Human Laboratory Screening of Semaglutide for Alcohol Use Disorder
Phase: PHASE2
Conditions: Alcohol Use Disorder, Cigarette Smoking
Sponsor: University of North Carolina, Chapel Hill

 
 
 
 
 
 
Human Laboratory Screening of Semaglutide for Alcohol 
Use Disorder 
Protocol Number: 21-1689 
National Clinical Trial (NCT) Identified Number: NCT05520775  
Investigators: 
Dr. Christian Hendershot (Principal Investigator) 
Dr. Robyn Jordan (Co-Investigator) 
Dr. Amanda Tow (Co-Investigator) 
Dr. Sarah Dermody (Co-Investigator, Biostatistician) 
Dr. Eric Claus (Co-Investigator) 
Dr. Klara Klein (Co-Investigator)  
Dr. Paul Fletcher (Other Significant Contributor) 
Funded by: NIAAA 
Version Number:  v.1.7 
9 Feb 2023 
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1.1 
(population), 
5.1, 5.2 
 
 
Revised inclusion/exclusion criteria to remove 
cigarette smoking and use of nicotine products 
as eligibility factors; expanded BMI range for 
eligible participants (from 25-24 to 23+), and 
removed eligibility criterion related to TSH 
values (thyroid disease will still be exclusionary). 
Adjustments are intended to make 
eligibility less restrictive, and to 
remove criteria that are not central to 
the primary objectives. 

  
NIAAA-FDA Human Laboratory Screening of Semaglutide for Alcohol Use Disorder – v1.7 9 February 2023 
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1 
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ........................................................................................ 1 
1 
PROTOCOL SUMMARY ............................................................................................... 1 
1.1 
Synopsis .............................................................................................................................. 1 
1.2 
Schema ................................................................................................................................ 3 
1.3 
Schedule of Activities (SoA) ............................................................................................ 4 
2 
INTRODUCTION ............................................................................................................ 5 
2.1 
Study Rationale .................................................................................................................. 5 
2.2 
Background ......................................................................................................................... 6 
2.3 
Risk/Benefit Assessment .................................................................................................. 8 
2.3.1 
Known Potential Risks ....................................................................................................................... 8 
2.3.2 
Known Potential Benefits ................................................................................................................ 10 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................................ 10 
3 
OBJECTIVES AND ENDPOINTS ............................................................................... 11 
4 
STUDY DESIGN ........................................................................................................... 13 
4.1 
Overall Design .................................................................................................................. 13 
4.2 
Scientific Rationale for Study Design ........................................................................... 22 
4.3 
Justification for Dose ...................................................................................................... 22 
4.4 
End of Study Definition ................................................................................................... 23 
5 
STUDY POPULATION ................................................................................................. 23 
5.1 
Inclusion Criteria .............................................................................................................. 23 
5.2 
Exclusion Criteria ............................................................................................................. 23 
5.3 
Lifestyle Considerations ................................................................................................. 24 
5.4 
Screen Failures ................................................................................................................ 25 
5.5 
Strategies for Recruitment and Retention ................................................................... 25 
6 
STUDY INTERVENTION ............................................................................................. 26 
6.1 
Study Intervention(s) Administration ........................................................................... 26 
6.1.1 
Study Intervention Description ....................................................................................................... 26 
6.1.2 
Dosing and Administration .............................................................................................................. 27 
6.2 
Preparation/Handling/Storage/Accountability ............................................................. 28 

