Enhancing the Effects of Adolescent Alcohol Treatment With Atomoxetine
Phase: PHASE2
Conditions: Alcohol Use Disorder
Sponsor: Brown University

Atomoxetine – Proof-of-Concept Trial   
 
Brown University 
NCT#: NCT04565288 
 
28APR2025 
 
 
 
 
1
                                              
 
 
Enhancing the Effects of Adolescent Alcohol 
Treatment with Atomoxetine 
 
Funding Source: 
National Institute on Alcohol Abuse and Alcoholism (NIAAA) 
National Institutes of Health 
Division of Medications Development 
6700B Rockledge Dr.  
Bethesda, MD 20892-6902 
 
Principal Investigator: 
 
Robert Miranda Jr., PhD, ABPP 
Brown University 
Center for Alcohol and Addiction Studies 
Box G-S121-4 | Providence, RI 02912 – US Postal Service 
121 S. Main Street | Rm. 409 | Providence, RI 02903 – Other 
Phone: 401-863-6658 
Fax: 401-863-6647 
E-mail: Robert_Miranda_Jr@brown.edu 
 
Medical Monitor: 
Robert Swift, MD, PhD 
Brown University Alpert Medical School 
Chief of Mental Health and Behavioral Sciences & Associate Chief of  
Staff for Education 
Providence VA Medical Center 
Phone: (401) 457-3057 
Email: Robert_Swift_MD@brown.edu 
 
 
 
 
 
 

Atomoxetine – Proof-of-Concept Trial   
 
Brown University 
NCT#: NCT04565288 
 
28APR2025 
 
 
 
 
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Statement of Compliance 
 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CRF Part 
46, 21 CFR Part 50, 21 CFR Part 56 and 21 CFR Part 312) 
• 
International Conference on Harmonisation (ICH) E6 
 
All key personnel (all individuals responsible for the design and conduct of this study) have completed 
Human Subjects Protection Training. 
 
 
 

Atomoxetine – Proof-of-Concept Trial   
 
Brown University 
NCT#: NCT04565288 
 
28APR2025 
 
 
 
 
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Protocol Synopsis 
Name of Sponsor/Company: National Institute on Alcohol Abuse and Alcoholism (NIAAA) 
Name of Investigational Product: Atomoxetine HCl, oral administration, 40mg to 80mg QD 
Name of Active Ingredient: Atomoxetine 
Protocol Number: ATOM-000 
Study Title: Enhancing the Effects of Adolescent Alcohol Treatment with Atomoxetine 
Principal Investigator: Robert Miranda Jr., PhD, ABPP 
Study Centers: 1 site in the United States (Brown University) 
Study Period: Estimated date first subject enrolled: 03/01/2021; Last completed: 03/31/2022  
Phase of Development: 2 
 
 
Primary Objectives 
The first primary objective of this study is to evaluate the feasibility, acceptability, and tolerability of atomoxetine 
(40 mg/day for 3 days then 80 mg/day thereafter) as compared to placebo for 6 weeks plus a psychosocial 
platform comprised of motivational enhancement therapy and cognitive behavioral therapy (MET-CBT; “Path 
180”) among adolescents (ages 14 to 20 years) with alcohol use disorder as confirmed by the Diagnostic and 
Statistical Manual of Mental Disorders – Fifth Edition (DSM-5™).  
The second primary objective is to leverage a human laboratory paradigm (H-LAB) to evaluate the effects of 
atomoxetine on an intermediate phenotype (alcohol craving) associated with alcohol use and outcomes in clinical 
trials. We hypothesize that atomoxetine, as compared to placebo, will decrease the likelihood of craving in the 
human laboratory during in vivo alcohol cue reactivity.  
 
Methodology 
This proof-of-concept study is a double-blind, randomized, placebo-controlled, parallel group, single-site clinical 
trial. After obtaining consent/parent permission/assent, potential subjects and, if younger than 18 years, their 
parent(s) will complete a medical history and psychiatric diagnosis interview (about the adolescent) to screen for 
eligibility. Youth will also complete a physical examination, vital signs, drinking history by the timeline follow-
back (TLFB) method, alcohol breathalyzer test, Clinical Institute Withdrawal Assessment for Alcohol-revised 
(CIWA-AR), prior/current medication use, urine toxicology screen, clinical chemistry, and the Columbia Suicide 
Severity Rating Scale (CSSR-S). Females of child-bearing potential will have a pregnancy test.  
If eligible for the study, 50 subjects will be randomized in an approximate 1:1 ratio (targeting 21 subjects per 
group – 42 subjects total) to either atomoxetine or placebo for 6 weeks. 
Atomoxetine will be dosed at 40 mg/day for three days then increased to the maintenance dose of 80 mg (active) 
taken orally once daily (QD) for an additional 5.5 weeks. Subjects randomized to the placebo condition will be 
given an equal number of visually matched capsules.   
At the randomization/baseline visit and after 4 weeks of investigational product administration (i.e., Study Week 
5), subjects will undergo a human laboratory paradigm (i.e., alcohol cue reactivity assessment). 
Number of Subjects (Planned): 50 (targeting 21 subjects per group – 42 subjects total) 
Main Inclusion/Exclusion Criteria: Subjects will be male and female adolescents, ages 14 to 20 years old, who 
meet DSM-5 criteria for alcohol use disorder. They must be seeking to reduce their alcohol use.  

Atomoxetine – Proof-of-Concept Trial   
 
Brown University 
NCT#: NCT04565288 
 
28APR2025 
 
 
 
 
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Investigational Product, Dosage and Mode of Administration: Dose titration and maintenance will occur as 
scheduled below. Atomoxetine will be self-administered by subjects once daily after eating and with a full glass 
of water beginning on Study Week 1, Day 1 and continuing through Study Week 6, Day 7. The first dose will be 
taken in the study clinic whenever possible. Subjects will be provided with water and a snack to take with first 
dose. Dose will be titrated, as tolerated, to a target dose of 80 mg once per day of atomoxetine. Capsules should 
be swallowed whole and should not be cut, crushed, or chewed. Capsules should be taken with food and water. 
Schedule of Administration of Investigational Product 
Study Period 
Time Period 
AM Dose 
(# of capsules) 
PM Dose 
(# of capsules) 
Titration 
Study Week 1, Day 1 – 3 
40 mg (1) 
None 
Maintenance 
Study Week 1, Day 4 – Week 6, Day 7 
40 mg (2) 
None 
 
Reference Therapy, Dosage and Mode of Administration: Identically over encapsulated placebo tablets will be 
dispensed according to the same schedule as the atomoxetine capsules. 
 
 
 

Atomoxetine – Proof-of-Concept Trial   
 
Brown University 
NCT#: NCT04565288 
 
28APR2025 
 
 
 
 
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Table of Contents 
Statement of Compliance ........................................................................................................................................ 2 
Regulatory History .................................................................................................................................................. 3 
Protocol Synopsis .................................................................................................................................................... 3 
List of Abbreviations and Definition of Terms ..................................................................................................... 7 
Introductory Statement .......................................................................................................................................... 9 
1.1 
 Alcohol Use Disorder ............................................................................................................................................. 9 
1.2 
 Human Laboratory Studies ..................................................................................................................................... 9 
1.3 
 Rationale for Atomoxetine ................................................................................................................................... 10 
1.4 
 General Investigative Plan .................................................................................................................................... 12 
Study Objectives .................................................................................................................................................... 14 
2.1 
 Primary Objectives ............................................................................................................................................... 14 
Study Interventions ............................................................................................................................................... 14 
3.1 
 Investigational Products: Atomoxetine and Placebo ............................................................................................ 14 
3.2 
 Investigational Product Acquisition ..................................................................................................................... 14 
3.3 
 Investigational Product Storage and Stability....................................................................................................... 14 
3.4 
 Investigational Product Dispensing ...................................................................................................................... 15 
3.5 
 Investigational Product Accountability ................................................................................................................ 15 
3.6 
 Investigational Product Administration ................................................................................................................ 15 
3.7 
 Psychosocial/Behavioral Platform ........................................................................................................................ 16 
3.8 
 Concomitant Medications ..................................................................................................................................... 17 
Study Procedures .................................................................................................................................................. 17 
4.1 
 Recruitment of Subjects ........................................................................................................................................ 17 
4.2 
 Informed Consent, Assent, and Parent Permission ............................................................................................... 18 
4.3 
 Selection and Withdrawal of Subjects .................................................................................................................. 19 
4.4 
 Eligibility Screening Assessments ........................................................................................................................ 21 
4.5 
 Randomization/Baseline Visit(s) and Final Eligibility Assessments ................................................................... 22 
4.6 
 Measures Taken to Minimize/Avoid Bias ............................................................................................................ 22 
4.7 
Human Laboratory Paradigm Testing (H-LAB).................................................................................................... 24 
4.8 
 Final Clinic Visit (End of Study Visit) ................................................................................................................. 25 
4.9 
Telephone Follow-up Assessments ....................................................................................................................... 26 
4.10 
Conducting Sessions Remotely ............................................................................................................................. 26 
Dose-Adjustment Criteria .................................................................................................................................... 26 
5.1 
 Safety Criteria for Dose Adjustment or Stopping Doses ...................................................................................... 26 
5.2 
 Investigational Produce Dose Reduction .............................................................................................................. 26 
5.3 
 Investigational Product Discontinuation............................................................................................................... 26 
5.4 
 Subject Withdrawal or Discontinuation Procedures ............................................................................................. 27 
5.5 
 Situations Requiring Discontinuation from the Study or Investigational Product ............................................... 27 
Study Termination Criteria ................................................................................................................................. 27 
Study Endpoints .................................................................................................................................................... 27 
6.1 
 Feasibility and Acceptability Endpoints ............................................................................................................... 27 
6.2 
 Secondary Outcome: Alcohol Craving Assessed in the H-LAB Paradigm .......................................................... 28 
Safety Monitoring Plan ......................................................................................................................................... 28 
Adverse Event Assessment ................................................................................................................................... 29 
7.1 
 Adverse Events and Serious Adverse Events ....................................................................................................... 29 
Statistical Methods ................................................................................................................................................ 33 
8.1 
 Feasibility and Acceptability Endpoints ............................................................................................................... 33 

Atomoxetine – Proof-of-Concept Trial   
 
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NCT#: NCT04565288 
 
28APR2025 
 
 
 
 
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8.2 
 Secondary Outcome: Alcohol Craving Assessed in the H-LAB Paradigm .......................................................... 33 
Quality Control and Quality Assurance ............................................................................................................. 34 
Audits and Inspections .......................................................................................................................................... 34 
Ethics ...................................................................................................................................................................... 34 
9.1 
Ethics Review ........................................................................................................................................................ 34 
9.2 
Ethical Conduct of the Study ................................................................................................................................. 35 
Data Handling and Record Keeping ................................................................................................................... 36 
10.1 
Subject Identification and Confidentiality ............................................................................................................. 36 
10.2 
Retention of Records ............................................................................................................................................. 36 
10.3 
Trial Registration ................................................................................................................................................... 36 
References .............................................................................................................................................................. 37 
 
