will complete a cue-exposure paradigm at two time points during the study, once on Day 1 prior to ingesting the first dose of study medication, and again on Day 14, approximately 90 minutes after study drug administration. Alcohol cue exposure will follow well-established experimental procedures. Sessions will begin with a 3-minute relaxation period. Participants will then hold and smell a glass of water for 3 minutes to control for the effects of simple exposure to any potable liquid. Next, participants will hold and smell a glass of their preferred alcoholic beverage for 3 minutes. Order is not counterbalanced because of carryover effects that are known to occur. Participants (who are smokers) will be allowed a smoke break immediately prior to the CR assessment. After every 3 minutes of exposure, participants will rate their urge to drink on the Alcohol Urge Questionnaire (AUQ) and their mood on the Profile of Mood States (POMS). AUQ score (alcohol minus water) is the primary outcome for the CR.

Brief Counseling Session: All participants will meet with a trained study counselor briefly after the second cue exposure session on Day 14 to discuss their responses to the alcohol cues and discuss local treatment options. The counselor will begin by introducing him/herself and thanking the participant for his/her participation. He/she will continue by providing the participant with feedback on their responses on various individual difference measures (drinking patterns, severity of AUD diagnosis, family history, CIWA, depression, and other drug use). The counselor will probe for participants' attitudes towards these responses and diagnoses, and provide both informational and emotional support. Next, the counselor will go over the participant's history of alcohol treatment, in order to identify potential barriers to treatment access. He/she will discuss local treatment options with the participant, including the participant's primary care provider, self-help groups, and the UCLA Psychology Clinic. Lastly, the counselor will go over the "Rethinking Drinking" pamphlet with the participant, pointing out specific treatment options discussed in the session, and will address any questions or concerns.

Arms: arm 1: Matched to active medications arm 2: 1 mg twice a day arm 3: 50 mg once a day
Interventions: intervention 1: Placebo intervention 2: Naltrexone intervention 3: Varenicline
Intervention descriptions: intervention 1: Matched to active medication intervention 2: 50 mg once a day intervention 3: 1 mg twice a day

Protocol documents:
Prot_SAP_001.pdf: 
Practice Quit Study 
Protocol V8, Approved 02/08/2022 
PI: Lara Ray, PhD 
 
 
1 
 
 
 
 
 
 
 
 
A NOVEL HUMAN LABORATORY MODEL FOR SCREENING  
MEDICATIONS FOR ALCOHOL USE DISORDER 
 
STUDY PROTOCOL  
 
NCT #04249882 
 


Practice Quit Study 
Protocol V8, Approved 02/08/2022 
PI: Lara Ray, PhD 
 
 
2 
 
 
A NOVEL HUMAN LABORATORY MODEL FOR SCREENING  
MEDICATIONS FOR ALCOHOL USE DISORDER 
STUDY PROTOCOL 
 
1. INTRODUCTION 
 
Alcohol use disorder (AUD), as defined in DSM-5, represents a highly prevalent, costly, and 
often untreated condition in the United States [1]. Pharmacotherapy offers a promising avenue 
for treating AUD and for improving clinical outcomes for this debilitating disorder [2]. While 
developing novel medications to treat AUD remains a high priority research area, there are 
major opportunities to refine the process of screening novel compounds [3]. To that end, a key 
question in clinical studies of novel compounds for AUD is how to efficiently determine whether 
a novel medication has sufficient evidence of initial treatment efficacy to warrant proceeding to 
clinical trials. The process of screening novel compounds for initial efficacy, known as the early 
phase 2 of medications development, often consists of human laboratory studies assessing 
constructs of putative clinical relevance, such as alcohol craving, subjective response to alcohol, 
and alcohol self-administration under laboratory conditions [2-4]. Nevertheless, these controlled 
human laboratory models lack the ecological validity of clinical trials in which medication efficacy 
is established via clinically meaningful endpoints in individuals motivated to change their 
drinking behavior [5]. The scientific premise of this study is that screening novel AUD 
medications can be more efficient and clinically meaningful if early efficacy (phase 2) studies 
combine the internal validity of laboratory testing with the external validity of clinical trials. To 
that end, we propose to develop and validate a novel early efficacy paradigm informed by the 
smoking cessation medication development literature [6], to screen AUD medications in 
humans. Specifically, the proposed early efficacy paradigm consists of a study in which 
individuals with current AUD reporting intrinsic motivation to change their drinking (i.e., wanting 
to quit or reduce their drinking within the next 6 months) will complete a week-long “practice quit 
attempt” while on study medication. The primary outcomes of the practice quit attempt are (a) 
percentage of days abstinent and (b) drinks per drinking day. The proposed laboratory protocol 
has been carefully developed and validated for screening smoking cessation 
pharmacotherapies [6-10]. The objective of this proposal is to develop, refine, and validate this 
novel approach to screen pharmacotherapies for AUD. 
 
In order to advance this novel early efficacy detection paradigm to AUD medication 
development, two critical issues were carefully considered: (a) which medication(s) to use and 
(b) how to best validate the novel procedure against a well-established model. First, we decided 
that the use of an established, well-known, and FDA-approved medication for AUD would be 
ideal as a probe of this new model. Thus, we propose to use naltrexone (NTX), a well-known 
pharmacotherapy for AUD [11]. Second, we decided to include varenicline (VAR), a medication 
approved for smoking cessation that may have beneficial effects on alcohol use as well [12, 13], 
as an additional probe of this new model.  Third, we believe that having an alcohol cue-reactivity 
paradigm conducted at each medication condition would allow us to detect medication effects 
on cue-elicited alcohol craving and in turn validate the sensitivity of the novel paradigm for 
detecting medication effects. In brief, we propose to test this novel paradigm (i.e., practice quit 
attempt) in combination with a well-established paradigm (i.e., alcohol cue-reactivity), using an 
established and well-known pharmacotherapy for AUD (NTX) and an experimental, but 
promising pharmacotherapy for AUD (VAR). 


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PI: Lara Ray, PhD 
 
 
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Building upon the need to develop more effective models for screening novel medications for 
AUD, we propose a randomized, double-blind, placebo-controlled, 3-arm, parallel-group study. 
A total of 108 men and women with current AUD (moderate or severe) and reporting intrinsic 
motivation to change their drinking will be randomly assigned to receive NTX (50 mg QD), VAR 
(1 mg BID), or matched placebo (PLA). Post-randomization, all participants will complete an 
alcohol cue-reactivity paradigm prior to the initial dose of study medication. After a week-long 
medication titration period, participants will be asked to come in to the laboratory to receive their 
second pack of medication and to begin a 7-day practice quit attempt, during which they will 
have daily virtual (online and phone) visits where they will report on their alcohol use. 
Additionally, a second cue-reactivity paradigm and behavioral economics procedure will be 
conducted 90 minutes following study drug administration on final day of the practice quit 
attempt (Day 14).  
 
The successful completion of this study will advance medications development for AUD by 
developing and validating a novel early efficacy model for screening AUD pharmacotherapies, 
which in turn can serve as an efficient strategy for making go/no-go decisions as to whether to 
proceed with clinical trials. Specifically, a valid model of initial efficacy will allow us to reliably 
detect an initial efficacy signal for AUD pharmacotherapies and in turn decide whether to 
proceed to the full-scale efficacy (Phase 2) testing. 
 
2. BACKGROUND AND SIGNIFICANCE 
 
2.1. Medications for AUD are only modestly effective and developing novel treatments 
is crucial. 
 
Although treatments for alcoholism have improved in past decades [14], there is still great need 
to develop more effective interventions. Pharmacotherapies for alcoholism are used less often 
than psychosocial interventions [15]. The limited use of pharmacotherapy for alcoholism is due, 
in part, to the relative lack of pharmacological options to treat AUD. The only 
pharmacotherapies currently approved by the Food and Drug Administration (FDA) for the 
treatment of AUD are disulfiram (Antabuse®), naltrexone, acamprosate, and Vivitrol, an 
injectable extended-release formulation of naltrexone. Psychotherapy is generally used more 
often than these pharmacotherapies [15], but alcohol produces impairments in neurocognitive 
functioning that are theorized to limit the effectiveness of cognitive-based treatments for many 
individuals with AUD [16]. Given the potentially limited efficacy of both psychosocial 
interventions and the available pharmacological treatments, NIAAA has identified medication 
development for the treatment of AUD as a top research priority and has highlighted the need 
for the testing of new molecular targets and novel compounds [2, 3, 17]. In line with these 
research priorities, the proposed project seeks to develop and validate a novel early efficacy 
model for screening AUD pharmacotherapies. 
 