  
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6.2.1 
Acquisition and accountability ........................................................................................................ 28 
6.2.2 
Formulation, Appearance, Packaging, and Labeling .................................................................. 28 
6.2.3 
Product Storage and Stability ......................................................................................................... 28 
6.2.4 
Preparation ........................................................................................................................................ 29 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................ 29 
6.4 
Study Intervention Compliance ..................................................................................... 29 
6.5 
Concomitant Therapy ...................................................................................................... 29 
6.5.1 
Rescue Medicine .............................................................................................................................. 30 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................... 30 
7.1 
Discontinuation of Study Intervention .......................................................................... 30 
7.2 
Participant Discontinuation/Withdrawal from the Study ........................................... 30 
7.3 
Lost to Follow-Up ............................................................................................................. 31 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................ 32 
8.1 
Efficacy Assessments ..................................................................................................... 32 
8.2 
Safety and Other Assessments ..................................................................................... 32 
8.3 
Adverse Events and Serious Adverse Events ............................................................. 33 
8.3.1 
Definition of Adverse Events (AE) ................................................................................................. 33 
8.3.2 
Definition of Serious Adverse Events (SAE) ................................................................................ 33 
8.3.3 
Classification of an Adverse Event ................................................................................................ 33 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ......................................... 34 
8.3.5 
Adverse Event Reporting ................................................................................................................ 35 
8.3.6 
Serious Adverse Event Reporting .................................................................................................. 35 
8.3.7 
Reporting Events to Participants .................................................................................................... 36 
8.3.8 
Events of Special Interest ............................................................................................................... 36 
8.3.9 
Reporting of Pregnancy ................................................................................................................... 36 
8.4 
Unanticipated Problems .................................................................................................. 36 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................................... 36 
8.4.2 
Unanticipated Problem Reporting .................................................................................................. 37 
8.4.3 
Reporting Unanticipated Problems to Participants ...................................................................... 37 
9 
STATISTICAL CONSIDERATIONS ............................................................................ 37 
9.1 
Statistical Hypotheses .................................................................................................... 37 
9.2 
Sample Size Determination ............................................................................................ 38 
9.3 
Populations for Analyses ............................................................................................... 38 

  
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9.4 
Statistical Analyses ......................................................................................................... 38 
9.4.1 
General Approach ............................................................................................................................ 38 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................................... 39 
9.4.3 
Analysis of the Secondary Endpoint(s) ......................................................................................... 39 
9.4.4 
Safety Analyses ................................................................................................................................ 40 
9.4.5 
Baseline Descriptive Statistics ....................................................................................................... 40 
9.4.6 
Planned Interim Analyses ............................................................................................................... 40 
9.4.7 
Sub-Group Analyses ........................................................................................................................ 40 
9.4.8 
Tabulation of Individual participant Data ....................................................................................... 40 
9.4.9 
Exploratory Analyses ....................................................................................................................... 40 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 40 
10.1 Regulatory, Ethical, and Study Oversight Considerations ....................................... 40 
10.1.1 
Informed Consent Process ............................................................................................................. 40 
10.1.2 
Study Discontinuation and Closure ............................................................................................... 41 
10.1.3 
Confidentiality and Privacy .............................................................................................................. 42 
10.1.4 
Future Use of Stored Specimens and Data .................................................................................. 42 
10.1.5 
Key Roles and Study Governance ................................................................................................. 43 
10.1.6 
Clinical Monitoring ............................................................................................................................ 43 
10.1.7 
Quality Assurance and Quality Control ......................................................................................... 44 
10.1.8 
Data Handling and Record Keeping .............................................................................................. 44 
10.1.9 
Protocol Deviations .......................................................................................................................... 44 
10.1.10 
Publication and Data Sharing Policy ......................................................................................... 44 
10.1.11 
Conflict of Interest Policy ............................................................................................................. 45 
10.2 Additional Considerations .............................................................................................. 45 
10.3 Abbreviations ................................................................................................................... 45 
10.4 Protocol Amendment History ......................................................................................... 48 
11 
REFERENCES .......................................................................................................... 50 
 

Human laboratory screening of semaglutide for alcohol use disorder 
Version 1.7 
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9 Feb 2023 
 
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STATEMENT OF COMPLIANCE 
(1) The trial will be carried out in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Human Laboratory Screening of Semaglutide for Alcohol Use Disorder  
  
Study Description: 
This is an early-Phase II human laboratory trial using a randomized, 
placebo-controlled, dose-ranging design to investigate the effects of 
semaglutide (Ozempic®), a GLP-1 receptor agonist, on laboratory alcohol 
responses and consumption, naturalistic alcohol and cigarette 
consumption, and weight loss in smokers with alcohol use disorder (AUD). 
Participants will attend weekly visits while semaglutide dosage is increased 
to 1.0mg over a period of approximately 10 weeks. Participants will attend 
weekly visits for medication or placebo administration. At scheduled 
intervals, participants will complete 4 laboratory sessions involving alcohol 
self-administration and alcohol challenge to characterize medication 
effects on alcohol-related outcomes.  
  