 
 

Atomoxetine – Proof-of-Concept Trial   
 
Brown University 
NCT#: NCT04565288 
 
28APR2025 
 
 
 
 
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List of Abbreviations and Definition of Terms 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUD 
Alcohol use disorder 
AUQ 
Alcohol Urge Questionnaire 
BAC 
Blood alcohol concentration 
BrAC 
Breath alcohol content 
CAP 
College of American Pathologists 
CFR 
Code of Federal Regulations 
CSQ-8 
Client Satisfaction Questionnaire – 8 
CLIA 
Clinical Laboratory Improvement Act 
CIWA-AR 
Clinical Institute Withdrawal Assessment for Alcohol-revised 
CrCl 
Creatinine clearance 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CRF 
Case Report Form 
CTCAE 
Common terminology criteria for adverse events 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
DSMB 
Data and Safety Monitoring Board 
EOS 
End of study 
FDA 
Food and Drug Administration 
g 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HIPAA 
Health Insurance Portability Accountability Act 
H-LAB 
Human Laboratory Paradigm (i.e., alcohol cue reactivity assessment) 
hr 
Hour 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
K-SADS 
Schedule for Affective Disorders for School-Age Children 
L 
Liter 
MAOI 
Monoamine oxidase inhibitors 
MedDRA 
Medical Dictionary for Regulatory Activities 
MET-CBT 
Motivational Enhancement and Cognitive Behavioral Therapy  
mg 
Milligram 

Atomoxetine – Proof-of-Concept Trial   
 
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NCT#: NCT04565288 
 
28APR2025 
 
 
 
 
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Abbreviation 
Definition 
μg 
Microgram 
min 
Minutes 
mITT 
Modified intention-to-treat 
mL 
Milliliter 
mm 
Millimeter 
NIAAA 
National Institutes on Alcohol Abuse and Alcoholism 
oz 
Ounce 
PI 
Principal Investigator 
PT 
Preferred Term  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDU 
Standard drinking unit 
SOC 
System Organ Class 
SNRI 
Serotonin-norepinephrine reuptake inhibitors 
SSRI 
Selective serotonin reuptake inhibitors 
THC 
Tetrahydrocannabinol 
TLFB 
Timeline/follow-back interview  
ULN 
Upper limit of normal 
US 
United States 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
 
 

Atomoxetine – Proof-of-Concept Trial   
 
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NCT#: NCT04565288 
 
28APR2025 
 
 
 
 
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Introductory Statement 
1.1  
Alcohol Use Disorder 
Alcohol use disorder (AUD) affects nearly one-third of adults in the United States during their lifetime 
(1). Excessive alcohol use causes myriad acute and long-term medical, psychological, and social problems 
(2) and carries an economic burden of $249 billion each year (3). Although advances in pharmacotherapy 
have improved treatment options for adults who struggle to reduce their alcohol use, treatment options for 
youth are limited.  
Adolescent alcohol use is a leading public health concern. The harmful effects of underage drinking are 
irrefutable and include premature death and possible irreversible damage to the developing brain (4, 5). In 
addition, adolescence is a critical period in the pathogenesis of AUD; an estimated 3 to 15% of youth 
develops AUD before age 18 (6, 7). Clinical trials have tested psychosocial interventions with youth, 
including family treatments, cognitive behavior therapy (CBT), and motivational enhancement therapy 
(MET) that yield only modest short-term benefit (8-11). Our group has contributed substantially to this 
body of work (12-17).  
One potential way to improve treatments is to augment psychosocial interventions with pharmacotherapy. 
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) has mounted a concerted effort to 
identify medications that reduce drinking for nearly three decades. Although this effort improved 
treatment for adults, no medication is indicated for adolescent use and randomized controlled trials with 
teenagers are almost nonexistent. This gap raises key questions about if and how medications could 
benefit youth. Optimizing treatment options for youth requires closing this important gap, and FDA 
guidelines require that all applications for new pharmacotherapies include data from pediatric 
populations. 
1.2  
Human Laboratory Studies 
Human laboratory studies of acute responses to alcohol, alcohol cues, or other experimental 
manipulations have progressed in important ways and hold potential to advance our understanding of how 
medications exert beneficial effects on drinking outcomes (18). These studies may help identify important 
individual difference factors affecting alcohol response, such as personality traits, drinking characteristics, 
and genotype, and aid in our understanding of the variability in cue and craving states, and provide 
additional information relevant to the design of clinical studies to assess the effectiveness of 
pharmacological agents.  
The study to be conducted in this protocol utilizes an alcohol cue reactivity paradigm to attempt to 
recreate in the human laboratory risk conditions for relapse like those experienced by individuals with 
AUD in their natural environment. Alcohol cue reactivity, which involves systematic exposure to in vivo 
alcohol cues and simulates high-risk situations for relapse, is one of the most widely studied laboratory 
paradigms in the context of AUD (19, 20). Exposure to alcohol cues reliably elicits responses presumed to 
relate to the motivational processes that underlie drinking (21), and it is sensitive to medication effects 
among treatment seeking and non-treatment seeking adults and adolescents. 
Impact on individual variability. Reactivity to alcohol and other drug cues varies from person to person, 
with some individuals showing little or no increase in target variables (e.g., craving) from the baseline or 
neutral cue trials to alcohol/drug cue trials (22-25). Some researchers have operationalized “responders” 
as individuals who show any change (22, 23, 26-28), whereas others have specified an exact minimum 
change (e.g., > 1-point increase in average craving) (25, 29, 30). Potential sources of variability include 
sex (31), genetic factors (32, 33), personality (26, 34), and substance use factors, such as lifetime alcohol 

Atomoxetine – Proof-of-Concept Trial   
 
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NCT#: NCT04565288 
 
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use indices and parental drinking problems (35), and these individual differences may moderate the 
effects of medications on alcohol cue reactivity (36-38). 
Reproducibility. A highly cited meta-analysis of cue reactivity studies reported robust effects for self-
reported craving in response to cues and a somewhat smaller, albeit still meaningful, effect size for 
physiological responses to cues (39). The autonomic profile of cue reactivity is fairly similar across drugs 
of abuse (40) and is often characterized by increases in heart rate and sweat gland activity and decreases 
in peripheral temperature. These physiological reactions are sensitive to medication effects (22, 41, 42). 
Sensitivity to detect differences between experimental medication and placebo. The alcohol cue 
reactivity paradigm reliably detects significant medication-placebo differences for most, but not all, 
medications studied. Studies show that cue-induced craving is blunted by a variety of medications, such 
as naltrexone (22, 41, 43-47), gabapentin (48), mifepristone (49), prazosin (50), d-cycloserine (51), and 
olanzapine (52), as well as combinations of these medications (53). Some studies of these and other 
medications, however, did not find these effects (36, 54-56). Nonetheless, cue reactivity effects are 
generally consistent with decreases in craving observed in clinical trials of these medications (49, 57-61). 
It is noteworthy that certain medications that reduce drinking, namely topiramate and acamprosate, 
consistently fail to show medication-placebo differences in cue reactivity (62-65), and thus require other 
paradigms to characterize medication-placebo effects on clinically meaningful phenotypes.  
Predictability of clinical trial success. Craving and other indices of cue reactivity are associated with 
relapse (66-68) and, as such, they are considered clinically relevant endophenotypes predictive of alcohol 
use outcomes (69). Craving is a strong predictor of drinking in the laboratory (46, 70, 71) and the natural 
environment (27, 54, 72-80), and medications (e.g., gabapentin, naltrexone) that decrease cue-elicited 
craving in the laboratory typically also reduce craving and drinking in clinical trials (43, 49, 58, 81). 
Indeed, human studies and animal models suggest that individuals for whom drug cues attain incentive 
motivational value or incentive salience are most likely to exhibit relapse (40, 82, 83). Although few 
studies have directly examined whether cue reactivity measured in the laboratory prospectively predicts 
clinical trial success, mounting evidence suggests it may be a powerful tool for understanding how 
interventions work and for identifying promising new treatment options for addiction (66, 84-91). Craving 
in response to alcohol or affective cues is predictive of subsequent drinking outcomes, including relapse 
(54, 75-80, 92); albeit others did not find this association. (93). Researchers have also examined the 
association between physiological cue reactivity and relapse and findings are mixed (94). Yet many 
studies show physiological reactivity (e.g., heart rate) predicts relapse (68, 77, 95-97).  
1.3  
Rationale for Atomoxetine 
Atomoxetine is safe with adolescents and does not adversely interact with alcohol. It is a highly selective 
norepinephrine reuptake inhibitor that is FDA-approved to treat attention-deficit/hyperactivity disorder 
(ADHD) in children, adolescents, and adults. Unlike other ADHD pharmacotherapies, atomoxetine is not 
a stimulant and has no abuse potential (98-102). Pooled data from four trials showed it is equally well 
tolerated by heavy drinkers, non-heavy drinkers, and non-drinkers (103).  
Atomoxetine targets brain mechanisms implicated in the pathogenesis of AUD, namely the 
norepinephrine system (104, 105). Norepinephrine innervates key limbic areas that govern arousal, 
reinforcement, and stress. Dysfunction in norepinephrine underlies problems with maintaining attentional 
homeostasis (106) and behavioral responses to stress (104, 107, 108), two key contributors to alcohol 
misuse. Although it does not appear to increase intracellular dopamine in regions involved in reward and 
reinforcement (e.g., nucleus accumbens), it increases extracellular dopamine in regions that drive craving 
and compulsive drug seeking (e.g., prefrontal cortex) (109).   