2.2. Human laboratory models are ideal for screening novel compounds but lack 
clinical validity. 
 
Human laboratory methods have been proposed as efficient approaches to medications 
development by simultaneously addressing two important endpoints: (1) safety/tolerability, and 
(2) medication early efficacy in clinically-relevant phenotypes (e.g. subjective responses to 
alcohol, cue-induced craving, and alcohol self-administration) [3, 18, 19]. The success of a 


Practice Quit Study 
Protocol V8, Approved 02/08/2022 
PI: Lara Ray, PhD 
 
 
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human laboratory study with a well-established laboratory paradigm is believed to inform go/no-
go decisions regarding large scale clinical trials. For example, it has been proposed that a 
medication’s ability to blunt the positive subjective effects of alcohol (i.e. “block the buzz”) or 
potentiate the aversive aspects of alcohol intoxication predicts clinical efficacy [20, 21]. 
Supporting this claim is the broad literature linking subjective responses to alcohol and 
alcoholism etiology [22, 23], as well as the effects of a small number of exemplar medications, 
most notably naltrexone [24], which blunts the rewarding effects of alcohol and have 
established, albeit modest, clinical benefit. However, while medication effects in the laboratory 
are generally believed to predict clinical efficacy, this hypothesis has never been subjected to 
the rigorous quantitative analysis necessary to establish translational validity. It remains 
unknown whether medication effects observed in the human laboratory reliably predict clinical 
efficacy.  
 
The practice quit attempt model used by Perkins and colleagues initially tested FDA-approved 
smoking cessation medications in order to validate their model [8, 9, 25]. These studies found 
that in individuals with high motivation to quit, there was a significant increase in number of days 
abstinent when on active medication compared to placebo; the same pattern of findings was not 
evident in individuals with low motivation to quit [8, 9, 25]. Further, when modafinil, a medication 
that has not shown efficacy as a smoking cessation aid, was added as a study arm, they 
demonstrated model specificity, as bupropion was effective at improving abstinence, while 
modafinil was not [25]. More recently, Perkins and colleagues have moved to testing novel 
medications using their practice quit attempt model [26, 27]. They did not find a significant 
reduction in days abstinent when testing a novel fibrate medication [27] or a novel positive 
allosteric modulator of nicotinic receptors [26], which provides a critical “no-go” signal for both 
medications. In summary, the development of the practice quit attempt model for medication 
development in nicotine dependence provides strong “road map” for the development of a 
similar approach modified to AUD and strengthens the scientific premise of this study. 
 
2.3. Developing valid and efficient screening paradigms will optimize medication 
development. 
 
Medications development, particularly for CNS disorders is a cumbersome process, taking 
nearly 20 years from discovery to market, and costing nearly $2 billion [3, 18]. Alcoholism 
treatment development appears especially difficult with over 20 medications having been tested 
in humans yet only three compounds have received FDA approval, the last of which was 
granted over a decade ago [5]. There is a pressing need to develop valid and efficient methods 
for shepherding novel compounds from initial discovery and safety testing through RCTs and 
ultimately approval/dissemination. While traditional human laboratory methods have been 
proposed to serve these aims, at present no human laboratory method has demonstrated 
translational validity. To address this central limitation in the alcoholism medications 
development field, we are proposing to expand the traditional laboratory methodology to more 
closely mirror actual treatment processes. Through combining a well-established laboratory 
paradigm (i.e. cue-reactivity), with an abbreviated “practice” quit attempt in intrinsically 
motivated individuals with AUD, this proposal reduces the conceptual distance between the lab 
and the clinic, thus reducing the possibility for laboratory effects to “fade” when applied to the 
clinical context. 
 
2.4.  Established medication should be used to test a novel model.   
 


Practice Quit Study 
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Naltrexone is the most widely studied of the FDA-approved medications for AUD. NTX is an 
opioid antagonist, with the highest affinity for the mu-opioid receptor. The neurobiological basis 
for the use of NTX stems from the neurocircuitry through which alcohol exerts its effects [28, 
29]. Alcohol increases release of endogenous opioids in the mesolimbic dopamine system 
contributing to the pleasurable effects of alcohol [28, 29], thus an opioid antagonist is proposed 
to block these reinforcing effects. Oral NTX was approved by the FDA in 1994 after initial trials 
suggested that NTX resulted in significantly fewer drinking days and lower rates of relapse, 
defined as drinking 5 or more drinks on an occasion for men or four or more drinks on an 
occasion for women (23% relapse rate for NTX versus 54% relapse rate for placebo) following 
three months of treatment [30, 31]. These initial results have been largely supported by more 
recent trials of NTX that have generally demonstrated NTX reduces the subjective pleasurable 
effects of alcohol [32, 33], craving for alcohol [34, 35], drinks per drinking day [36], rates of 
relapse [37, 38], and time to first relapse [39, 40]. However, the support for NTX is not uniform. 
A few trials, including a large multisite trial, have reported no significant outcome differences 
between NTX and placebo treated patients [41-43]. Moreover, the effect sizes of previous 
findings are often modest even when they reach statistical significance. Extended-release 
injectable NTX was developed to address poor medication adherence with oral NTX [44]. A 
multi-site trial of long-acting NTX identified significant reductions in the number of heavy 
drinking days over a period of 6 months compared to placebo [45]; however this effect was only 
significant for men [45]. Improvements in drinking outcomes were greater in individuals who 
were abstinent for at least 4 days prior to randomization [45, 46]. In sum, studies of NTX 
suggest a moderate effect on the reduction of alcohol use. While we considered using a novel 
compound and are aware that new studies of NTX are not encouraged by NIAAA, we agree with 
the comments of the reviewers which argued for the use of an established medication to test the 
novel paradigm. As such, we propose to use NTX in this study. We would like to clarify that this 
is not a NTX study per se, but instead is a study of a novel experimental approach to screen 
pharmacotherapies for AUD and that NTX is used simply because it is a well-known medication, 
ideal for testing a novel paradigm.  
 
2.5. Varenicline is a promising novel compound for AUD. 
 
Varenicline is a partial agonist at the α4β2 receptor and a full agonist at the α7 nicotinic 
acetylcholine receptor, and is FDA-approved for smoking cessation. A number of studies have 
highlighted the role of the nicotinic acetylcholine receptor (nAChR) system in alcohol 
dependence phenotypes. Studies have suggested that alcohol produces mesolimbic activation 
through its effects on nAChRs [47-49]. Therefore, there is considerable enthusiasm for 
varenicline as a possible treatment for alcohol problems. Preclinical studies have found that 
varenicline decreases ethanol self-administration in rats [50, 51]. Recent human studies of 
varenicline for alcohol use found that, compared to placebo, varenicline reduced alcohol self-
administration in the human laboratory [52], as well as alcohol craving [53] and alcohol 
consumption [53, 54] in smoking cessation trials. Interestingly, one study found that varenicline 
increased dysphoria and tended to reduce alcohol liking ratings following a controlled alcohol 
administration in the laboratory, suggesting that varenicline may potentiate the aversive effects 
of alcohol [55]. A recent multisite RCT of varenicline in individuals with AUD found that 
varenicline reduced the percentage of heavy drinking days, and the number of drinks per 
drinking day and alcohol craving [12]. Together, these studies suggest that varenicline may 
have beneficial effects on alcohol use. Including varenicline, a widely studied, promising AUD 
pharmacotherapy as a third arm in this study will enable us to further validate this novel alcohol 
quit paradigm. 
 


Practice Quit Study 
Protocol V8, Approved 02/08/2022 
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2.6. Medication effects on behavioral economic measures.  
 
The Sponsor’s laboratory completed a proof-of-concept study assessing naltrexone efficacy in 
terms of alcohol demand [45]. Participants were 35 heavy-drinking (AUDIT ≥ 8) Asian 
Americans. A within-subjects cross-over medication design was used along with an intravenous 
alcohol challenge completed after four days of both naltrexone and placebo. At baseline and 
with a BrAC = 0.06 g/dl, participants completed an Alcohol Purchase Task, which assessed 
estimated alcohol consumption along escalating prices. Results revealed a medication main 
effect such that naltrexone, relative to placebo, significantly reduced three indices of alcohol 
demand. 
2.7. Varenicline effects on behavioral economic measures.  
 
The laboratory has also conducted a randomized placebo-controlled, crossover study aimed to 
examine effects of varenicline on cigarette demand using hypothetical cigarette purchase tasks 
[46]. Non-treatment seeking (n = 37) daily smokers (>10 cigarettes per day) completed a 
measure of subjective craving for cigarettes and the Cigarette Purchase Task following 
overnight nicotine abstinence. Participants completed these measures after 10 days on 
varenicline (1 mg twice per day) and matched placebo. There was a Medication main effect 
such that varenicline, compared to placebo, reduced maximum expenditure. Taken together, 
these studies demonstrate the Sponsor’s experience in medications development, including the 
application of behavioral economics. They also suggest that behavioral economic measures are 
sensitive to the effects of AUD medications. 
3. STUDY OBJECTIVES 
 
3.1. Specific Aims 
 
Primary Aim #1: To test whether NTX (50 mg) or VAR (2 mg) results in a (a) higher percentage 
of days abstinent and (b) lower number of drinks per drinking day during the 7-day practice quit 
attempt, as compared to placebo. 
 