Objectives: 
 
Primary Objective: To examine effects of semaglutide vs. placebo on 
laboratory alcohol intake during a validated alcohol self-administration 
medication screening procedure. 
  
 
 
 
Secondary Objectives: To examine medication vs. placebo group 
differences in 1) laboratory responses to alcohol, and 2) changes in 
naturalistic alcohol use and cigarette consumption over the course of the 
treatment period.  
 

Human laboratory screening of semaglutide for alcohol use disorder 
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Tertiary Objectives: To generate preliminary data on weight loss, HbA1c 
reductions and alcohol elimination among participants with AUD during 
treatment with a GLP-1 receptor agonist. 
 
 
Endpoints: 
Primary Endpoint: Change in amount of alcohol consumed during a 
validated laboratory alcohol self-administration protocol (primary 
endpoint). The specific effect of interest is the change in laboratory 
consumption from baseline to the maintenance dose (.5mg) as a function 
of medication condition (semaglutide vs. placebo) (i.e., treatment x time 
interaction). 
Secondary Endpoints: Secondary endpoints will include laboratory 
measures of alcohol and cigarette demand (behavioral economic indices of 
drug motivation) and subjective responses to alcohol during an alcohol 
challenge procedure, and changes in naturalistic alcohol use and cigarette 
smoking over the treatment period. Within-person changes in these 
outcomes before vs. after treatment (baseline vs. 0.5mg) will be compared 
as a function of medication condition. 
 
Study Population: 
Participants who meet criteria for alcohol use disorder/AUD (N=48) will be 
enrolled. Participants will be recruited from the Triangle area (community 
and hospital settings). Participants must not be seeking current treatment 
for alcohol. 
  
Phase: 
Phase II  
  
Description of 
Sites/Facilities Enrolling 
Participants: 
This is a single-site study (UNC-Chapel Hill). The project will be based at 
the Bowles Center for Alcohol studies and the Department of Psychiatry, 
with clinical operations taking place at Eastowne Clinical Research Unit 
and CTRC.  
 
Description of Study 
Intervention: 
Semaglutide (Ozempic®) will be administered according to the FDA-
approved schedule, which begins with a starting dose of 0.25mg once per 
week for four weeks. At week five, dosage is increased to 0.5mg/week for 
a subsequent four weeks (maintenance dose). Following four weeks at the 
maintenance dose, dosage will be increased to 1.0mg provided the patient 
has tolerated the medication. Semaglutide is administered subcutaneously 
via the Ozempic® pen, a cartridge-based device that calibrates medication 
delivery. The placebo condition will consist of weekly sham doses, which 
will involve a brief needle insertion (without an injection). 
Study Duration: 
Up to 13 months. 
  
Participant Duration: 
Up to 40-50 hours total (including in-person visits and remote 
questionnaires) over a period of approximately 12 weeks. 
 
 

Human laboratory screening of semaglutide for alcohol use disorder 
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1.2 
SCHEMA 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In-person screening/Baseline visit 
Discharge + Blood draw 
N: 18 Semaglutide 
Randomize 
0.25 mg Semaglutide administration 
Telephone screen 
0.25 mg Semaglutide administration 
0.25 mg Semaglutide administration 
0.25 mg Semaglutide administration + Blood draw 
0.5 mg Semaglutide administration 
0.5 mg Semaglutide administration 
0.5 mg Semaglutide administration 
1 mg Semaglutide administration 
Week 10 
Week 8 
Week 7 
Week 6 
Week 5 
Week 4 
Week 3 
Week 2 
Week 1 
Prior to 
Enrollment 
Alcohol self-administration 2 
N: 18 Placebo 
0.5 mg Semaglutide administration + Blood draw 
Alcohol challenge 1 
Alcohol self-administration 1 
Alcohol challenge 2 
Week 9 
Week 15 
Telephone follow-up 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures and Questionnaires 
Telephone Screening 
 