Atomoxetine – Proof-of-Concept Trial   
 
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There is strong preclinical evidence that altering the norepinephrine system reduces alcohol use and 
reinforcement. Selective pharmacological and neurotoxin-specific disruption of norepinephrine function 
reduces voluntary alcohol intake in rats (110, 111), and selective depletion of norepinephrine in the 
medial prefrontal cortex of high alcohol-consuming mice decreases alcohol consumption (112). Similarly, 
mice unable to synthesize norepinephrine because of dopamine-beta hydroxylase show reduced 
preference for alcohol (113). In addition, propranolol, a hypertensive and migraine medication that blocks 
the effects of norepinephrine on both β1- and β2-adrenergic receptors, suppresses progressive ratio operant 
alcohol-reinforced responding in alcohol-dependent and non-dependent rats (114). These findings further 
support the idea that manipulation of the norepinephrine system suppresses both the appetitive and 
consummatory reinforcing properties of alcohol.    
These preclinical findings were supported by a rigorous double blind, placebo-controlled 12-week 
randomized controlled trial with 147 adults with comorbid AUD and ADHD (115). Individuals 
randomized to atomoxetine (mean dose = 90 ± 17.6 mg/day) had 26% fewer heavy drinking days 
compared to placebo. Reductions in ADHD symptoms were correlated with decreases in alcohol craving, 
and this association was more pronounced in the atomoxetine group (116). Two additional smaller and 
less scientifically rigorous studies also examined atomoxetine effects, including one with adolescents. In 
an open-label trial (N = 14) of adjunctive atomoxetine (41.9 ± 13.7 mg/day) to drug abuse treatment as 
usual, adult patients had longer durations of abstinence and reengaged in treatment more quickly 
following relapse when taking atomoxetine as compared to their past maximum period of abstinence 
(117). Patients also reported a significantly better quality of life and higher treatment efficacy scores after 
taking atomoxetine. There was no difference between patients with and without ADHD in terms of 
treatment responsiveness. Alcohol was the primary substance of abuse for 8 patients; the onset of 
dependence occurred on average during adolescence. In an additional trial, 70 adolescents, ages 13 to 19 
years, with comorbid ADHD and substance use disorders were randomized to atomoxetine (weight-
adjusted up to 100 mg/day) or placebo plus psychotherapy for 12 weeks (118). Youth were not selected 
for a specific substance use disorder and thus varied in their type of substance use disorder (i.e., cannabis, 
nicotine, and alcohol use disorders). Although atomoxetine was well tolerated, substance use was a single 
aggregate outcome (no alcohol-specific outcomes reported; only 7 teens randomized to atomoxetine had 
AUD), and there was no effect of atomoxetine on ADHD symptoms or substance use. 
Atomoxetine enhances executive function in patients with ADHD and healthy controls, especially in 
improving response inhibition (119) and researchers hypothesize that these effects may attenuate factors 
that confer liability for AUD and maintain pathological drinking habits (117). From this perspective, 
atomoxetine may not only affect drinking by blunting craving or altering the reinforcing properties of 
alcohol use, as observed in preclinical and clinical studies, but also by improving executive function. 
Attention, working memory, and decision-making are core facets of executive function and key to 
regulating behavior (120-122). Disruption of brain regions that govern executive function are strongly 
related to compulsive alcohol use and drug taking as well as problems associated with use (123, 124). 
Studies consistently show bidirectional relations of executive function and substance use, such that lower 
levels of executive function confers increased risk for developing addictions (125) and substance use 
produces acute (126) and long term (127) decreases in executive function. Indeed, impaired executive 
function is related to drinking in adults (128) and adolescents (129), and improved executive function via 
cognitive training is related to reduced alcohol use one-month post treatment, especially for those with 
strong automatic impulses to drink (130). Enhancing executive function may also improve outcomes of 
behavioral therapy by facilitating skill acquisition and durability of skill uptake. 

Atomoxetine – Proof-of-Concept Trial   
 
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NCT#: NCT04565288 
 
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Possible adverse effects of atomoxetine are considered mild given the dose (80 mg/day) and titration 
period proposed; participants randomized to atomoxetine will take one 40 mg capsule for the first 3 days, 
followed by one 80 mg capsule each day for the remainder of the active medication phase of the study. 
The FDA approved atomoxetine for treating children (ages 6 and older), adolescents, and adults with 
ADHD. As such, side effect data for atomoxetine comes from clinical trials research on children (ages 6 
and older), adolescents, and adults with ADHD. The most common adverse reactions to atomoxetine, 
defined as ≥ 5% and at least twice the incidence of placebo patients, in child and adolescent trails are 
nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence. In adult clinical trials, the 
most common adverse reactions are constipation, dry mouth, nausea, decreased appetite, dizziness, 
erectile dysfunction, and urinary hesitation. 
As indicated by the FDA, pooled analyses of 12 short-term (6 to 18 weeks) placebo-controlled trials of 
atomoxetine with a total of 2,200 children and adolescents, including 11 trials for ADHD and 1 for 
enuresis, showed a greater risk of suicidal ideation early during treatment in those receiving atomoxetine 
compared to placebo. The average risk of suicidal ideation in patients receiving atomoxetine was 0.4% (N 
= 5/1357 patients), compared to none in the placebo condition (N = 851 patients). No suicides occurred in 
these trials. Notably, all suicidal ideation reactions in these trials occurred in children 12 and younger. We 
will be excluding youths younger than age 14 years. Studies with adults with ADHD or major depressive 
disorder have not revealed an increased risk of suicidal ideation among patients prescribed atomoxetine. 
1.4  
General Investigative Plan 
This proof-of-concept study is a double-blind, randomized, placebo-controlled, parallel group, single-site 
clinical trial. After obtaining consent/parent permission/assent, potential subjects and, if younger than 18 
years, their parent(s) will complete a medical history and psychiatric diagnosis interview (about the 
adolescent) to screen for eligibility. Youth will also complete a physical examination, vital signs, drinking 
history by the timeline follow-back (TLFB) method, alcohol breathalyzer test, Clinical Institute 
Withdrawal Assessment for Alcohol-revised (CIWA-AR), prior/current medication use, urine toxicology 
screen, clinical chemistry, and the Columbia Suicide Severity Rating Scale (CSSR-S). Females of child-
bearing potential will have a pregnancy test.  
If eligible for the study, 50 subjects will be randomized in an approximate 1:1 ratio (targeting 21 subjects 
per group – 42 subjects total who complete the protocol) to either atomoxetine or placebo for 6 weeks.  
Atomoxetine will be dosed at 40 mg/day for three days then increased to the maintenance dose of 80 mg 
(active) taken orally once daily (QD) for an additional 5.5 weeks. Subjects randomized to the placebo 
condition will be given an equal number of visually matched capsules.  
As shown in Figure 1, subjects will be seen in the clinic (or remotely) at the screening appointment, the 
randomization/baseline session, and at weekly visits during the study. At the randomization/baseline visit 
and after 4 weeks of investigational product administration (i.e., Study Week 5), subjects will undergo a 
human laboratory paradigm (i.e., alcohol cue reactivity assessment). 
 
 
 

Atomoxetine – Proof-of-Concept Trial   
 
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Consent and Screening 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization/Baseline 
Assessment Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ATOM + Behavioral 
Platform 
(6 weeks) 
 
 
 
 
Placebo + Behavioral 
Platform 
(6 weeks) 
 
 
 
 
 
 
 
 
 
 
 
 
2-Week Phone 
Interview 
 
 
 
 
2-Week Phone 
Interview 
 
 
Figure 1: Overview of Study Chronology 
 

Atomoxetine – Proof-of-Concept Trial   
 
Brown University 
NCT#: NCT04565288 
 
28APR2025 
 
 
 
 
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Study Objectives 
2.1  
Primary Objectives  
• Evaluate the feasibility, acceptability, and tolerability of atomoxetine (40 mg/day for 3 days 
then 80 mg/day thereafter) plus MET-CBT (i.e., “Path 180”) for 6 weeks among adolescents 
with AUD as confirmed by the Diagnostic and Statistical Manual of Mental Disorders – Fifth 
Edition (DSM-5™).  
• Apply our H-LAB paradigm to evaluate the effects of atomoxetine on intermediate 
phenotypes associated with alcohol use and outcomes in clinical trials. We hypothesize that 
atomoxetine, as compared to placebo, will reduce the likelihood of craving in the human 
laboratory during in vivo alcohol cue reactivity. 
Study Interventions 
3.1  
Investigational Products: Atomoxetine and Placebo 
Atomoxetine (40 mg/day for 3 days then 80 mg/day thereafter) will be over encapsulated and supplied by 
a contracted pharmacy, along with identical matching placebo capsules. Capsules in identical blister 
packaging configurations will be prepared in kits for each subject containing one blister card with 7 days 
of drug/placebo for each week of drug/placebo administration + 2 extra blister cards (with enough 
drug/placebo for one week if a subject loses or misplaces an entire blister card or is late for an 
appointment and needs an additional blister card until the next appointment is scheduled). 
3.2  
Investigational Product Acquisition  
All compounding and packaging of study medications is done at a compounding pharmacy. The 
pharmacy is licensed with the Rhode Island Board of Pharmacy and registered with the DEA. They 
adhere to the U.S. Pharmacopeial Convention (USP) 795 standards for compounding non-sterile  
preparations. All work is conducted in conformity with all applicable federal, state and local laws and 
regulations. They are certified HIPAA compliant and a member of the International Academy of 
Compounding Pharmacists. They utilize all the latest compounding equipment and techniques. They 
utilize Air Science PurAir powder containment hoods. These are HEPA/ULPA-filtered hoods that 
eliminate any chemical powders from being in the work environment. The pharmacy employs Registered 
Pharmacists and technicians. 
3.3  
Investigational Product Storage and Stability 
Kits will be stored at room temperature (within the range of 59°F to 86°F) in a secured area at the clinical 
site. Our facility, the Brown University Center for Alcohol and Addiction Studies (CAAS), is restricted to 
authorized personnel, with a security guard stationed 24/7 at the building’s entrance. CAAS has a secure 
alarmed and monitored room for onsite drug storage, dispensing and record keeping. This area is DEA 
approved for the storage and monitoring of controlled substances. Only authorized personnel have access 
to the room. Our facilities have adequate lighting, ventilation, temperature, sanitation, humidity, space, 
and security for suitable storage. Storage areas are secure from unauthorized entry, clean, sanitary, and 
orderly. Each incoming shipment of medication from the compounding pharmacy is carefully inspected 
for identity and possible damage of the drug products. All medications are stored at appropriate 
temperatures and under appropriate conditions in accordance with requirements, if any, in the labeling of 
such drugs, or with requirements in the current edition of an official compendium, such as the United 
States Pharmacopeia/National Formulary (USP/NF).  