Primary Aim #2: To test whether NTX (50 mg) or VAR (2 mg) reduces cue-induced craving for 
alcohol, as compared to placebo. This aim allows us to confirm NTX effects using an 
established and widely studied paradigm. 
 
Primary Aim #3:  In order to validate this early efficacy paradigm, we will test the association 
between medication effects on cue-reactivity in the laboratory and drinking behavior during the 
practice quit attempt. 
 
Secondary Aim #1:  To determine whether the effects of medication on the multiple-choice 
paradigm are mediated by changes in discounting or demand for alcohol.  
 
Secondary Aim #2:  To determine whether the number of drinks per drinking day and 
percentage of days abstinent during the practice quit attempt predict alcohol choice.  
 
Exploratory Aim: In order to test medication efficacy, we will directly compare NTX and VAR on 
percentage days abstinent and number of drinks per drinking day during the 7-day practice quit 
attempt. 
 


Practice Quit Study 
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PI: Lara Ray, PhD 
 
 
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4. STUDY DESIGN 
 
4.1. Design Overview 
 
This study design consists of a randomized, double-blind, placebo-controlled, 3-arm, parallel-
group study of naltrexone (50 mg QD) and varenicline (1 mg BID). A total of 108 men and 
women with current AUD (moderate or severe) and reporting intrinsic motivation to change their 
drinking, will be randomly assigned to receive naltrexone (50 mg QD), varenicline (1 mg BID) or 
matched placebo. Post-randomization, all participants will complete an alcohol cue-reactivity 
paradigm prior to the initial dose of study medication. After a week-long medication titration 
period, participants will be asked to come in to the laboratory to receive their second medication 
blister pack and to begin a 7-day practice quit attempt, during which they will have daily virtual 
(online and phone) visits where they will report on their alcohol use. Additionally, a second cue-
reactivity paradigm will be conducted 90 minutes after study drug administration, followed by a 
behavioral economics paradigm on the final day of the practice quit attempt (Day 14). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. STUDY PROCEDURES 
 
5.1. Recruitment of Subjects 
 
Participants will be recruited from the community through online and newspaper 
advertisements. Campaigns in local buses and print publications (e.g., LA Weekly) will also be 
implemented. Targeted recruitment will also take place through a lab database of previous study 
participants who agreed to be contacted for future studies.   
 
5.2. Eligibility Criteria 
 
5.2.1. Inclusion Criteria 
 
To be included in the study, participants must:  
(1) 
Be between the ages of 21 and 65  
(2) 
Meet current (i.e., past 12-month) DSM-5 diagnostic criteria for AUD moderate or severe 
(3) 
Have intrinsic motivation to reduce or quit drinking (defined as self-reported intention to 
reduce or quit drinking within the next 6 months) 
Medication Titration 
Practice Quit Attempt 


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PI: Lara Ray, PhD 
 
 
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(4) 
Report drinking at least 14 drinks per week if male (7 drinks per week if female) in the 28 
days prior to the initial consent 
(5) 
Have reliable internet access 
 
5.2.2. Exclusion Criteria 
 
To be included in the study, participants must not:  
(1) 
Have a current (last 12 months) DSM-5 diagnosis of substance use disorder for any 
psychoactive substances other than alcohol and nicotine  
(2) 
Have a lifetime DSM-5 diagnosis of schizophrenia, bipolar disorder, or any psychotic 
disorder 
(3) 
Have a positive urine screen for drugs other than cannabis  
(4) 
Have clinically significant alcohol withdrawal symptoms as indicated by a score ≥ 10 on 
the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-R)  
(5) 
Have an intense fear of needles or have had any adverse reactions to needle puncture 
(6) 
Be pregnant, nursing, or planning to become pregnant while taking part in the study; and 
must agree to one of the following methods of birth control (if female), unless she or 
partner are surgically sterile:  
• 
Oral contraceptives 
• 
Contraceptive sponge 
• 
Patch 
• 
Double barrier 
• 
Intrauterine contraceptive device 
• 
Etonogestrel implant  
• 
Medroxyprogesterone acetate contraceptive injection 
• 
Complete abstinence from sexual intercourse 
• 
Hormonal vaginal contraceptive ring 
(7) 
Have a medical condition that may interfere with safe study participation (e.g., unstable 
cardiac, renal, or liver disease, uncontrolled hypertension or diabetes)  
(8) 
Be currently taking any psychotropic medications that, in the opinion of the investigators, 
compromises participant safety  
(9) 
Be currently taking either naltrexone or varenicline 
(10) 
Have any other circumstances that, in the opinion of the investigators, compromises 
participant safety 
 
5.3. Screening Phase 
 
5.3.1. Telephone Screen 
 
Individuals who call the lab (in response to flyers and advertisements) expressing interest in the 
study will receive detailed information about the study procedures, and if they remain interested 
they will complete a telephone screen performed by a trained research assistant for self-
reported inclusion and exclusion criteria. Those who appear eligible will be invited to the 
laboratory for an initial in-person screening session.  
 
5.3.2. Initial Screening Visit 
 
Prior to conducting any research related procedures, research staff will conduct the informed 
consent process, which details the procedures to take place during the screening visit.  


Practice Quit Study 
Protocol V8, Approved 02/08/2022 
PI: Lara Ray, PhD 
 
 
9 
 
Informed consent will be a three-part process. First, participants will be asked to read and 
provide verbal consent for breathalyzer. If the breathalyzer is above 0.000, the visit will be 
stopped and the participant will not be compensated. The participant will be given an 
opportunity to reschedule the visit for another day. If the breathalyzer test is negative, the 
written informed consent form will be reviewed and signed by the participant and study staff 
outlining procedures for the initial screening visit. A second written consent form will be 
reviewed and signed in the presence of the study physician at the medical screening visit if the 
participant is found eligible to continue to that visit.  
 
At the initial screening visit, subjects will be asked to provide a urine sample to test for drugs of 
abuse and pregnancy (if female), and will complete a series of questionnaires and interviews 
(described in detail below) to determine initial eligibility. This visit will take approximately 1 hour.  
 
Following the initial in-person screening, the study coordinator will meet with the PI to determine 
if the participant is eligible to continue to the medical screening based on study 
inclusion/exclusion criteria. 
 
5.3.3. Medical Screening Visit 
 
Those participants who appear to be eligible after the initial screening visit, will then be 
scheduled for a second screening visit, which will start with a breathalyzer test administered by 
study staff. If the breathalyzer is above 0.000, the visit will be stopped and the participant will 
not be compensated. The participant will be given an opportunity to reschedule the visit for 
another day. If the breathalyzer test is negative, the physician or nurse practitioner will conduct 
the second written (experimental) consent. The experimental consent process will be conducted 
in person or remotely via the UCLA HIPAA-compliant Zoom meeting platform.  In cases where 
the web-based consent process occurs, both participant and physician will provide electronic 
signatures on the consent form via DocuSign, following guidance set forth by the UCLA 
Compliance Office. After informed consent, the physician will conduct a medical history 
interview and physical exam. In addition, a urine sample will be obtained for repeat drug screen 
and pregnancy tests. The participant will then be accompanied by research personnel to the 
CTRC for blood specimen collection including Comprehensive Metabolic Panel and Complete 
Blood Count to evaluate overall health; and EKG to screen for medical conditions that could 
make study participation medically unsafe.  The study physician will review each participant’s 
medical history, vital signs, weight, review of systems, and laboratory tests, including liver 
function tests (LFTs), drug screen, chemistry screen, and urine pregnancy screen to determine 
if it is medically safe for the participant to take the study medication.  
 
Any subject who is excluded from the study will be compensated for their time in the screening 
session and will be offered referrals for alcohol treatment in the community. 
 
5.4. Medication Phase 
 
5.4.1. Randomization and Medication Titration 
 
Participants who are eligible after the physical exam will be randomized to one of three 
treatment conditions (VAR, NTX, or PLA). Urn randomization will be used to balance the groups 
by gender, smoking status (as reported on question 1 of the Fagerstrom Test for Nicotine 
Dependence), and drinking status (‘heavy’ drinker defined as 14 or more drinks per week for 


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10 
 
males/7 or more drinks per week for females, or ‘very heavy’ drinker, defined as 35 or more 
drinks per week for males/28 or more drinks per week for females). The UCLA Research 
Pharmacy will manage the blind. The three treatment conditions will not be different in 
appearance or method of administration. All participants will undergo a week-long medication 
titration period prior to the onset of the practice quit attempt.   
 