Screening/Baseline 
 
Study Visit 1 – 3  
Target Day 7, 14, 21 
Study Visit 4 
Target Day 28 
Study Visit 5 – 7 
Target Day 35, 42, 49 
Study Visit 8 
Target Day 56  
Study Visit 9 
Target Day 63  
Discharge 
Target Day 70  
Telephone follow-up 
Target Day 77, 105 
Alcohol Challenge 
Target Day -10, 58 
Alcohol Self-Admin. 
Target Day -12, 60 
Telephone screening 
X 
 
 
 
 
 
 
 
 
 
 
Administer 0.25 mg Semaglutide or placebo 
 
 
X 
X 
 
 
 
 
 
 
 
Administer 0.5 mg Semaglutide or placebo 
 
 
 
 
X 
X 
 
 
 
 
 
Administer 1.0 mg Semaglutide or placebo 
 
 
 
 
 
 
X 
 
 
 
 
Breath Alcohol Concentration (BrAC) Test 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Urine Drug Screen 
 
X 
 
 
 
 
 
 
 
X 
X 
Expired carbon monoxide (CO) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Locator 
 
X 
 
 
 
 
 
 
 
 
 
Timeline Follow-Back (TLFB) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
BAC 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Blood Draw  
 
X 
 
X 
 
X 
 
X 
 
 
 
Blood glucose – finger prick 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
Pregnancy (females only) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
BMI 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
Vitals (HR, BP) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Temperature 
 
X 
 
 
 
 
 
 
 
 
 
Demographics Form 
 
X 
 
 
 
 
 
 
 
 
 
Structured Clinical Interview for DSM-5 
 
X 
 
 
 
 
 
 
 
 
 
MINI Neuropsychiatric Interview 
 
X 
 
 
 
 
 
 
 
 
 
Medical and Substance Use History Interviews 
 
X 
 
 
 
 
 
 
 
 
 
Prediction of Alcohol Withdrawal Severity Scale 
(PAWS) 
 
X 
 
 
 
 
 
 
 
 
 
Short Alcohol Withdrawal Scale (SAWS) 
 
X 
 
 
 
 
 
 
 
X 
X 
Saliva Collection for DNA and nicotine metabolite 
 
X 
 
 
 
 
 
 
 
 
 
Case Report Forms (CRFs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alcohol Use Disorder Identification Test (AUDIT) 
 
X 
 
 
 
 
 
 
 
 
 
Alcohol, Cigarette, and Food Purchase Test 
 
X 
 
 
 
 
 
 
 
X 
X 
Self-Report of the Effects of Alcohol 
Questionnaire (SRE) 
 
X 
 
 
 
 
 
 
 
 
 
Fagerstrom Test for Nicotine Dependence (FTND) 
 
X 
 
 
 
 
 
 
 
 
 
Nicotine Dependence Syndrome Scale (NDSS) 
 
X 
 
 
 
 
 
 
 
 
 
Penn Alcohol Craving Scale (PACS) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Tiffany Questionnaire of Smoking Urges (TQSU) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Wisconsin Smoking Withdrawal Scale (WSWS)  
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Alcohol and Smoking Contemplation  
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Three Factor Eating Questionnaire (TFEQ)  
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Monetary Choice Questionnaire (MCQ) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Cigarette Abstinence Self-Efficacy (CASE) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Alcohol Abstinence Self-Efficacy (AASE) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Inventory of Drinking Situations (IDS) 
 
X 
 
 
 
 
 
 
 
 
 
Impaired Control Scale (ICS)  
 
X 
 
 
 
 
 
 
 
 
 
Barratt Impulsivity Scale (BIS-11) 
 
X 
 
 
 
 
 
 
 
 
 
UPPS Impulsive Behavior Scale (UPPS) 
 
X 
 
 
 
 
 
 
 
 
 
Systematic Assessment for Treatment Emergent 
Effects (SAFTEE) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