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Outdated, damaged, and otherwise unused medication is stored in a separate secure location and container 
from other medications; the pharmacy disposes of all outdated, damaged, and otherwise unused 
medication. We develop and maintain study medication logs where we record all transactions regarding 
the receipt and distribution or other disposition of medications. These records include the source of the 
medications, and the identity and quantity of the medications received, distributed, and returned to the 
pharmacy. 
3.4  
Investigational Product Dispensing 
 
 
One blister card containing 7 days of drug/placebo and 1 additional (emergency) blister card containing 7 
days of drug/placebo will be distributed after randomization (and on or prior to Study Week 1, Day 1). 
Each week the subject will receive a new blister card with enough medication for 7 days of drug/placebo. 
The extra blister card will be collected at the end of the study or at the next clinic visit if drug/placebo was 
used during the week prior. A second emergency blister card will be dispensed if the subject returns the 
first used emergency blister card prior to the end of the study. 
3.5  
Investigational Product Accountability 
The principal investigator, Dr. Robert Miranda Jr., or designated study personnel will maintain a log of 
the receipt of all investigational products and record of dispensing of all investigational products to the 
subject. Investigational product for each subject will be inventoried and accounted for throughout the trial. 
The principal investigator or his staff will count the capsules remaining at the end of the study and record 
the capsules count on the appropriate drug accountability form. Subject compliance with investigational 
product will be assessed by comparing unused capsule count to dispensing logs and dosing records 
(number of capsules dispensed, number of capsules prescribed, versus the number returned). Subjects will 
also be asked to account for any missing capsules. If the blister card is not returned, the subject will be 
asked to report daily drug self-administration. 
3.6  
Investigational Product Administration 
A licensed individual (i.e., study physician, nurse practitioner) or their designee will ensure the 
appropriate study medication packets will be dispensed to the appropriate study subject (i.e. perform a 
drug utilization review on all study medication prior to it being given to a study subject).  
One blister card containing 7 days of drug/placebo and 1 additional (emergency) blister card containing 7 
days of drug/placebo will be distributed after randomization (and prior to Study Week 1, Day 1). Each 
week the subject will receive a new blister card with enough medication for 7 days of drug/placebo. The 
extra blister card will be collected at the end of the study or at the next clinic visit if drug/placebo was 
used during the week prior. A second emergency blister card will be dispensed if the subject returns the 
first used emergency blister card prior to the end of the study.  
Atomoxetine will be self-administered by subjects once daily after eating and with a full glass of water 
beginning on Study Week 1, Day 1 and continuing through Study Week 6, Day 7. The first dose will be 
taken in the study clinic whenever possible. Subjects will be provided with water and a snack to take with 
first dose. Dose will be titrated, as tolerated, to a target dose of 80 mg once per day of atomoxetine. Dose 
titration and maintenance will occur as shown in Table 1. Capsules should be swallowed whole and 
should not be cut, crushed, or chewed. 
 

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Table 1: Schedule of Administration of Investigational Project 
Study Period 
Time Period 
AM Dose 
(# of capsules) 
PM Dose 
(# of capsules) 
Titration 
Study Week 1, Day 1 – 3 
40 mg (1) 
None 
Maintenance 
Study Week 1, Day 4 – Week 6, Day 7 
40 mg (2) 
None 
 
Missed Doses: If a subject misses more than one dose of investigational product, s/he will be instructed to 
re-start taking the investigational product at the dosage level that s/he was taking before stopping. If one 
dose of investigational product is missed, s/he should take it immediately unless it is close to the time for 
the next dose. In that case the subject should skip taking the missed dose of investigational product and 
wait until the usual time to take their next dose of investigational product. The subject should not double 
up doses. 
Dose Reduction and Discontinuation. For problematic nausea (or other mild-moderate AEs), the dose 
may be reduced. If the adverse event (AE) resolves at the lower dose, another attempt to increase the dose 
to the target is permissible at the designated study physician’s discretion. 
3.7  
Psychosocial/Behavioral Platform 
The psychosocial/behavioral platform, Path 180, consists of a series of seven computerized alcohol 
intervention modules. This sophisticated interactive alcohol intervention was adapted from Take Control 
(131), a proven adult program co-developed by Megan Ryan (NIAAA) and Dr. Eric Devine (Boston 
University School of Medicine). Take Control is derived from a self-help approach developed by the 
NIAAA that provides evidence-based, field-tested information for individuals with alcohol problems, and 
suggestions for making changes in their drinking. The NIAAA material is available in a NIAAA booklet 
entitled “Rethinking Drinking” and on an NIAAA website http://rethinkingdrinking.niaaa.nih.gov.  
Path 180 is adapted from Take Control and modeled after work by Drs. Robert Miranda and Peter Monti 
and colleagues (132) and implemented in the principal investigator’s prior research (133). Seven sessions 
of motivational enhancement (MET) and cognitive behavioral therapy (CBT) were selected based on the 
positive relationship between intervention duration and successful treatment outcomes. Many adolescents 
are ambivalent about changing their alcohol use, consequently MET is often necessary to help challenge 
cognitive distortions regarding personal use and improve treatment readiness. CBT is grounded in social 
cognitive learning theory and targets common maladaptive beliefs and behaviors associated with alcohol 
misuse, including cognitive distortions, poor coping and communication skills, and maladaptive problem 
solving. 
Subjects will view a single module of Path 180 at each clinic visit starting at the baseline/randomization 
visit on Week 1, Day 1. If a visit is missed, missed modules will be reviewed at the next visit. As part of 
Path 180, subjects complete worksheets, which they take home with them (after study staff make 
photocopies for the subject’s reference at future sessions). Paper versions of the actual modules, however, 
are not to be given to the subject to take home and must remain at the laboratory.  
Delivering these materials in a computerized method in this trial mitigates COVID-19-related risks 
associated with face-to-face counseling sessions and has the advantage of standardizing the amount of 
educational material received by the subject. Subject viewing of the Path 180 Modules will be recorded 
on a CRF. 

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3.8  
Concomitant Medications 
For study inclusion, subjects cannot have taken any psychotropic medication in the 30 days prior to the 
date of randomization.  
Pharmaceutical treatments approved for treatment of AUD or treatments known to be used off-label or 
experimentally for treatment of AUD are prohibited during the study. The following drugs approved for 
the treatment of AUD are also prohibited (in the 30 days prior to randomization): 
• 
Oral naltrexone (Revia, Depade) 
• 
Depot naltrexone (Vivitrol) 
• 
Disulfiram (Antabuse) 
• 
Acamprosate (Campral) 
• 
Nalmefene (Selincro) 
Subjects will be instructed to check with study staff before taking any new medications or stopping 
current medications. Subjects will be informed that starting any new medication without consulting study 
staff could pose health risks and/or result in their discontinuation from the study drug. 
Management of investigational products and concomitant medications during the study (i.e., post-
randomization) is at the discretion of a designated study physician. The principal investigator or designee 
may consult with the medical monitor if there are questions. 
Study Procedures 
4.1  
Recruitment of Subjects 
Subject recruitment methods will include standard tactics (i.e., flyers, newspaper advertisements, social 
media advertisements, radio advertisements, and television advertisements). The Brown University 
Institutional Review Board (IRB) will approve all advertising materials used for subject recruitment.  
Interested youth that see our social media ads will be provided a link to a brief online (Qualtrics) survey 
to determine whether they are tentatively eligible based on our IRB-approved subject selection criteria. 
Specifically, in our IRB-approved social media advertisements, interested youth will click on the ad, 
which will link them to the brief online survey. If tentatively eligible, youth will be asked to provide their 
contact information so that study staff can reach out to them and conduct further screening. 
Interested candidates responding to recruitment materials either initially by telephone or after providing 
their contact information on the online survey, will be asked to complete a standardized telephone 
interview that includes questions about their drinking behavior, health status, interest in participation, and 
availability for the entire trial. Study staff will ask these questions without revealing the entry criteria for 
the study. Candidates who report drinking and other information consistent with the entry criteria and 
appear to be available and interested in the study will meet with the principal investigator or designated 
investigational staff, ideally within 14 days after the initial inquiry, to start the informed consent/assent 
and assessment process. If interested volunteers contact us by email, a telephone appointment will be 
scheduled and the email will be deleted as soon as possible to decrease risks associated with a breach of 
confidentiality. Phone messages will also be deleted as soon as possible. Interested volunteers can also 
leave their name and phone number and/or email address with study staff, so that we can contact them. 

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Research assistants and if applicable, any other staff, will be charged with monitoring recruitment 
inquires. Research staff will contact potential subjects via text, email, or phone call to schedule a 
telephone interview. All staff will be trained, first with mock sessions and subsequently supervised, in 
administration of the telephone interview and responding to extensive questions regarding the study. 
4.2  
Informed Consent, Assent, and Parent Permission 
Informed Consent Process. At the in-person screening visit, candidates and their parent(s)/legal 
guardian(s) (if younger than 18 years) — herein referred to as ‘parent’ — will meet with the principal 
investigator or his designee and receive an explanation of the study purpose and requirements. Potential 
subjects must have breath alcohol content (BrAC) of 0.000 measured by breathalyzer when signing the 
form (tested before review and signing of document). Repeat measurements of BrAC are permitted at the 
discretion of the investigator. If still interested after receiving an explanation of the study, the candidate 
and his/her parent(s) (if < 18 years) will be given the opportunity to review, inquire about, and sign the 
study informed consent, assent, or parent permission form approved by the Brown University IRB. The 
purpose and procedures of the study will be fully explained orally and in writing in a manner that is 
understandable and appropriate for all youth and parents. The informed consent/assent/parent permission 
process will be carried out in a manner and location that ensures privacy; provides adequate information 
about the study in language understandable to the potential subject and their parent(s) (i.e., we will require 
all potential subjects and, if younger than 18 years, their parents to understand English); ensures the 
potential subject and parents of youth younger than age 18 years comprehends the information provided 
(i.e., embedded comprehension questions throughout the informed consent/assent/parent permission 
documents and process); affords adequate opportunity for the potential subject and, if applicable, their 
parent(s) to consider all options; adequately addresses all of the questions from the potential subject and, 
if applicable, their parent(s); and obtains the potential subject’s voluntary agreement to participate.  
Parents of youth younger than 18 years will provide informed written parent permission. Parents will be 
informed that the purpose of the study is to test if and how a medication, in combination with counseling, 
helps to decrease alcohol use among adolescents who want to reduce their drinking. Our assent process 
considers each minor’s level of understanding of the research protocol, including potential risks, actively 
conveys respect for their autonomy and rights in the context of clinical research, and requires all minors to 
voluntarily agree to participate in the study. It will be made clear that all information obtained during 
assessments is confidential and that parents will not have access to adolescents’ responses, except if youth 
endorse intent to harm themselves or others. Subjects and if applicable their parent(s) will be given a copy 
of the signed informed consent/assent/parent permission form(s). Parents of individuals 18 years of age 
and older will not be involved in the study. 
Facilitate Understanding. Throughout the consent/assent/parent permission forms and during consent 
review with potential subjects and if applicable their parent(s) there are embedded questions to facilitate 
understanding. These embedded questions highlight the most essential aspects of the study. Potential 
subjects and parents (if applicable) will be reminded and encouraged to ask questions, not only during the 
consent process but throughout the study. Potential subjects and parents (if applicable) will be given a 
copy of the consent/assent/parent permission form to review at their discretion. Subjects and parents (if 
applicable) will be required to understand simple English and thus, translators will not be required. 
Documentation. A form will be maintained after each consented subject. This form will include the 
subject’s first name, date/time consented, version of consent form consented, and whether they were 
randomized or not. Assent and parent permission forms will be similarly completed when appropriate. 
These forms will be kept away from subject data and with locator forms. 