5.4.2. Practice-Quit Attempt 
 
During the practice-quit attempt, participants will be instructed to abstain completely from 
drinking alcohol during a 7-day practice quit period. This period will begin on Day 8 of study 
medication dosing. During this period, participants will complete daily online and phone visits to 
report on their drinking, mood and craving for alcohol during the previous day in a daily diary 
assessment (DDA). For each virtual visit, participants will be contacted over the phone by 
research staff. Participants will first be asked about adverse events (open-ended) and about use 
of concomitant medications. Research staff will then administer the CIWA-Ar to measure alcohol 
withdrawal. Next, they will ask participants to report on their past day drinking as well as 
cigarette and marijuana use. Finally, while participants are still on the phone, research staff will 
send a link to the daily diary assessment (administered via Qualtrics). Research staff will 
request that participants’ report the completion of this assessment via phone call or text 
message. Upon confirmation of assessment completion, staff will schedule a time for the 
following day’s virtual visit. Depending on interest and eligibility, participants may be asked to 
wear a sleep tracking wristband during the 7-day practice quit period. Participants will be 
reminded to sync wristband data to an app during the daily calls and instructed to only use the 
wristband for sleep tracking purposes. Staff will also request a picture of the medication blister 
pack to monitor medication compliance. This procedure has been designed to maintain study 
integrity while reducing participant safety burden by limiting direct, in-person contact.   
 
5.4.3. Study Medication 
 
On Day 1, participants will report to the laboratory to complete the alcohol cue-reactivity 
paradigm and receive their first medication dose under direct observation of study staff. They 
will receive a 7-day supply of study medication in blister packs with AM and PM dosing clearly 
distinguished for the titration procedure. After reaching full medication dose at the end of one 
week, participants will come to the laboratory on Day 8 to receive their second, 7-day supply of 
study medication and to begin the 7-day practice quit attempt. Participants will be asked to take 
AM dose of study medication on Day 8 in the lab under direct observation of study staff. All 
study medication will be prepared by the UCLA Research Pharmacy and will be identically 
matched in appearance (opaque capsules) and the medication labels will not reveal the drug 
identity.         
 
5.4.3.1. 
Dosing Schedule 
 
Group: 
NTX 
VAR 
PLA 
Day: 
AM 
PM 
AM 
PM 
AM 
PM 
Medication Titration 
1 
1 capsule 
(12.5mg NTX) 
1 capsule 
(placebo) 
1 capsule 
(0.5mg VAR) 
1 capsule 
(placebo) 
1 capsule 
(placebo) 
1 capsule 
(placebo) 
2 
1 capsule 
(12.5mg NTX) 
1 capsule 
(placebo) 
1 capsule 
(0.5mg VAR) 
1 capsule 
(placebo) 
1 capsule 
(placebo) 
1 capsule 
(placebo) 
3 
1 capsule 
(12.5mg NTX) 
1 capsule 
(placebo) 
1 capsule 
(0.5mg VAR) 
1 capsule 
(placebo) 
1 capsule 
(placebo) 
1 capsule 
(placebo) 


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4 
1 capsule 
(25mg NTX) 
1 capsule 
(placebo) 
1 capsule 
(0.5mg VAR) 
1 capsule 
(0.5mg VAR) 
1 capsule 
(placebo) 
1 capsule 
(placebo) 
5 
1 capsule 
(25mg NTX) 
1 capsule 
(placebo) 
1 capsule 
(0.5mg VAR) 
1 capsule 
(0.5mg VAR) 
1 capsule 
(placebo) 
1 capsule 
(placebo) 
6 
1 capsule 
(25mg NTX) 
1 capsule 
(placebo) 
1 capsule 
(0.5mg VAR) 
1 capsule 
(0.5mg VAR) 
1 capsule 
(placebo) 
1 capsule 
(placebo) 
7 
1 capsule 
(25mg NTX) 
1 capsule 
(placebo) 
1 capsule 
(0.5mg VAR) 
1 capsule 
(0.5mg VAR) 
1 capsule 
(placebo) 
1 capsule 
(placebo) 
Practice Quit Attempt 
8 
1 capsule 
(50mg NTX) 
1 capsule 
(placebo) 
1 capsule 
(1mg VAR) 
1 capsule 
(1mg VAR) 
1 capsule 
(placebo) 
1 capsule 
(placebo) 
9 
1 capsule 
(50mg NTX) 
1 capsule 
(placebo) 
1 capsule 
(1mg VAR) 
1 capsule 
(1mg VAR) 
1 capsule 
(placebo) 
1 capsule 
(placebo) 
10 
1 capsule 
(50mg NTX) 
1 capsule 
(placebo) 
1 capsule 
(1mg VAR) 
1 capsule 
(1mg VAR) 
1 capsule 
(placebo) 
1 capsule 
(placebo) 
11 
1 capsule 
(50mg NTX) 
1 capsule 
(placebo) 
1 capsule 
(1mg VAR) 
1 capsule 
(1mg VAR) 
1 capsule 
(placebo) 
1 capsule 
(placebo) 
12 
1 capsule 
(50mg NTX) 
1 capsule 
(placebo) 
1 capsule 
(1mg VAR) 
1 capsule 
(1mg VAR) 
1 capsule 
(placebo) 
1 capsule 
(placebo) 
13 
1 capsule 
(50mg NTX) 
1 capsule 
(placebo) 
1 capsule 
(1mg VAR) 
1 capsule 
(1mg VAR) 
1 capsule 
(placebo) 
1 capsule 
(placebo) 
14 
1 capsule 
(50mg NTX) 
- 
1 capsule 
(1mg VAR) 
- 
1 capsule 
(placebo) 
- 
 
5.4.4. Alcohol Cue Reactivity Sessions (CR) 
 
Randomized participants will complete a cue-exposure paradigm at two time points during the 
study, once on Day 1 prior to ingesting the first dose of study medication, and again on Day 14, 
approximately 90 minutes after study drug administration. Alcohol cue exposure will follow well-
established experimental procedures. Sessions will begin with a 3-minute relaxation period. 
Participants will then hold and smell a glass of water for 3 minutes to control for the effects of 
simple exposure to any potable liquid. Next, participants will hold and smell a glass of their 
preferred alcoholic beverage for 3 minutes. Order is not counterbalanced because of carryover 
effects that are known to occur. Participants (who are smokers) will be allowed a smoke break 
immediately prior to the CR assessment. After every 3 minutes of exposure, participants will 
rate their urge to drink on the Alcohol Urge Questionnaire (AUQ) and their mood on the Profile 
of Mood States (POMS). AUQ score (alcohol minus water) is the primary outcome for the CR. 
 
5.4.5. Behavioral Economics Procedure 
 
Participants will complete the behavioral economic protocol at the final day of the practice quit 
attempt (Day 14). Specifically, the multiple-choice procedure and measures will be completed 
after the cue-reactivity procedure in order to maintain the scientific integrity of the trial. The 
primary behavioral economic measure is the multiple-choice protocol. The multiple-choice 
protocol consists of choices between immediate alcohol (a single standard-sized drink of the 
participant’s preferred alcoholic beverage, available today) and 17 delayed monetary reward 
amounts in the form of cash or electronic gift card (1¢, 5¢, 10¢, 25¢, 50¢, $1, $1.50, $2, $3, $4, 
$5, $6, $8, $10, $15, $20, and $30, available after one week). Participants will receive one 
randomly selected choice from the multiple-choice protocol. Participants will select a poker chip 
from a bowl containing chips pertaining to all of their choices on the multiple-choice protocol. A 
computerized random number generator program may be used in lieu of the poker chips if 
COVID safety regulations require. If the participant’s choice on that item is for alcohol, they will 
receive one standard drink at that moment. If their choice is for the delayed money, they will 


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receive the money in cash or electronic gift card after one week. All participants will remain in 
their respective visit room for a 15-minute consumption period. Participants who receive alcohol 
are permitted to consume their beverage during this time. This will be followed by a recovery 
period in a laboratory lounge. The order of presentation will be multiple-choice procedure, 
hypothetical delay discounting task (Monetary Choice Questionnaire), and the hypothetical 
purchase task (Alcohol Purchase Task). Completion of the multiple-choice paradigm and 
hypothetical measures will take approximately 30 minutes. All participants will be required to 
stay in the laboratory for at least 1.5 hours after completing measures and the multiple-choice 
procedure. This will be done to standardize the procedure and prevent participants from 
choosing money instead of alcohol to limit the amount of time spent in the laboratory. 
Participants will be required to remain in the laboratory until BrAC reaches 0.00 g/dl. 
 