Human laboratory screening of semaglutide for alcohol use disorder 
Version 1.7 
Protocol 21-4939 
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Reward Based Eating Drive Scale (R-BEDS) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Simplified Nutritional Appetite Questionnaire 
(SNAQ) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Control of Eating Questionnaire (CEQ) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Wisconsin Inventory of Smoking Dependence 
Motives (WISDM) 
 
X 
 
 
 
 
 
 
 
 
 
Sweet Taste Preference Test 
 
X 
 
 
 
 
 
X 
 
 
 
Center for Epidemiological Studies Depression 
Scale (CES-D) 
 
X 
 
 
 
 
 
 
 
 
 
Reward Probability Index – Environmental 
Reward Observation Scale (RPI-EROS) 
 
X 
 
 
 
 
 
 
 
 
 
Toronto Alexithymia Scale (TAS-20) 
 
X 
 
 
 
 
 
 
 
 
 
Profile of Mood States – Short Form (POMS-SF) 
 
 
 
 
 
 
 
 
 
X 
X 
Biphasic Alcohol Effects Scale (BAES) 
 
 
 
 
 
 
 
 
 
X 
X 
Alcohol Urge Questionnaire (AUQ) 
 
 
 
 
 
 
 
 
 
X 
X 
Drug Effects Questionnaire (DEQ) 
 
 
 
 
 
 
 
 
 
X 
X 
Obsessive-Compulsive Drinking Scale 
 
X 
 
 
 
 
 
 
 
 
 
Graded Pain Scale 
 
X 
 
 
 
 
 
 
 
 
 
 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Pharmacotherapy development is a critical objective for reducing health and societal burdens associated 
with alcohol use disorder (AUD) [1-3]. Despite advances in this area, medication development remains a 
slow- moving endeavor with a protracted path from drug discovery to market [2-4]. Given the high 
degree of heterogeneity in AUD clinical presentation and treatment response, it is recognized that no 
single medication will be effective for all patients [5]. Therefore, the National Institute on Alcohol Abuse 
and Alcoholism (NIAAA) medication development strategy specifies the long-term objective of 
establishing a repertoire of therapies to facilitate targeted interventions for specific AUD subgroups [3, 
5, 6]. Strategies for expediting the study of novel treatments are central to these aims [3, 5, 6].  
Epidemiological and clinical evidence shows that cigarette smokers comprise a sizable AUD subgroup 
with disproportionately high health burdens [7, 8]  Alcohol and cigarette use are two of the three 
leading causes of preventable mortality worldwide, jointly accounting for an estimated seven million 
deaths per year [9]. Population-based research shows that cigarette consumption increases as a 
function of alcohol use severity [7]. In one large epidemiological study, nearly half (44.6% of men, 47.3% 
of women) of those with alcohol dependence also met criteria for nicotine dependence [7]. Co-use of 
alcohol and cigarettes predicts synergistic increases in risk for numerous disease conditions [8, 10, 11], 
including esophageal and laryngeal cancers [12, 13]. Given these health burdens, increasing effort has 
been allocated to developing targeted interventions for smokers with AUD [8, 11, 14, 15]. 
In the absence of FDA-approved medications for concurrent alcohol and nicotine addiction, identifying 
candidate drugs for this indication is a priority [11, 15, 16]. Several recent studies have examined 
whether FDA- approved AUD and smoking cessation drugs, either alone or in combination, can facilitate 
joint reductions in alcohol and cigarette use [11]. For instance, naltrexone reduces alcohol consumption 
in heavy-drinking smokers [17, 18], and in some cases reduces cigarette consumption [17, 19]. Recent 
findings further suggest that naltrexone's efficacy for reducing drinking is stronger in AUD participants 