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Additional Considerations. We will obtain assent from minors; for details, see above (Informed Consent 
Process).  
4.3  
Selection and Withdrawal of Subjects 
4.3.1  
Inclusion Criteria 
The study physician will make all medical eligibility and termination decisions. To be eligible, the subject 
must: 
1. 
Be 14 to 20 years old, inclusive; we will exclude children < 14 due to diversity across adolescence 
and youths > 20 because our focus is teenagers 
2. 
Self-report consuming alcohol ≥ 2 days/week on average in the past 28 days 
3. 
Meet the DSM-5 criteria for AUD 
4. 
Be interested in reducing alcohol use 
5. 
Be able to verbalize an understanding of the consent/assent form, able to provide written informed 
consent/assent, verbalize willingness to complete study procedures, able to understand written and 
oral instructions in English and able to complete the questionnaires required by the protocol. 
6. 
Have parent permission, if younger than 18 years 
7. 
Be able to take oral medication and be willing to adhere to the medication regimen 
8. 
Complete all assessments required at screening and baseline.  
9. 
Agree to the schedule of visits, verbally acknowledge that s/he will be able to attend each 
scheduled visit, participate in phone visits and that s/he does not have any already scheduled 
events or a job that may substantially interfere with study participation. 
10. 
Not anticipate any significant problems with transportation arrangements or available time to 
travel to the study site over the next 2 months. 
11. 
Agree (if the subject is female and of childbearing potential) to use at least one reliable method of 
birth control, unless she is surgically sterile, partner is surgically sterile or she is postmenopausal. 
Examples of reliable methods include (but may not be limited to): 
a. oral contraceptives 
b. contraceptive sponge 
c. contraceptive skin patch 
d. diaphragm or condom 
e. intrauterine contraceptive system 
f. levonorgestrel implant 
g. medroxyprogesterone acetate contraceptive injection 
h. complete abstinence from sexual intercourse 
i. hormonal vaginal contraceptive ring 
j. surgically sterile 
k. postmenopausal 

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l. partner is surgically sterile 
4.3.2  
Exclusion Criteria 
To be eligible, the subject must not: 
1. Be currently receiving AUD treatment 
NOTE: Current psychotherapy for other reasons will be considered on a case-by-case basis. 
Psychotherapy for a disorder that may be related to the subject’s use of alcohol will be 
exclusionary. However, shorter term focused behavioral therapy for defined problems for non-
alcohol related problems may be acceptable. 
2. Have significant alcohol withdrawal symptoms (score > 10) on the Clinical Institute Withdrawal 
Assessment for Alcohol-Revised (CIWA-AR)  
3. Have a coexisting moderate to severe substance use disorder other than cannabis and nicotine, as 
defined by DSM-5 criteria 
4. Have a urine toxicology screen positive performed during screening or baseline for any of the 
following substances:  
a. benzodiazepines 
b. cocaine 
c. opiates  
d. amphetamines 
e. buprenorphine 
f. methadone 
g. barbiturates 
h. oxycodone 
i. 3, 4-methylenedioxy-methamphetamine (MDMA, also known as ecstasy) 
j. methamphetamines 
NOTE: Testing for tetrahydrocannabinol (THC) will be included in the urine drug test; 
however, subjects who test positive for THC are still eligible to participate in the study. 
The results for THC will be recorded for information only. 
 
5. Have been treated with a pharmacotherapy for AUD or a carbonic anhydrase inhibitor within 30 days 
prior to randomization 
6. Compelled to alcohol treatment by the justice system or has probation or parole requirements that 
might interfere with study participation 
7. Have a history of liver disease or have clinically significant abnormal laboratory values, including 
elevation of liver enzymes (AST, ALT) 5-fold above the upper limit of normal (ULN). 
8. Have a history of renal impairment or renal stones 
9. Have a history of narrow angle glaucoma or pheochromocytoma  
10. Have a history of heart problems or defects, abnormal blood pressure 

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11. Have a history of progressive neurodegenerative disorder, or clinically significant neurological 
disorders 
12. Have clinically significant physical abnormalities per physical exam 
13. Be pregnant or nursing, if female 
14. Have taken prescribed psychotropic medication use in the past 30 days 
15. Have any of the following, based on DSM-5 criteria as assessed using the K-SADS: 
a. Current or lifetime diagnosis of psychotic disorders 
b. Current bipolar disorder 
c. Current major depressive episode 
NOTE: Subjects diagnosed with psychiatric disorders not specifically excluded above may be 
included at the discretion of the principal investigator as long as the concurrent treatment for 
the comorbid psychiatric condition does not compromise the study integrity by virtue of its 
type, duration, or intensity. 
 
16. Have any of the following: 
a. Attempted suicide ever  
b. Current (past year) suicidality risk in accordance with DSM-5 criteria as assessed using the 
K-SADS (see note below about assessment of subjects at low risk) 
c. Current (since screening K-SADS) suicidality risk as indicated during the conduct of the 
C-SSRS with concurrence after a study physician’s evaluation if the response to C-SSRS 
questions 1 or 2 is “yes”  
NOTE: The K-SADS suicidality module is inadequate to fully determine the potential 
suicidal risk of an individual, any subject who endorses any item should be evaluated 
further by a study clinician using the C-SSRS who should document whether the subject is 
appropriate for study inclusion based on his/her clinical judgment of the potential suicide 
risk of the subject. Likewise, if the subject responds “yes” to either the first two questions 
on the screening C-SSRS performed on the day of randomization as a final eligibility 
check, the subject should also evaluated by a study clinician for current suicidality risk, 
who should document the subject’s suitability for study inclusion. 
 
17. Have a known sensitivity to atomoxetine 
18. Have a history of prior treatment with atomoxetine 
19. Have a serious or unstable medical illness or any potentially life-threatening or progressive medical 
condition other than addiction that may compromise subject safety or study conduct 
4.4  
Eligibility Screening Assessments 
After the subject signs informed consent/assent form and, if younger than 18 years, their parent signs the 
parent permission form, screening may begin. After providing written informed consent, subjects 
complete the Screening Visit for initial evaluation of eligibility.  
Prohibitions and Restrictions. Potential subjects must be willing/able to adhere to the following 
prohibitions and restrictions to be eligible for the H-LAB session: 

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• 
Refrain from consuming alcohol during the H-LAB alcohol cue exposure trials. 
• 
Refrain from smoking during the H-LAB session except for designated smoke breaks 
(approximately 1-1.5 hours prior to lab session). 
Subjects will be instructed not to take atomoxetine prescribed from a doctor outside of the study during 
their time in the study and that they should report any new medications they are taking at each visit or 
telephone contract.  
The above assessments can be performed in any order except that it is recommended to perform all self-
report and vital sign assessments prior to the blood draw assessments. If any of the assessments reveals 
that the subject is not eligible for the study, screening can be immediately terminated. Clinical chemistry 
tests may be repeated at the discretion of the study physician if the first assessment yields values outside 
normal laboratory limits. The eligibility checklist will be reviewed, and if the subject is still eligible after 
the assessments are completed at the first screening visit (or additional screening visits), the subject will 
be scheduled for Randomization/Baseline Visit, where final eligibility will be determined. Hypertensive 
subjects will be referred to their primary care physician for additional assessment and possible treatment. 
4.5  
Randomization/Baseline Visit(s) and Final Eligibility Assessments 
If the subject is eligible after performing all the initial screening assessments, s/he will be scheduled to 
start the study and will come to the clinic for a final eligibility check and physical exam approximately 1 
week after the initial screening visit. 
An eligibility checklist will be completed and reviewed by a study investigator and/or his designee. 
NOTE: The Randomization/Baseline Visit may be conducted over additional days/appointments if 
necessary. 
4.6  
Measures Taken to Minimize/Avoid Bias 
4.6.1  
Randomization 
If eligible for the study, subjects will be randomized in an approximate 1:1 ratio (N = 50; targeting 21 
subjects per group – 42 subjects total) to either atomoxetine or placebo for 6 weeks. Urn randomization 
will ensure approximately equal representation of males and females.  
If the subject is randomized and is never dispensed study drug, then the subject will be considered a 
randomization failure and an additional subject will be randomized with the next randomization sequence 
at the time s/he is randomized. Likewise, if the subject was randomized and then is determined to not be 
eligible for the study and never received study drug, then another subject will be randomized such that the 
total numbers of subjects who were eligible, randomized, and dispensed study drug meet the enrollment 
goals. In the case of a subject who was eligible, randomized, and dispensed study drug but did not return 
for follow-up visits, this subject will not be replaced. Any subject who received study drug but was later 
determined to be ineligible will likewise not be replaced. The reason(s) that a subject was considered a 
randomization failure or screen failure will be documented in source documents and case report forms 
(CRFs). 
4.6.2  
Blinding 
Atomoxetine and placebo capsules will be identically matched in appearance and the blister cards labeled 
not to reveal the drug identity. The principal investigator or designated study physician will make the 
decision to unblind the identity of the investigational product if the study blind needs to be broken to 

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make medical decisions regarding subject treatment. If it is determined that unblinding is necessary to 
assess AEs or SAEs for expedited reporting, the Data and Safety Monitoring (DSMB) may request 
unblinding of a subject. The principal investigator will notify the medical monitor. 
4.6.3  
Interventions on Study Week 1, Day 1 (Baseline Visit) 
After the subject is randomized, s/he will receive the first blister pack of study drug. Project staff will 
explain the dosing plan to the subject.  
Every study subject will be provided with a wallet card and instructed to carry this card that identifies the 
potential investigational products that s/he could be taking during the study. The card will provide the 
name and 24-hour phone number of the investigator (study physician) who can be contacted in the event 
of an emergency. The card will also instruct the non-study physician rendering emergency care to contact 
the study physician and inform him/her about the care. 
Visits may be scheduled and conducted on any day of the week. Visits can be conducted outside of the 
scheduled study week, but only based upon subject request (e.g., for reasons related to patient non-
compliance with the study schedule) and with prior approval from the principal investigator. Each subject 
will receive a visit schedule to take home for future reference. 
4.6.4  
Study Week 1 Telephone Contact  
 