5.4.6. Brief Counseling Session 
 
All participants will meet in-person or via an online platform with a trained study counselor briefly 
after the behavioral economics procedure, either on Day 14 or scheduled on a separate day 
shortly after the Day 14 visit depending on participant and counselor availability.  This brief 
intervention draws from motivational interviewing and SBIRT models. It uses the therapeutic 
stance of motivational interviewing which is collaborative and client-centered. Consistent with 
the literature on brief intervention, the therapist will seek opportunities to engage in- and to 
amplify change talk. Together, the combination of evidence-based practices and principles 
applied to AUD, coupled with the experience of change in the context of study participation, is 
expected to result in an opportunity for health behavior change (i.e., reductions in alcohol use).   
 
5.5. Compensation for Participation 
 
Participants will be compensated up to $325 for their time and effort as follows: 
Initial Screening: 
 
$40 
 
Day 11 Online Visit:   
$5 
Medical Screening: 
 
$40 
 
Day 12 Online Visit:   
$5 
Cue-Exposure #1: 
 
$20 
 
Day 13 Online Visit:   
$5 
Day 1 In-person Visit:  
$30 
 
Day 14 In-person Visit: 
$30 
Day 8 In-person Visit:  
$50 
 
Sleep Tracking Wristband: 
$20 
Day 9 Online Visit:  
 
$5 
 
Cue-Exposure #2:  
 
$20 
 
Day 10 Online Visit:   
$5                    Completion Bonus:   
$50 
 
In addition, participants will have the opportunity to earn between 1¢ and $30 in the form of cash 
or electronic gift card one week after the behavioral economics paradigm described above. All 
participants will be provided with free parking validation, round-trip bus fare or transportation via 
Uber for attendance to each study visit.  Participants are free to discontinue participation at any 
time and will receive compensation for the amount of time they participated. The completion 
bonus will be given to participants who complete at least 7 of the 8 in-person and online study 
visits. 
 
6. ASSESSMENTS 
 
6.1. Schedule of Assessments Table 


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                                                    STUDY VISIT: 
Initial 
Screening 
Medical 
Screening 
CR Sessions  
(Days 1 & 14) 
Randomization 
(Day 1) 
Practice Quit 
(Days 8-14) 
SCREENING/INDIVIDUAL DIFFERENCE MEASURES: 
Alcohol Dependency Scale (ADS) 
 
 
 
x 
 
Beck Anxiety Inventory (BAI) 
 
 
 
x 
x* 
Beck Depression Inventory (BDI) 
 
 
 
x 
x* 
Brief AUD Severity Scale 
 
 
 
x 
 
Cannabis Use Disorder Identification Test (CUDIT) 
 
 
 
x 
 
Demographics 
x 
 
 
 
 
Fagerstrom Test for Nicotine Dependence (FTND) 
x 
 
 
 
 
Family Tree Questionnaire (FTQ) 
 
x 
 
Graded Chronic Pain Scale 
 
 
 
x 
 
ImBIBe 
 
 
 
x 
 
Inventory of Drinking Situations (IDS) 
 
 
 
x 
 
Locator Form 
x 
 
 
 
 
Monetary Choice Questionnaire (MCQ) 
 
 
 
x 
x* 
Obsessive Compulsive Drinking Scale (OCDS) 
 
 
 
x 
x* 
Penn Alcohol Craving Scale (PACS) 
 
 
 
x 
x* 
Perceived Stress Scale (PSS) 
 
 
 
x 
 
Pittsburgh Sleep Quality Index (PSQI) 
 
 
 
x 
x* 
Readiness to Change (RTC) Ladder 
 
 
 
x 
 
Self-Report Habit Index (SRHI) Drinking & Smoking 
 
 
 
x 
 
Structured Clinical Interview for DSM-5 Screener & AUD Module 
x 
 
 
 
 
Timeline Follow Back (TLFB) 
x 
x 
 
X 
x 
UCLA Reward Relief Habit Drinking Scale (UCLA RRHDS) 
 
 
 
X 
 
UPPS-P Impulsive Behavior Scale 
 
 
 
X 
 
SAFETY MEASURES/BIOMARKERS: 
Adverse Events/SAFTEE 
 
 
 
 
x 
Alcohol Breathalyzer 
x 
x 
x 
X 
x 
Birth Control Assessment 
x 
 
 
 
 
Clinical Institute Withdrawal Assessment (CIWA-AR) 
x 
x 
 
X 
x 
Columbia Suicide Severity Rating Scale (C-SSRS) 
x 
 
 
 
 
Comprehensive Metabolic Panel/Complete Blood Count 
 
x 
 
 
 
Concomitant Medications 
x 
x 
 
X 
x 
Electrocardiogram (EKG) 
 
x 
 
 
 
Medical History/Physical Exam 
 
x 
 
 
 
Urine Ethyl Glucuronide (EtG) Test 
 
 
 
 
x 
Urine Drug Screen 
x 
x 
 
X 
 
Urine Pregnancy Test 
x 
x 
 
X 
x* 
Vital Signs 
x 
x 
X 
x 
EXPERIMENTAL MEASURES: 
Alcohol Purchase Task (APT) 
 
 
 
 
x* 
Alcohol Urge Questionnaire (AUQ) 
 
 
x 
 
 
Daily Diary Assessment 
 
 
 
 
x 
Multiple Choice Procedure (MCP) 
 
 
 
 
x* 
Profile of Mood States (POMS) 
 
 
x 
 
 


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Sleep Tracking Wristband 
 
 
 
 
x 
*Measure collected on Day 14 only 
 
6.2. Description of Assessments 
 
6.2.1. Alcohol Dependency Scale 
 
The Alcohol Dependency Scale is a 25-item scale that measures alcohol dependence 
symptoms over the past 12 months.  The ADS is a self-report measure that assesses problems 
that are relevant for alcohol dependent drinkers and will be completed by the participant 
electronically at the randomization visit. 
 
6.2.2. Beck Anxiety Inventory (BAI) 
 
The Beck Anxiety Inventory (BAI) surveys anxiety symptomatology including physical and 
cognitive indicators of anxious mood. The BAI will be completed electronically at the 
randomization and final (Day 14) visit. 
 
6.2.3. Beck Depression Inventory (BDI-II) 
 
The Beck Depression Inventory, Revised (BDI-II) captures depressive symptomatology.  The 
BDI-II will be completed at the Day 1 (randomization), and Day 14 visits.  
 
6.2.4. Brief AUD Severity Scale (BASS) 
 
The Brief AUD Severity Scale (BASS) is a 9-item self-report measure used to assess alcohol use 
disorder severity.  The BASS will be completed at the randomization visit. 
 
6.2.5. Cannabis Use Disorder Identification Test (CUDIT) 
 
The Cannabis Use Disorder Identification Test (CUDIT) is an 8-item measure used to screen for 
cannabis use disorders (CUD) and will be completed at the randomization visit. 
 
6.2.6. Demographics 
 
Demographics data include the participant’s age, gender, race/ethnicity, marital status, 
education, employment pattern, occupation, and income level. This questionnaire will be 
administered electronically at the initial screening visit. 
 
6.2.7. Fagerström Test for Nicotine Dependence (FTND) 
 
The Fagerström Test for Nicotine Dependence will be used to assess smoking status at the 
initial screening visit. This questionnaire will be completed by the subject electronically. 
 
6.2.8. Family Tree Questionnaire (FTQ) 
 
Information on family history of alcohol problems will be collected using the Family 


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Tree Questionnaire. The questionnaire provides subjects with a family tree listing of relatives to 
identify blood relatives with alcohol problems. This questionnaire will be completed by the 
subject electronically at the randomization visit (Day 1). 
 
6.2.9. Graded Chronic Pain Scale 
 
The Graded Chronic Pain scale is a 7-item measure used to evaluate an individual’s overall 
severity of chronic pain if they have suffered from chronic pain that has lasted at least six 
months. The measure assesses on two dimensions: pain severity, and pain-related disability. 
This questionnaire will be completed by participants electronically at the randomization visit. 
 
6.2.10. ImBIBe 
 
The ImBIBe is a 15-item questionnaire in which the subject responds on a 5-point scale 
responses to questions on the consequences of alcohol use. The ImBIBe will be completed at 
the randomization visit (Day 1). 
 