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who smoke relative to non-smokers [20, 21]. However, a Cochrane review [22] and a large, prospective 
AUD trial [19, 23] concluded that naltrexone does not appear to reduce cigarette smoking [11, 23].  
Varenicline has also been tested as a candidate therapy for smokers with heavy drinking or AUD. 
Informed by early findings that varenicline reduced alcohol self-administration in a human laboratory 
trial [16], large-scale clinical trials supported efficacy of varenicline for reducing alcohol consumption in 
heavy-drinking smokers [24, 25] and those with AUD [26]. Recent laboratory-based studies have also 
examined the combination of varenicline and naltrexone as a novel treatment [27, 28]. Because those 
with concurrent alcohol and nicotine addiction reflect a high-priority subgroup, further efforts are 
needed to screen candidate treatments for this population [8, 11, 28] . As reflected in these recent trials, 
and as noted explicitly under the NIAAA medication development framework [1-3], drug repurposing 
strategies can significantly expedite new treatment approaches by capitalizing on therapies that have 
already passed the extensive regulatory steps required for FDA approval.  
Compounds with preclinical evidence for reducing both alcohol and nicotine intake are particularly good 
candidates for investigating new treatments for heavy-drinking smokers. Accumulating evidence 
suggests that Glucagon-like peptide 1 (GLP-1) receptor agonists may have promise in this respect. GLP-1 
is an incretin hormone produced and secreted both peripherally (in the intestines) and centrally (in the 
hindbrain) [29]. GLP-1 is stimulated following food consumption and stimulates satiety and decreases in 
blood glucose. As a peptide with both hormonal and neurotransmitter functions, GLP-1 plays a role in 
the "gut-brain axis," which has recently been invoked as a target for addiction therapies [30]. GLP-1 
agonist medications were designed to mimic the function of the endogenous GLP-1 peptide, with the 
benefit of a much longer half-life than endogenous GLP-1. Based on their glucose-lowering and appetite-
reducing properties, GLP-1 agonists were developed as anti-diabetic therapies. 
Several GLP-1 receptor agonists are now in widespread use as treatments for type II diabetes (T2D), 
including exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide and semaglutide. These medications 
have also proven efficacious for promoting weight loss, reducing glycated hemoglobin (HbA1c), and 
reducing risk for some cardiovascular events [29]. Although the primary indication of GLP-1 agonists is 
T2D, these therapies are increasingly being studied for other indications in non-diabetic patients, 
including obesity/weight management. 
Of note, GLP-1 agonists require subcutaneous administration, typically by way of a pre-filled medication 
cartridge with a micro-needle attachment, which allows for easy self-administration in the home 
without assistance from medical staff. Semaglutide is a recently approved (2017) FDA-approved GLP-1 
agonist. A new oral formulation of semaglutide was approved by the FDA in 2019, making semaglutide 
the first drug in its class to be available in both subcutaneous and oral formulations.  
 
2.2 
BACKGROUND  
Accumulating evidence from preclinical studies suggests that GLP-1 agonists reduce alcohol and other 
drug intake and/or reinstatement in animal models. In a recent review of 17 preclinical studies [31], all 
studies reported significant effects of GLP-1 agonists on indices of drug motivation and intake, with the 
evidence being most robust for alcohol [30, 31]. Notably, the effects of GLP-1 agonists on drug intake 
appear to extend to several addictive drugs, including nicotine [32]. These findings have led to recent 
studies aiming to investigate the efficacy of GLP-1 agonists as candidate therapies for reducing intake or 
reinstatement of alcohol, nicotine, and other drugs (e.g., cocaine). Although several human trials are 