On Study Week 1, Day 3 subjects will be called for a safety assessment including alcohol withdrawal 
symptoms and given a reminder their dose will increase Study Week 1, Day 4. 
4.6.5  
Maintenance Phase 
During the six-week active treatment phase of the study (Study Weeks 1 to 6), subjects will be seen in 
person at our offices or remotely, as needed and appropriate, each week. Reminder phone calls, text 
messages, and/or emails will be sent prior to each visit.  
Note that the maintenance phase begins 4 days after study drug administration (Week 1 Day 1). The Week 
1 visit needs to be completed between Week 1 Day 3 and Week 1 Day 7 (inclusive).  
An alcohol breathalyzer will be administered at each visit, prior to any study assessments, to determine if 
the subject meets the BrAC requirement of a BrAC ≤ 0.00 before proceeding with assessments. A urine 
drug test will be performed at each visit. At each of the clinic visits, subjects will meet with one or more 
study staff members who will assess for possible adverse events since the last visit, take vital signs, 
inquire about other medication use and assess drinking by TLFB. Pregnancy test and birth control 
methods (if female) will be assessed. 
A new supply of investigational product will be given and the blister cards from the previous period will 
be collected and a capsule count will be performed for accountability. Blister cards with unused capsules 
will be returned to the subject. The dosing schedule will be reviewed. The subject will be instructed to 
bring the blister cards with them to the next visit so the project staff can perform drug accountability 
(capsule counts). The subject will also be instructed to contact project staff if they are experiencing any 
intolerable adverse events and/or are contemplating drug discontinuation.  
Additional in-clinic visits are permitted under the protocol, if needed, due to the following circumstances: 
(a) the subject has concerns either about the medication or their drinking and wishes to be seen at a time 
other than their next scheduled in-clinic visit, (b) the subject has missed a visit and wishes to resume 
regular participation before their next scheduled visit, (c) the subject has reported some change in health, 
functioning, or circumstances that necessitates a visit to conduct safety assessments and evaluate the risk 

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of continued participation in the trial, (d) clinical laboratory measurements need to be repeated, or (e) a 
study physician or principal investigator deems it necessary. 
Subjects desiring additional counseling or professional therapy for non-crisis psychiatric matters (e.g., 
family or relationship problems, transient school issues) will neither be discouraged from such activity 
nor asked to postpone until their study participation is concluded. Subjects who initiate outside 
psychotherapy during the study will not be withdrawn. Subjects may (or may not) be withdrawn if they 
start new medications, at the discretion of the study physician, if there are any safety concerns. 
During the Study Week 5 clinic visit, subjects will complete a second H-LAB paradigm session, which 
will follow the same procedures as the pretreatment baseline assessment session. 
4.6.6  
Telephone Assessments 
A brief telephone interview (approximately 10 minutes) will occur if a subject misses a clinic visit but 
agrees to check-in by telephone to assess AEs, concomitant medication use and the emergence of 
withdrawal symptoms, to encourage the subject to continue taking investigational products, to verify that 
the subject is taking the prescribed dose, and to remind the subject of the next scheduled visit and dose 
increases. A summary of the telephone script follows: 
1. 
AEs: An open-ended question will be asked as follows: “How have you been feeling since your 
last clinic visit or phone contact?” If the subject reports a new AE, the resolution of an AE, or a 
change in the severity of an AE, ask additional questions to determine the severity and dates of 
occurrence or resolution.  
2. 
CIWA-AR: Subjects will be assessed for the emergence of withdrawal symptoms using the 
CIWA-AR. The subject may be asked about changes in drinking status after responses to the 
CIWA-AR interview indicate significant withdrawal. 
3. 
Concomitant Medications: Ask the following question: “Have you taken any new medications 
since you were last seen in the clinic or since our last call? If the subject responds affirmatively, 
record the name of the medication, the daily dose, route of administration, and reason used. If the 
medication is contraindicated for the study, then notify a study physician, nurse practitioner, or 
physician assistant for follow-up with the subject. 
4. 
Drug Compliance: Verification that the subject is taking the prescribed dose and a reminder to 
take investigational product and to return the blister card(s) with untaken capsules at the next visit 
will be made. During the Study Week 1 telephone contact, the subject will be reminded of the 
drug escalation schedule. 
5. 
Reminders: Remind the subject of their next scheduled clinic visit, and adjust the date within the 
visit week if they have a conflict.  
4.7  
Human Laboratory Paradigm Testing (H-LAB) 
During the Randomization/Baseline Visit (prior to taking the study medication) and in Study Week 5, 
subjects will be seen in-person in the clinic for the human laboratory paradigm testing. The human lab 
session will last for approximately 45 minutes. Laboratory sessions should occur in the late afternoon if 
possible. The subject must have BAC = 0.00 prior to starting the H-LAB session. Whenever possible, to 
ensure that subjects take the capsule on the day of cue reactivity, subjects should either self-report taking 
their study medication earlier that day or take their study medication while observed by study staff just 

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before the cue reactivity session. If the subject, for whatever reason, cannot take their study medication 
that day, they can be rescheduled to complete the cue reactivity paradigm. 
After confirmation of eligibility for the H-LAB paradigm, subjects who use nicotine will have the 
opportunity to use it approximately 1 hour prior to starting the H-LAB paradigm. All subjects will be 
asked (but not required) to drink 4 oz of water and a restroom break prior to the lab session will be 
provided. Upon completion of clinical assessments, subjects will be escorted to a comfortable chair in a 
lighting-controlled, sound-attenuated room for alcohol exposure.  
Subjects will be presented with either their most commonly consumed alcoholic beverage (e.g. vodka, 
lager beer) or bottled water. The alcohol or water beverage is presented in the subject’s preferred mode of 
consumption (e.g., small tumbler for vodka, Pilsner glass for beer). Specific alcohol brand preferences are 
accommodated whenever possible, including choices of mixers (e.g., vodka will be poured into a glass 
along with orange juice if the favorite drink were a screwdriver).  
The H-LAB paradigm will follow our standardized procedures. Audio-recorded instructions ensure 
standardization within and across subjects. After attaching the physiological monitor (i.e., blood pressure 
cuff), the session begins with a 3-minute relaxation period that involves subjects sitting quietly and doing 
nothing. Then a 3-minute water trial begins, in which subjects hold and smell a glass of water as a 
standard procedure to control for the effects of simple exposure to any potable liquid, including all aspects 
of stimuli and movement except the nature of the beverage. A second 3-minute relaxation period follows 
the water trial. Next, subjects hold and smell a glass of their most desired or commonly consumed 
alcoholic beverage for two consecutive 3-minute alcohol trials. Order of water and alcohol trials is not 
counterbalanced due to known carryover effects. The water is accompanied by a commercially labeled 
water bottle and alcohol by the bottle or can from which it was poured and prepared as the teen usually 
drinks it. Across water and alcohol trials, subjects sniff the beverage for 5 seconds each time a tone 
sounds: 13 tones sound at variable intervals during each 3-minute block to ensure that all youth receive 
the same olfactory exposure. Observation via one way window ensures compliance. Subjects rate their 
alcohol craving after each 3-minute trial.  
After every 3 minutes of exposure, each subject will rate his/her urge to drink alcohol using a visual 
analogue scale (VAS). The primary efficacy endpoint in the H-LAB is the “strength” of alcohol craving 
measured on a visual analogue scale (VAS; Item 1 below).  
Following the H-LAB paradigm, subjects will receive a 7-day supply of the blinded study medication, and 
the dosing schedule will be reviewed. The subject will be instructed to bring the blister cards with them to 
the next visit so the project staff can perform drug accountability (capsule counts). The subject will also 
be instructed to contact project staff if they are experiencing any intolerable adverse events. 
4.8  
Final Clinic Visit (End of Study Visit) 
The final in-clinic assessment will occur at the end of (or immediately following) the active treatment 
phase, typically Study Week 6, Day 7. This visit should occur after the subject takes the last dose of 
study drug. Subjects will complete the Client Satisfaction Questionnaire - 8 (134), an instrument used to 
assess patients’ satisfaction with psychiatric treatment (135, 136). If a subject withdraws from the study 
early for any reason, the subject will be asked to return to the clinic for the conduct of the final clinic visit 
assessments. 

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4.9 Telephone Follow-up Assessments 
Subjects will be contacted by telephone for a follow-up interview 2 weeks after the final in-clinic visit. 
During this 2-week follow-up interview, the subject will be asked about any ongoing AEs that they may 
have been experiencing at the last clinic visit and any newly emerged medical conditions/AEs since that 
visit. To prompt reporting of new AEs, the subject will also be asked about any ongoing or new 
medication use. 
4.10 
Conducting Sessions Remotely 
Study visits may be conducted remotely, when necessary. By limiting in-person contact, allowing remote 
sessions may effectively decrease COVID-19-related risks. At the study physician’s discretion, the 
physical exam may be conducted via the Brown University HIPAA-compliant Zoom platform (either in 
an adjacent room or remotely). Research staff still need to collect vital signs, weight, a urine toxicology 
drug screen, and a urine pregnancy best (if biological sex at birth is female) in person (prior to the 
physical exam). Blood chemistry and related tests must be done at a local laboratory.  
For weekly visits, Zoom video conferencing will be used to conduct the session for those items amenable 
to remote collection. Extra medication will be mailed from participants to the laboratory via pre-paid 
postal mail. When remote sessions are held, biospecimen collection will not be done. Even so, to capture 
biospecimens on a regular basis, no two consecutive post-randomization weekly checkups may be done 
remotely unless approved beforehand by a study physician. 
Dose-Adjustment Criteria 
5.1  
Safety Criteria for Dose Adjustment or Stopping Doses 
The principal investigator or sub-investigator will follow the protocol to identify and intervene with 
subjects experiencing clinical deterioration during study participation. Criteria to determine when a 
subject requires a higher level of care and discontinuation from the trial intervention are detailed below.  
5.2  
Investigational Produce Dose Reduction 
The daily dosage of investigational product may be reduced by the study physician for any AE 
determined, by the study physician, to compromise the subject’s ability to maintain activities of daily 
living or if the subject reports undue discomfort. While at the target dose (80 mg/day), the dose may be 
reduced to 40 mg once daily. If the AE resolves at the lower dose, another attempt to increase the dose to 
the target dose is appropriate at the study physician’s discretion.  
5.3  
Investigational Product Discontinuation 
Subjects who are discontinued from investigational product should continue in the study and complete all 
assessments, including the follow-up assessments, as well as Path 180. If the subject discontinues the 
investigational product before Study Week 5 then they will not complete the H-LAB paradigm.  
a. Pregnancy. Females who become pregnant during the medication phase of the study, Study 
Weeks 1 through 6, will be immediately discontinued from the investigational product. The 
investigator must report a pregnancy within 1 working day of the site being aware to the 
medical monitor.  
b. Physical Illness. Subjects will need to be removed from investigational products if they have a 
serious illness or a disabling condition that precludes them from taking the investigational 
product. 