6.2.11. Inventory of Drinking Situations (IDS) 
 
The Inventory of Drinking situations (IDS) is a questionnaire developed to characterize the 
particular high-risk situations of a problem drinker.  The IDS will be completed by the participant 
electronically at the randomization visit.   
6.2.12. Locator Form 
 
The Locator Form asks participant to provide his/her name, address, and phone number and to 
provide names, addresses, and phone numbers of friends and family members who can be 
contacted if the subject cannot be located. This information is essential and will be collected 
during the initial screening, and will be updated throughout the study as necessary. 
 
6.2.13. Monetary Choice Questionnaire (MCQ) 
 
The Monetary Choice Questionnaire is a 27-item self-administered questionnaire in which the 
participant chooses between a smaller, immediate monetary reward and a larger, delayed 
monetary reward.  The MCQ will be completed at randomization and Day 14 visit, as part of the 
behavioral economics paradigm. 
 
6.2.14. Obsessive Compulsive Drinking Scale (OCDS) 
 
The 14-item Obsessive Compulsive Drinking Scale (OCDS) is a quick and reliable self-rating 
instrument that provides a total and two subscale scores that measure some cognitive aspects 
of alcohol craving.  The OCDS will be completed at the randomization and Day 14 visits.   
 
1.1.1. Penn Alcohol Craving Scale (PACS) 
 
The PACS is a five-item, self-report measure that includes questions about the frequency, 
intensity, and duration of craving, the ability to resist drinking, and asks for an overall rating of 
craving for alcohol for the previous week. Each question is scaled from 0 to 6. Participants will 
complete this scale at randomization and Day 14. 


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1.1.2. Perceived Stress Scale (PSS) 
 
The PSS is a measure of the degree to which situations in one’s life are appraised as stressful.  
Items were designed to tap how unpredictable, uncontrollable, and overloaded respondents find 
their lives.  The PSS will be completed at randomization.   
 
1.1.3. Pittsburgh Sleep Quality Index (PSQI) 
 
The Pittsburgh Sleep Quality Index (PSQI) is a self-report questionnaire that assesses sleep 
quality over a 1-month time interval.  The measure consists of 19 individual items, creating 7 
components that produce one global score, and takes 5-10 minutes to complete.  The PSQI will 
be completed at the randomization and Day 14 visits.   
 
1.1. Readiness to Change (RTC) Ladder 
 
The Readiness to Change Ladder is a measure with 11 response items designed to assess 
motivation to reduce or cut back on drinking.  This assessment will be completed at the 
randomization visit. 
 
1.1.1. Self-Report Habit Index Form (SRHI) 
 
The Self-Report Habit Index (SRHI) is an instrument that measures self-reported perceptions of 
habit strength for an identified behavior.  In addition to measuring prior behavior and 
automaticity, the SRHI measures identity expression as a component of habit.  The SRHI will be 
assessed for drinking and smoking and will be completed at the randomization visit.   
 
1.1.4. Sleep Tracking Wristband  
 
The Fitbit Charge 5 is a health tracker used as a passive sleep tracking device. Interested 
participants will be asked to wear the sleep tracking wristband every night during the practice 
quit attempt (Days 8 – 14). Sleep data from the previous day will be synced to the Fitbit app 
every day.  
 
1.1.5. Structured Clinical Interview for DSM-5 Disorders 
 
The SCID is a semi-structured interview for making the major DSM-5 diagnoses.  The SCID 
screener assessment and alcohol module, used to assess current (past 12-month) AUD 
diagnosis will be completed by appropriately trained research personnel.  Any positive 
responses on the SCID screener will be further assessed by the study physician to determine 
eligibility.  
 
1.1.6. Timeline Follow Back (TLFB) 
 
The Time Line Follow Back will be administered to assess quantity and frequency of alcohol, 
cigarette and marijuana use and will be completed at the initial screening (for the 30 days prior 
to that visit) and at each subsequent visit, including phone visits, to gather data for every day 
prior to and including the last visit. Information obtained in this interview will be recorded on the 
TLFB Calendar and transcribed to the database.   
 


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1.1.7. UCLA Reward Relief Habit Drinking Scale (UCLA RRHDS) 
 
The UCLA RRHDS is a 4-item self-report questionnaire to assess reward, relief and habit 
drinking sub-types.  It will be completed electronically at the randomization visit. 
 
1.1.8. UPPS-P Impulsive Behavior Scale 
 
The UPPS-P Impulsive Behavior Scale is a 59-item self-report that assesses five subscales 
(urgency, premeditation, perseverance, sensation seeking, and positive urgency) that are used 
to measure 5 distinct dimensions of impulsive behavior.  This measure will be completed 
electronically at the randomization visit.   
1.1.9. Adverse Events/SAFTEE Assessment 
 
On each day of the practice-quit attempt (Days 8-14) participants will be asked by study staff if 
they have experienced any symptoms or side effects since the last visit.  With guidance from the 
study physician, each participant response will be coded into one of the listed items on the 
SAFTEE (Systematic Assessment of Treatment Emergent Effects).   
 
1.1.10. Alcohol Breathalyzer 
 
An alcohol breathalyzer will be administered at consent, and at every in-person study visit as a 
safety measure. BrAC must be equal to 0.000 prior to performing any study assessments.  
Results will be recorded on the paper checklist, and later entered into the database. 
 
1.1.11. Birth Control Assessment 
 
The Birth Control Assessment is designed to confirm a female subject’s compliance with the 
birth control specifications detailed in the inclusion criteria.  Birth Control Assessment 
information will be recorded on the checklist at the initial screening visit for participant safety 
purposes. 
 
1.1.12. Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) 
 
The CIWA-AR is a brief 10-item measure used to provide a quantitative index of the severity of 
the alcohol withdrawal syndrome. The CIWA-AR has been used both in clinical and research 
applications and has demonstrated both reliability and validity.  This questionnaire will be 
administered by appropriately trained staff during the initial and medical screening, and at each 
visit during the medication phase.  Participant responses will then be entered electronically. 
 
1.1.13. Columbia Suicide Severity Rating Scale (C-SSRS) 
 
The C-SSRS is a 4-page form asking questions about suicidal ideation, intensity of ideation, and 
suicidal behavior developed by Posner and collaborators at the New York State Psychiatric 
Institute. This scale is intended for use by trained administrators. The questions contained in the 
C-SSRS are suggested probes. Ultimately, the determination of the presence of suicidality 
depends on clinical judgment. Training is required before administering the C-SSRS through a 
30-minute interactive slide presentation followed by a question-answer session through the 
Columbia University Medical Center. Those completing the training are certified to administer 
the C-SSRS, and will receive a training certificate. This scale will be used to assess current 


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18 
 
suicidal ideation at each visit and will be administered at the initial screening visit by a trained 
staff member with responses recorded on paper first, then entered electronically. 
 
1.1.14. Comprehensive Metabolic Panel/Complete Blood Count 
 
Blood will be drawn for a comprehensive metabolic panel and complete drug count during the 
medical screening to assess for participant safety. The total blood volume to be collected is 
approximately 8 mL. Additional laboratory samples may be taken at the discretion of the study 
physician if the results of any tests fall outside reference ranges or clinical symptoms 
necessitate testing to ensure safety.  
 
1.1.15. Concomitant Medications 
 
All medications taken by the participant 2-weeks prior to the start of screening and through the 
final visit, collected via participant self-report will be recorded on a source document and later 
entered electronically. 
   
1.1.16. Electrocardiogram (EKG) 
 
A 12-lead resting EKG will be obtained at the medical screening visit to assess for medical 
safety. Any abnormalities will be noted and an assessment of clinical significance will be made 
by the study physician. 
 
1.1.17. Medical History 
 
A Medical History interview will be conducted by the study physician at the medical screening 
visit and will screen for medical conditions that would make participation unsafe. 
 
1.1.18. Physical Exam 
 
A physical examination of the oral cavity, head, eyes, ears, nose, and throat, cardiovascular 
system, lungs, abdomen, extremities, skin, neuropsychiatric mental status and sensory/motor 
status, musculoskeletal system and general appearance will be performed during the medical 
screening visit.   
 
1.1.19. Urine Ethyl Glucuronide Test (EtG) 
 
The ethyl glucuronide (EtG) test is widely used to detect the presence in the urine of ethyl 
glucuronide, a breakdown product of ethanol, the intoxicating agent in alcohol.  A urine EtG test 
will be conducted during the practice quit attempt on day 8 and day 14 to assess for recent 
alcohol use.   
 
1.1.20. Urine Drug Screen 
 
An FDA cleared, CLIA waived urine drug test card will be used at all visits to assess for recent 
use of opioids, cocaine, amphetamines, methamphetamine, THC, buprenorphine, methadone or 
benzodiazepines. Subjects must be negative for all substances except THC. Results will be 
recorded on the visit checklist first and then entered into the database. 
 


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19 
 
1.1.21. Urine Pregnancy Test 
 
An FDA approved rapid result urine pregnancy test will be used (i.e., dipstick test) to assess for 
pregnancy in female participants at each screening visit and on Day 1 and Day 14 of the 
medication phase.  If applicable, participants will be asked to sign a release of information form 
for study personnel to access medical records to obtain information regarding the outcome of a 
pregnancy that occurred during the study. 
 
1.1.22. Vital Signs 
 
Vital signs include sitting blood pressure, pulse rate (after sitting for at least 3 minutes) and 
weight. Values will be recorded on the visit checklist and entered into the database. Vital signs 
will be collected at every in-person visit. 
 
1.1.23. Alcohol Purchase Task (APT) 
 
The Alcohol Purchase Task (APT) will be used to assess state-level alcohol demand during the 
behavioral economics paradigm at Day 14. The APT is a hypothetical assessment wherein 
participants report how many standard drinks they would immediately consume at 17 price 
points: free, 5¢, 10¢, 25¢, 50¢, $1, $1.50, $2, $3, $4, $5, $6, $8, $10, $15, $20, and $30. A 
hypothetical APT will be used given evidence that derived alcohol demand indices correlate with 
both self-reported drinking measures and alcohol consumption during actual purchase tasks. 
 
1.1.24. Alcohol Urge Questionnaire (AUQ) 
 
The Alcohol Urge Questionnaire (AUQ) is comprised of eight items rated on a 7-point Likert 
scale with items related to the subjective experience of alcohol craving. The AUQ has 
demonstrated high reliability in experimental studies of state alcohol craving and will be 
completed after every 3 minutes of exposure during the cue exposure paradigm on Days 1 and 
14. 
 
1.1.25. Daily Diary Assessment (DDA) 
 
Participants will complete daily diary assessments reporting on their mood, alcohol and cigarette 
craving, motivation to change, self-efficacy, pain, and drinking behavior from the previous day.  
Participants will complete the DDA electronically during the practice quit attempt (days 8-14).  
Research staff will distribute the link to the online daily diary assessment during each in-person 
and virtual visit.  
 
1.1.26. Multiple Choice Procedure (MCP) 
 
The Multiple Choice Procedure (MCP) is the primary behavioral economic measure.  The 
multiple-choice protocol consists of choices between immediate alcohol (a single standard-sized 
drink of the participant’s preferred alcoholic beverage, available today) and 17 delayed 
monetary reward amounts (1¢, 5¢, 10¢, 25¢, 50¢, $1, $1.50, $2, $3, $4, $5, $6, $8, $10, $15, 
$20, and $30, available after one week). Participants will receive one randomly selected choice 
from the multiple-choice protocol. Participants will select a poker chip from a bowl containing 
chips pertaining to all of their choices on the multiple-choice protocol. A computerized random 
number generator program may be used in lieu of the poker chips if COVID safety regulations 


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require. If the participant’s choice on that item is for alcohol, they will receive one standard drink 
at that moment. If their choice is for the delayed money, they will receive the money in cash 
after one week. All participants will remain in their respective visit room for a 15-minute 
consumption period. Participants who receive alcohol are permitted to consume their beverage 
during this time. This will be followed by a recovery period in a laboratory lounge. 
 
1.1.27. Profile of Mood States (POMS) 
 
The POMS measures dimensions of mood and will be completed during the cue reactivity 
sessions.  
 
2. SAFETY MONITORING PLAN 
 
Safety monitoring will be conducted throughout the study; therefore, safety concerns will be 
identified by continuous review of the data by the PI and study physician, internal quality 
assurance checks, and DSMB. 
 
2.1. PI and Study Physician Safety Monitoring 
 
Participants will be given a 24-hour telephone number for calling the physician to discuss side 
effects, and physician office hours will be available as needed. Adverse events, including signs 
of sickness will be collected in an open-ended way at each in-person and phone study visit.  
Vital signs will be monitored at multiple time points during the experimental study visits. Alcohol 
withdrawal will be monitored at each visit through administration of the CIWA, and any 
significant withdrawal, as indicated by a score of 10+ on the CIWA will be reported to the study 
physician immediately.  In the event that significant medical problems are encountered, the 
study blind will be broken and appropriate medical treatment will be provided.  
 
2.2. Internal Quality Assurance Monitoring 
 
The PI will designate appropriately qualified personnel to periodically perform quality assurance 
checks at mutually convenient times during and after the study. These monitoring visits provide 
the opportunity to evaluate the progress of the study and to obtain information about potential 
problems. The monitor will assure that data are accurate and in agreement with any paper 
source documentation used, verify that subjects’ consent for study participation has been 
properly obtained and documented, confirm that research subjects entered into the study meet 
inclusion and exclusion criteria, verify that study procedures are being conducted according to 
the protocol guidelines, monitor review AEs and SAEs, and assure that all essential 
documentation required by Good Clinical Practices (GCP) guidelines are appropriately filed.  At 
the end of the study, they will confirm that the site has the appropriate essential documents on 
file, and advise on storage of study records. 
 
3. STATISTICAL METHODS AND POWER CONSIDERATIONS 
 
3.1. Statistical Power 
 
Power analyses were conducted using G*Power 3.1.9.2. In order to conduct a one-way ANOVA 
with fixed effects, we estimated a medium-to-large effect size (f=0.40 and an alpha error 
probability of 0.05). Specifically, with 3 groups a sample size of 90 completers, the proposed 


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study has an actual power of 0.91%. Therefore, we propose to randomize 108 individuals (36 in 
each group) to reach a final sample of 30 completers per group. This will allow us the statistical 
power to detect a medium-to-large effect size as projected. 
 
3.2. Data Analytic Plan 
 
Descriptive statistics will be computed for continuous outcome variables, and frequencies for 
categorical variables to summarize the study data. Box plots, histograms, and Q-Q plots will be 
used to check for skewness and normality for continuous variables. Transformations of 
continuous outcome variables will be performed as necessary to ensure that the normality 
assumptions in parametric tests are met. The models described below will test whether 
medication effects in reducing drinking behavior during the practice quit attempt are associated 
with concurrent blunting of cue reactivity. To improve model fit and hypothesis testing, we will 
consider covariates, such as age, sex, ethnicity, medication order, and AUD symptom count. 
 
3.2.1. Primary Aim 1: To test that NTX and VAR will reduce drinking during the 
practice quit attempt as compared to placebo. 
 
A series of repeated measures ANCOVAs will be conducted using PROC GLM in SAS 
Statistical Software. Specifically, we will conduct repeated measures ANCOVAs on Percent 
Days Abstinent (PDA), and Drinks per Drinking Day (DPDD), our two co-primary outcomes, as 
predicted by Medication (NTX vs. PLAC and VAR vs. PLAC) a between-subjects factor and the 
covariate of baseline PDA and DPDD. 
 
3.2.2. Primary Aim 2: To test that NTX and VAR will reduce cue-induced craving for 
alcohol as compared to placebo. 
 
We will conduct a series of repeated measures ANOVAs on Alcohol Cue – Water Cue change 
scores on the AUQ as predicted by Medication condition (NTX vs. PLAC and VAR vs. PLAC).  
 
3.2.3. Primary Aim 3: To test that medication effects on cue-reactivity are 
associated with medication effects on drinking outcomes during the quit 
attempt. 
 
A series of regression analyses will be conducted testing whether medication effects on drinking 
(indicated by NTX – PLAC and VAR – PLAC change scores) are predicted by medication 
effects on cue reactivity (indicated by NTX – PLAC and VAR – PLAC change scores on the cue 
reactivity outcomes described for Aim #2).  
 
3.2.4. Secondary Aim 1:    Medication Effects on Alcohol Choice, Delay 
Discounting, and Alcohol Demand. 
 
One-way Analysis of Covariance (ANCOVAs) will be used to determine significant mean 
differences in crossover points on the multiple-choice paradigm, delay discounting, and alcohol 
demand between the medication groups (naltrexone, varenicline, and placebo). Mediation 
analyses will be used to determine whether the effects of medication on the multiple-choice 
paradigm were mediated by changes in discounting or demand for alcohol. Baseline covariates 
such as age, sex, and smoking status will be included in the model. 
 


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3.2.5. Secondary Aim 2:  Alcohol Choice and Drinking Behavior During Practice 
Quit Attempt. 
 