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c. Adverse Events. If the subject experiences any AEs that are considered study drug related and 
for which the investigator has determined that continuation of the study drug could be 
detrimental to the health of the subject, then drug will be reduced for 1 week, then 
discontinued, or immediately discontinued as described above. 
5.4  
Subject Withdrawal or Discontinuation Procedures 
Each subject has the right to withdraw consent/assent and withdraw from the study at any time. Parents of 
minors younger than 18 years of age have the right to withdraw their permission for their child to 
participate in the study at any time. In addition, the investigator may find it necessary to discontinue a 
subject for any reason, including (but not limited to) the occurrence of an AE or noncompliance with the 
protocol.  
If a subject withdraws or is discontinued from the study, the reason(s) for the discontinuation from the 
study will be recorded and a pregnancy test (females only), vital signs, clinical chemistry, C-SSRS, TLFB 
and an assessment of AEs will be performed as soon as possible after discontinuation from the study.  
5.5  
Situations Requiring Discontinuation from the Study or Investigational Product 
It is possible that there will be some subjects who cannot be safely managed in the clinical study even 
though investigational products have been discontinued. Examples are given below. 
1. Increased Drinking. Subjects whose alcohol problems worsen and, in the opinion of the principal 
investigator, sub-investigators, or study nurses or physicians, require a more intense level of care than 
provided in the study may have the investigational product suspended and referred to more 
appropriate care.  
2. Psychiatric Crises. Examples of psychiatric crises include but are not limited to the following: 
a. Acute psychosis (hallucinations, impaired reality testing, paranoid ideation, etc.) requiring 
medication and/or hospitalization or intensive outpatient intervention;  
b. Suicidal or homicidal ideation that results in a credible threat of violence directed at oneself or 
others; 
c. Hospitalization for psychiatric symptoms.  
Subjects requiring more intensive treatment resulting from acute psychosis or suicidal/homicidal 
behavior will be referred to local treatment centers, emergency departments, or hospitals as 
appropriate, but will not be provided with medication or psychotherapy by study staff.  
Study Termination Criteria 
The principal investigator may terminate the study for reasonable cause after providing written notice to 
the funding agency in advance of the intended termination. Advance notice is not required if the study is 
stopped due to safety concerns. If the DSMB terminates the study for safety reasons, the principal 
investigator will immediately notify the medical monitor, IRB, and funding agency. 
Study Endpoints 
6.1  
Feasibility and Acceptability Endpoints 
6.1.1  
Primary Feasibility Endpoint 
The number and percentage of subjects who completed the 6-week active medication phase will 
determine feasibility.  

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6.1.2  
Primary Acceptability Endpoint 
The Client Satisfaction Questionnaire (CSQ-8), which ranges in scores from 8 to 32 (higher scores 
indicate higher satisfaction), will determine acceptability. Treatment satisfaction will be considered 
acceptable if the number and percentage of subjects who rate their treatment experience in the 
"satisfactory" or "highly satisfactory" range on the CSQ-8 is ≥ 80%. 
6.2  
Secondary Outcome: Alcohol Craving Assessed in the H-LAB Paradigm 
The secondary endpoint will be alcohol craving assessed during a laboratory alcohol-cue exposure 
paradigm, at week 5. During the paradigm, participants rated their alcohol craving immediately following 
exposure to water cues and again immediately following exposure to alcohol cues. 
The primary measure of alcohol craving will be the number and percentage of participants who report any 
level of alcohol craving during a laboratory alcohol-cue exposure paradigm using the following single 
item: How strong is your craving to drink alcohol? Scores range from 0 (None) to 20 (Extremely Strong). 
Individuals who endorse any level of alcohol craving (e.g., > 1) are considered to experience craving. 
Individuals who do not report any alcohol craving (e.g., 0) will be regarded as non-craving. 
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 principal investigator, clinic staff, medical monitor, and study nurses 
and physicians. 
The Brown University IRB, medical monitor, principal and sub-investigators, and study nurses and 
physicians will review any safety concerns throughout the trial. In addition, a DSMB will participate in 
this study.  
Quality control is central to all aspects of the activities detailed in this proposal to ensure clinical data 
accuracy and integrity. Day-to-day oversight of data quality will be delegated to the principal investigator, 
Dr. Robert Miranda and/or his designee. With assistance from our core team, he will provide direction 
with the development of data collection forms, recruitment and tracking databases, data management 
tasks, and statistical analyses and interpretation. The principal investigator or his designee will oversee the 
production of standard labels/codebooks for all data collection activities. He or his designee will oversee 
the production of reports that will track indices of project success, which will be reviewed weekly or 
biweekly at meetings of our core team, where issues or concerns will be deliberated and corrective action 
plans put into place.   
Our research team has substantial experience in the design and implementation of data management 
procedures that: (a) ensure the validity and integrity of data; (b) guarantee the accuracy and completeness 
of data during data collection, transmission, and analysis; and (c) maintain confidentiality and data 
security. These procedures are in accordance with FDA and ICH standards. All procedures involving 
human research subjects will be performed at the Brown CAAS. The principal investigator will be 
responsible for coordinating activities of the data safety and monitoring, including arranging weekly 
meetings and communications, and identifying and reviewing subject materials.   
Medical Monitor: A medical monitor, Dr. Robert Swift, MD, PhD, has been appointed by the principal 
investigator. Dr. Swift will be available for making recommendations to the investigator on the severity of 
any SAEs and the relatedness to the study interventions. Dr. Swift will also be responsible for tracking 
and assessing trends in the AEs reported.  

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Data and Safety Monitoring Board: Although an independent DSMB is not required because this 
project is not a Phase III clinical trial, we will assemble a DSMB. The DSMB for this project will consist 
of senior researchers in the field who have expertise in adolescent or pharmacotherapy research or both, 
and will include at least one physician. 
 
No member of this DSMB will be directly involved with the conduct of this study or have a conflict of 
interest with this study. The DSMB will meet at the onset of the study, at least once quarterly thereafter, 
and when 25%, 55%, and 85% of subjects have been enrolled. Ad hoc meetings may also be scheduled if 
the need arises (e.g., in the event of a study-related SAE). The DSMB will discuss study conduct and 
progress, subject safety, and, when appropriate, efficacy. Specifically, items to be reviewed include: 
interim/cumulative data for evidence of study-related adverse events, interim/cumulative data for 
evidence of efficacy when 85% of subjects have completed the protocol (if necessary), data quality, 
completeness and timeliness; adequacy of compliance with goals for recruitment and retention, including 
those related to females and minorities; adherence to the protocol; and factors external to the study, such 
as scientific or therapeutic developments that may impact subject safety or the ethics of the study.  
The Board will be blinded to subjects’ actual randomized group assignments but may request at any time 
that the blind be broken, if concerns arise from the blinded data. Ad hoc meetings will be convened if 
SAEs occur that are considered at least possibly related to the investigational product. At the end of each 
meeting, the DSMB will make a recommendation regarding trial continuation and will forward that 
recommendation to the principal investigator who will forward it to the Brown University IRB and the 
Program Official at the funding agency (i.e., NIAAA).  
In addition, the investigative team will meet on a weekly or biweekly basis to evaluate the study’s 
recruitment and retention procedures, to monitor any potential significant benefits or risks that may occur 
to warrant the early termination of the study and to monitor study progress. 
Adverse Event Assessment 
7.1  
Adverse Events and Serious Adverse Events 
The investigator and study project staff are responsible for the detection, documentation, classification, 
reporting, and follow up of events meeting the definition of an adverse event (AE) or serious adverse 
event (SAE).  
7.1.1 Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and may not necessarily have a causal relationship with the administered 
treatment. An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
laboratory abnormality), symptom, or disease temporally associated with the use of an investigational 
product, whether related to the investigational product. Pre-existing conditions, diseases, or disorders are 
not considered AEs unless there is a change in severity or frequency. 
7.1.2  
Serious Adverse Events and Serious Unexpected Adverse Events Definition 
An SAE is any untoward medical occurrence that meets one of the following: 
• Results in death 
• Is life-threatening (at the time of the event) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 

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• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
A serious and unexpected AE is an SAE that is not identified in nature, intensity, or frequency in the risk 
information included in the Product Label for the drug. 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered a serious adverse drug experience when, based upon appropriate medical judgment, they 
may jeopardize the study subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition.  
7.1.3  
Methods/Timing for Assessing, Recording, and Analyzing Safety Endpoints 
AEs will be assessed at study visits starting after the first administration of investigational product until 
the final follow-up visit. However, SAEs will be collected from the time of informed consent onward. 
General symptoms will be collected via an open-ended question: “How have you been feeling since your 
last visit or the last time we spoke?”  
AEs will be documented in the source records, and recorded on the CRFs using accepted medical terms 
and/or the diagnoses that accurately characterize the event. When a diagnosis is known, the AE term 
recorded on the CRF will be the diagnosis rather than a constellation of symptoms. The investigator will 
assess all AEs for seriousness, relationship to investigational product, and severity. When an event has not 
resolved by study closure, it will be documented on the AE CRF as “ongoing.” 
If a female has a positive or borderline pregnancy test after enrollment, the medical monitor will be 
contacted, and the pregnancy will be recorded as an AE. In accordance with standard clinical practice, 
results of pregnancy tests will not be disclosed to the subjects’ parents unless the subject is age 15 or 
younger. Parents will be informed of this point during the parent permission process. The site will contact 
the subject at least monthly and document the subject’s status until the pregnancy has been terminated or 
completed. The outcome of the pregnancy will be reported to the medical monitor, funding agency, and 
the Brown IRB without delay within 24 hours of knowledge of the event if the outcome is a SAE (e.g., 
death, abortion, congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).  
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless of 
severity, will be followed by study physicians until satisfactory resolution (the event either resolved or 
stabilized and is not expected to resolve in the near term). AEs will be reported up to 2 weeks following 
completion of, or termination from investigational product administration. At the follow-up telephone 
contact, AEs will be recorded and followed to resolution only if they are serious, or if the study physician 
assesses them to be clinically significant. 
7.1.4  
Classification of Adverse Event Intensity and Relationship to Investigational Product 
For each recorded AE or SAE, a study physician must assess severity. For those AEs included in the 
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 5.0), these 
severity criteria will apply. For those not listed in the CTCAE, the following criteria will be used: 

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Mild: 
An event that is usually transient, requiring no special treatment, and does 
not generally interfere with the subject’s daily activities. 
Moderate: 
An event that interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the 
subject. The event is usually ameliorated with additional specific 
therapeutic intervention.  
Severe: 
 
An event that interrupts usual activities of daily living or significantly 
affects clinical status. The event poses a significant risk of harm to the 
subject and hospitalization may be required, and typically requires 
intensive therapeutic intervention. 
Life-threatening 
An event that puts the subject into imminent risk of death without 
intervention. 
Clinical chemistry severity and blood pressure increases will be graded in accordance with the CTCAE 
version 5.0.  
The investigator must assess relationship to the investigational product based on the following criteria: 
Unrelated: 
The subject did not receive the investigational product, the temporal sequence 
of the AE/SAE onset relative to administration of the investigational product 
is not reasonable, or there is another obvious cause of the AE/SAE. 
Unlikely: 
There is evidence of exposure to the investigational product but there is 
another more likely cause of the AE/SAE. 
Possible: 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is reasonable, but the AE/SAE could have been due to another equally 
likely cause. 
Probable: 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is reasonable, and the AE/SAE is more likely explained by the 
investigational product than by any other cause. 
Definite: 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is reasonable, the AE/SAE is more likely explained by the 
investigational product than by any other cause, and the AE/SAE shows a 
pattern consistent with previous knowledge of the investigational product or 
investigational product class. 
 
7.1.6  
Outcomes and Actions Taken 
All unresolved AEs will be followed for a minimum of 14 days (unless the AE is an ongoing pregnancy 
which must be followed to conclusion) after the subject’s End of Study visit, unless the investigator’s 
judgment dictates otherwise, the event has resolved or stabilized prior to the 14-day period, or the subject 
is lost to follow-up.  

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Investigators are not obligated to actively seek AEs or SAEs in former study subjects that occur following 
the follow-up period.  
For each recorded AE or SAE, the investigator must assess outcome at the time of last observation, as 
follows: 
Fatal: 
The subject died. 
Resolved without Sequelae: 
The AE or SAE has ended. 
Resolved with Sequelae: 
The AE or SAE has ended but changes are noted from 
baseline. 
Unresolved – Ongoing: 
The AE has not ended and is ongoing at the end of the 
reporting period (i.e., 14 days after the final Follow-up visit) 
and the investigator deems that further follow up is not 
medically required 
Unknown – Lost to Follow-up: 
Lost to follow-up after repeated unsuccessful attempts to 
contact the subject. 
Actions taken with respect to investigational agents (discontinuation or not) will also be recorded. In 
addition, if the AE was treated (medications or other physical measures), this will also be recorded. 
7.2  
 
Reporting Serious Adverse Events 
7.2.1  
 
24-hour Reporting Requirements (Initial Report) 
Any SAE, including death due to any cause, which occurs to any subject from the time of admission 
through discharge whether related to the investigational product, must be reported within 24 hours of 
knowledge of the event to the medical monitor or alternate.  
The following information must be provided with the initial report of an SAE: 
• 
Name of person reporting the SAE/unexpected AE 
• 
Subject's ID number 
• 
Name of the principal investigator and institution 
• 
Date the subject signed informed consent 
• 
Date first dose of investigational product was ingested 
• 
Description of the SAE/unexpected AE 
• 
Date and time of Onset 
• 
Date/time of administration of last dose of investigational product prior to the SAE/unexpected 
AE 
• 
Severity of the SAE/unexpected AE 
• 
Investigator's assessment of the relationship of the SAE/unexpected AE to investigational 
product (related, possibly related, probably related, unlikely related, not related) 
• 
Any action taken with the investigational product, alteration to protocol defined schedule, 
diagnostics, and treatments secondary to the SAE/unexpected AE. 

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3-Day Supporting Documentation Requirements 
Written documentation for all SAEs/unexpected AEs must be received by the medical monitor/alternate 
within 3 days of reporting the event. Required documents that must be submitted include the following: 
• 
SAE Form 
• 
Concomitant Medication CRF pages  
• 
AE CRF pages 
• 
Copies of source documents pertinent to the event (lab reports, medical chart notes, etc.) 
• 
Any other relevant information necessary to facilitate the investigator’s judgment regarding 
the SAE’s relatedness to the severity OR by request of the medical monitor/alternate 
These documents must be submitted by either email attachments or via overnight courier. 
7.2.2  
 
Reporting to the IRB 
Unanticipated problems involving risk to subjects or others, SAEs related to participation in the study and 
all subject deaths should be promptly reported by phone, email, or fax to the Brown University IRB. 
An FDA cleared, CLIA waived urine drug test card will be used to assess candidates for recent use of 
opiates (i.e., morphine test), cocaine, amphetamines, methamphetamine, tetrahydrocannabinol (THC), 
buprenorphine, methadone, benzodiazepines, oxycodone, barbiturates, and 3,4-methylenedioxy-
methamphetamine (MDMA – also known as ecstacy). During screening subjects must be negative for all 
substances except THC. If positive for these drugs at other times during the study, the subject will not be 
removed from the study but should be asked about medication use and possibly re-evaluate their medical 
history for substance abuse. 
Statistical Methods 
8.1  
Feasibility and Acceptability Endpoints 
8.1.1  
Primary Feasibility Endpoint 
The number and percentage of subjects who completed the 6-week active medication phase will 
determine feasibility (target ≥ 70%).  
8.1.2  
Primary Acceptability Endpoint 
The Client Satisfaction Questionnaire (CSQ-8), which ranges in scores from 8 to 32 (higher scores 
indicate higher satisfaction), will determine acceptability. Treatment satisfaction will be considered 
acceptable if the number and percentage of subjects who rate their treatment experience in the 
"satisfactory" or "highly satisfactory" range on the CSQ-8 is ≥ 80%. 
8.2  
Secondary Outcome: Alcohol Craving Assessed in the H-LAB Paradigm 
The secondary endpoint will be alcohol craving assessed during a laboratory alcohol-cue exposure 
paradigm, at study week 5. During the paradigm, participants rated their alcohol craving immediately 
following exposure to water cues and again immediately following exposure to alcohol cues. The primary 
outcome measure will be is the number and percentage of participants who report any level of alcohol 
craving during a laboratory alcohol-cue exposure paradigm (following exposure to alcohol cues) using the 
following single item: How strong is your craving to drink alcohol? Scores range from 0 (None) to 20 
(Extremely Strong). Individuals who endorse any level of alcohol craving (e.g., > 1) are considered to 

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experience craving. Individuals who do not report any alcohol craving (e.g., 0) will be regarded as non-
craving. Using generalized estimating equations, we compared the likelihood of alcohol craving as a 
function of medication condition. 
Quality Control and Quality Assurance 
This study will be conducted under International Conference on Harmonization (ICH) Good Clinical 
Practice (GCP) guidelines and all applicable regulatory requirements.  
Actions to ensure the accuracy and reliability of data include the selection of qualified investigators and 
appropriate study centers; the review of protocol procedures with the investigator and study personnel 
prior to study start; the design of suitable source documents with appropriate instructions for use; the 
internal audit of source data according to GCP and internal procedures to ensure their accuracy, 
completeness, and verifiability; as well as the periodic site monitoring by the Sponsor’s representatives 
(clinical monitors). The Project Coordinator or Project Director will review source documents and CRFs 
for accuracy and completeness. Any discrepancies will be resolved with the investigator, as appropriate.  
Audits and Inspections 
Authorized representatives of the Sponsor and the IRB may visit the site to perform audits or inspections, 
including source data verification. The purpose of the audit or inspection is to systematically and 
independently examine all study related activities and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the protocol, 
GCP guidelines, and any applicable regulatory requirements. 
The principal investigator will notify the Brown University IRB and the sponsor, NIAAA, if contacted by 
a regulatory agency about an inspection. 
Ethics 
9.1 Ethics Review 
The study will be conducted under a protocol reviewed by the local 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. 
9.1.1  
Review/Approval of Study Protocol 
Written approval from the appropriate IRB before study initiation. Progress reports will be submitted to 
the IRB by the principal investigator at the frequency requested by the Brown University IRB (i.e., at least 
annually). 
9.1.2  
Protocol Modifications/Amendments 
All necessary protocol changes will be submitted in writing as protocol amendments to the Brown 
University IRB by the principal investigator for approval prior to implementation.  

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9.1.3  
Protocol Deviation Reporting Procedures 
All subject-specific deviations from the protocol will be documented. The principal investigator or his 
designee(s) 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 Brown University IRB. 
9.2 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 the sponsor’s representative and all study 
personnel abide by the principles of the ICH GCP Guideline and the Code of Federal Regulations (CFR).  
9.2.1  
Confidentiality 
To maintain subject confidentiality, all laboratory specimens, CRFs, 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 will have access to the records. Subject information will not be released without written 
permission, except as necessary for monitoring by the IRB, the sponsor, or regulatory agencies. We 
obtained a Certificate of Confidentiality from NIH.  
9.2.2  
Compensation for Participation 
Subjects will be compensated for travel expenses and for time contributed to this research study in the 
form of gift cards or ClinCard. 
9.2.3  
Written Informed Consent, Assent, and Parent Permission 
The informed consent/assent/parent permission process and documents were reviewed and approved by 
the Brown University IRB. The consent/assent/parent permission documents contain 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.  
A written informed consent/assent/parent permission 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 and 
when applicable his or her parent before any study-related procedures are initiated for each subject.  
All potential subjects for the study and when applicable their parents will be given a current copy of the 
appropriate informed consent, assent, and/or parent permission form(s) to read. All aspects of the study 
and informed consent/assent/parent permission will be explained in lay language to the subject and when 
applicable his or her parent(s) 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 and when applicable their parents will be given a copy of the signed informed 
consent/assent/parent permission form. 
9.2.4  
Delegation of Responsibilities and Adequate Resources 
The principal investigator will have adequate time to conduct the study properly and have an adequate 
number of qualified staff to assist with the conduct of the study.  

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The term “investigator” used throughout this protocol refers to the principal investigator and/or qualified 
sub-investigators. The principal investigator may delegate responsibilities to other study personnel. The 
principal investigator shall delegate tasks only to individuals qualified by education, training, and 
experience to perform the delegated tasks. The principal investigator shall have direct oversight of all 
delegated activities and shall document delegation of responsibilities. The principal investigator 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.  
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. Data will be transcribed from source 
documentation into paper CRFs. Only questionnaire data will be entered directly onto CRF (i.e., without 
prior written or electronic record of data). The transcribed data will be consistent with the source 
documents or the discrepancies will be explained.  
10.1 
Subject Identification and Confidentiality 
Subjects will be identified on CRFs 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. The IRB is 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. 
10.2 
Retention of Records 
The investigator is responsible for creating and/or maintaining all study documentation required by ICH 
E6 section 8, as well as any other documentation defined in the protocol. Investigators are required to 
retain a copy of all regulatory documents and records that support the data for this study for 3 years 
following study completion. 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. 
10.3 
Trial Registration 
The principal investigator registered the trial on the National Library of Medicine’s Clinical Trials 
Registry on the world wide web at http://www.clinicaltrials.gov prior study subject recruitment.  

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