Multiple regression analyses will be used to determine whether the number of drinks per 
drinking day and percentage of days abstinent during the practice quit attempt predict alcohol 
choice. Regression analyses will also include medication condition (naltrexone, varenicline, 
placebo) as a moderator of the relationship between alcohol drinking behaviors during the 
practice quit attempt and alcohol choice. Baseline covariates such as age, sex, and smoking 
status will also be included in the model. 
3.2.6. Exploratory Aim 
 
We will conduct direct comparisons between the two active medications (VAR vs. NTX) as part 
of the exploratory analyses for the study.  
4. ETHICS 
 
4.1. IRB Review  
 
The study will be conducted under a protocol reviewed by the UCLA IRB; the study is to be 
conducted by scientifically and medically qualified persons; the benefits of the study are in 
proportion to the risks; the rights and welfare of the subjects will be respected; the physicians 
conducting the study will ensure that the hazards do not outweigh the potential benefits; the 
results to be reported will be accurate; subjects will give their informed consent and will be 
competent to do so and not under duress; and all study staff will comply with the ethical 
principles in 21 Code of Federal Regulations (CFR) Part 50 and the Belmont Principles. 
 
4.1.1. Protocol Modifications 
 
All necessary protocol changes will be submitted in writing as protocol amendments to the IRB 
by the PI for approval prior to implementation.  
 
 
4.1.2. Protocol Deviation Reporting Procedures 
 
All subject-specific deviations from the protocol are to be documented. The PI or designee will 
be responsible for identifying and reporting all deviations, which are occurrences involving a 
procedure that did not follow the study protocol. Any protocol deviation that adversely affects the 
safety or rights of a subject or scientific integrity of the study is considered a major deviation and 
will be reported immediately to the UCLA IRB. 
 
 
4.2. Ethical Conduct of the Study 
 
This study will be conducted in accordance with all applicable Federal human research 
protections requirements and the Belmont Principles of respect for persons, beneficence, and 
justice.  The procedures set out in this study are designed to ensure that all study personnel 
abide by the principles of the ICH GCP Guideline and the Code of Federal Regulations (CFR). 
The PI confirms this by signing FDA Form 1572. 
 
 
4.2.1. Confidentiality of Data and Subject Records  


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To maintain subject confidentiality, all laboratory specimens, eCRFs, reports and other records 
will be identified by a subject number only. Research and clinical records will be stored in a 
locked cabinet. Only research staff, and other required regulatory representatives will have 
access to the records. Subject information will not be released without written permission. The 
PI has received a Certificate of Confidentiality for this study. 
 
 
4.2.2. Compensation for Participation 
 
 
Subjects will be compensated for travel expenses and for time contributed to this research study 
in the form of cash. Compensation will be provided at each subject visit and is detailed in the 
informed consent form. 
 
4.2.3. Written Informed Consent 
 
 
The informed consent process and document will be reviewed and approved by the IRB and 
prior to initiation of the study. The consent document contains a full explanation of the possible 
risks, advantages, and alternate treatment options, and availability of treatment in the case of 
injury, in accordance with 21 CFR Part 50. The consent document indicates that by signature, 
the subject, permits access to relevant medical records as described above. A written informed 
consent document, in compliance with 21 CFR Part 50, 32 CFR Part 219, and the Belmont 
Principles, and HIPAA Authorization will be signed by the subject before any study-related 
procedures are initiated for each subject. All potential subjects for the study will be given a 
current copy of the Informed Consent Form to read. All aspects of the study and informed 
consent will be explained in lay language to the subject by either the investigator, or a medically 
trained designee. Any subject who is unable to demonstrate understanding of the information 
contained in the informed consent will be excluded from study participation. All study subjects 
will be given a copy of the signed informed consent. 
 
4.2.4. Delegation of Responsibilities and Adequate Resources 
 
 
The PI should have adequate time to conduct the study properly and should have an adequate 
number of qualified staff to assist with the conduct of the study. The term “investigator” used 
throughout this protocol refers to the PI and/or qualified Sub-investigators. The PI may delegate 
responsibilities to other study site personnel. The PI shall delegate tasks only to individuals 
qualified by education, training, and experience to perform the delegated tasks. The PI shall 
have direct oversight of all delegated activities and shall document delegation of responsibilities. 
The PI is responsible for ensuring all delegated staff has been properly trained on the protocol 
and their assigned study responsibilities. A delegation log identifying all delegated duties and 
the individual to whom they have been delegated will be maintained at the study site. 
 
4.2.5. Financial Disclosure 
 
Clinical investigators are required to provide financial disclosure information for the submission 
of certification or disclosure statements required under 21 CFR § 54. As defined in 21 CFR 
§54.2, a clinical investigator is a listed or identified investigator or sub-investigator who is 
directly involved in the treatment or evaluation of research subjects. The term also includes the 
spouse and each dependent child of the investigator. In addition, investigators must promptly 
update financial disclosure information if any relevant changes occur during the course of the 
investigation and for 1 year following completion of the study. 


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5. DATA HANDLING AND RECORD KEEPING 
 
Source documents include but are not limited to original documents, data and records such as 
hospital/medical records (including electronic health records), clinic charts, laboratory results, 
data recorded in automated instruments, and pharmacy records, etc. This study will use an 
electronic data capture (EDC) eCRF system (Qualtrics) and paper source documents. Data will 
be transcribed from source documentation directly into a statistical program such as SPSS. 
Only questionnaire data will be entered directly into eCRF (i.e., without prior written or electronic 
record of data). Paper copies of the eCRFs will be available in the event that the EDC is not 
accessible at the time the questionnaire is being completed. The transcribed data will be 
consistent with the source documents or the discrepancies will be explained.  All entries, 
corrections, and alterations will be made by the investigator or other authorized study personnel.  
The EDC system maintains a full audit trail of data entry, data corrections, and data queries. 
 
 
5.1. Subject Identification and Confidentiality 
 
 
Subjects will be identified on eCRFs and paper source documents by a unique subject number. 
No personal identifier will be used in any publication or communication used to support this 
research study. The subject number will be used if it becomes necessary to identify data 
specific to a single subject. Regulatory bodies, such as the FDA and IRB, are eligible to review 
medical and research records related to this study as a part of their responsibility to protect 
human subjects in clinical research. Personal identifiers will be removed from photocopied or 
electronic medical and research records. 
 
5.2. Retention of Records 
 
The investigator is responsible for creating and/or maintaining all study documentation required 
by Title 21 Code of Federal Regulations (21CFR) Parts 50, 54, 56, and 312, ICH E6 section 8, 
as well as any other documentation defined in the protocol. Federal and local regulations 
require that the investigator retain a copy of all regulatory documents and records that support 
the data for this study for whichever of the following is the longest period of time: 
 
• 
A period of 2 years following the final date of approval by the FDA or other regulatory 
agency of the study drug for the purposes that were the subject of the investigation; or 
• 
A period of 5 years following the date on which the results of the investigation were 
submitted to the FDA or other regulatory agency in support of, or as part of, an 
application for a research or marketing permit for the study drug for the purposes that 
were the subject of the investigation. 
 
If the investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred to a person who will accept the 
responsibility.  
 
 
 


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22.  Mazas CA, Finn PR, Steinmetz JE. Decision-making biases, antisocial personality, and 
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31.  MacKillop J, Miranda R, Jr., Monti PM, Ray LA, Murphy JG, Rohsenow DJ, McGeary JE, 
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34.  Moallem NR, Ray LA. Dimensions of impulsivity among heavy drinkers, smokers, and 
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41.  Kiselica AM, Webber TA, Bornovalova MA. Validity of the alcohol purchase task: a meta-
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44.  MacKillop J, Murphy JG. A behavioral economic measure of demand for alcohol predicts 
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45.  Bujarski S, MacKillop J, Ray LA. Understanding naltrexone mechanism of action and 
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46.  Green R, Ray LA. Effects of varenicline on subjective craving and relative reinforcing value 
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60.  Schmitz JA, Sayre SL, Hokanson PS, Spiga R. Assessment of the relative reinforcement 
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66.  Nieto SJ, Grodin EN, Ray LA. On the path toward personalized medicine: implications of 
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74.  Iniguez SD, Aubry A, Riggs LM, Alipio JB, Zanca RM, Flores-Ramirez FJ, Hernandez MA, 
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75.  Iñiguez SD, Alcantara LF, Warren BL, Riggs LM, Parise EM, Vialou V, Wright KN, Dayrit G, 
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76.  Iñiguez SD, Riggs LM, Nieto SJ, Wright KN, Zamora NN, Cruz B, Zavala AR, Robison AJ, 
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77.  Nieto SJ, Patriquin MA, Nielsen DA, Kosten TA. Don't worry; be informed about the 
epigenetics of anxiety. Pharmacol Biochem Behav. 2016;146-147:60-72. PMCID: PMC4939112 


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78.  Grodin EN, Bujarski S, Venegas A, Baskerville WA, Nieto SJ, Jentsch JD, Ray LA. Reward, 
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79.  Ray LA, Du H, Grodin E, Bujarski S, Meredith L, Ho D, Nieto S, Wassum K. Capturing 
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