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underway in various regions, no RCTs have been published to date, and human data on the efficacy of 
GLP-1 agonists for reducing drug intake in substance-using populations is needed. 
Although the precise mechanisms mediating the effects of GLP-1 agonists on alcohol-related behaviors 
remain to be clarified, it has been suggested that cholinergic-dopaminergic pathways are involved in 
altering the reward value of alcohol following exposure to GLP-1 agonists [30]. Additionally, GLP-1 
agonists appear to exert their effects in part by way of interactions with the serotonin (5-HT) system, 
including interactions with 5-HT2C receptors. Specifically, GLP-1 agonists appear to induce serotonin 
release, and serotonin signaling appears critical to the efficacy of the medications [33, 34]. Some 
evidence also suggests that 5-HT2C receptors appear necessary for the efficacy and satiety-inducing 
effects of GLP-1 agonists [35, 36]. 
Of the approved FDA-approved GLP-1 agonists, most studies have focused on exenatide, an older GLP-1 
agonist first approved in 2005. As noted, semaglutide is the newest GLP-1 agonist and the first available 
in both subcutaneous and oral formulations. Some evidence suggests superiority of semaglutide relative 
to other GLP-1 agonists with respect to efficacy for glycemic control [37]. Although clinical trials of GLP-1 
receptor agonists in participants with substance use disorder are now underway, no studies (to our 
knowledge) are currently underway to examine semaglutide as a treatment for alcohol use disorder, or 
for the joint indication of alcohol use disorder and tobacco use disorder. Demonstrating tolerability and 
initial efficacy of semaglutide for these populations could ultimately allow for greater clinical flexibility if 
GLP-1 agonists prove efficacious for these populations, given that semaglutide is available in both 
subcutaneous and oral formulations.  
Human laboratory methods for Phase II medication screening  
As emphasized in the NIAAA medication development strategy [1, 4, 38], human laboratory methods 
play a pivotal role in drug development by providing a bridge from preclinical studies and full-scale 
Phase II/III trials [39-43]. Importantly, laboratory studies can expedite drug development by providing an 
efficient, cost-effective, and rigorous option for “early-Phase II” medication screening, thereby informing 
priorities for larger and more costly randomized trials. For example, we recently published meta-analytic 
evidence that human laboratory studies of naltrexone, when examined in aggregate, yield conclusions 
highly comparable to the aggregate data from large-scale randomized trials, reinforcing the notion that 
laboratory trials offer a valid and efficient approach for estimating the potential efficacy of candidate 
therapeutics [40]. Other advantages of laboratory trials include the ability to study putative treatment 
mechanisms under controlled conditions, and the ability to quickly generate initial data on drug 
tolerability in the clinical population of interest [1, 44].  
Phase II pharmacotherapy trials for alcohol use disorder often rely on alcohol administration procedures 
to study medication effects on acute responses to alcohol in human laboratory settings [40]. Controlled 
alcohol exposure offers a means of testing medication effects on subjective response to alcohol (e.g., 
stimulation, sedation) and alcohol-induced craving. These subjective responses to alcohol are targets of 
existing pharmacotherapies, such as naltrexone [40].  Alcohol self-administration has also been used as 
a laboratory model of alcohol motivation, and has successfully been used to screen candidate AUD 
therapies [40]. Some have argued that alcohol self-administration should serve as the central endpoint 
in human laboratory studies, and validated procedures exist for modeling alcohol self-administration 
safely in the laboratory [16] [40]. More recently, behavioral economic measures have also been utilized 
as a means of studying drug motivation in laboratory contexts, and appear sensitive for detecting 
experimental manipulations on alcohol-related motivation. For example, alcohol demand indexes the 

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relative reinforcing value of alcohol at a particular point in time [45]. Measures of drug demand, such as 
the alcohol purchase task (APT) and cigarette purchase task (CPT), are considered objective and 
sensitive experimental assays of drug motivation [45]. The APT predicts frequency of heavy drinking 
days after treatment [45], and is sensitive to temporal changes in alcohol’s relative reinforcing efficacy 
during drug administration [46]. Notably, initial evidence suggests that these measures are sensitive to 
the effects of pharmacological treatments, including naltrexone and varenicline [47, 48]. Measures of 
drug demand offer an alternative to studying self-administration in the laboratory, complementing 
measures of subjective drug responses. 
One limitation of many laboratory-based pharmacotherapy trials is the tendency to focus on heavy 
drinkers without AUD, rather than participants who report symptoms of the disorder [49, 50]. A recent 
systematic review found evidence that recruiting non-clinical samples for laboratory trials can 
potentially limit the ability of laboratory findings to generalize to larger clinical trials, perhaps 
undermining translational research efforts [51]. While ethical considerations normally preclude 
laboratory alcohol administration methods with treatment-seeking AUD participants [50], studies of 
non-treatment-seeking AUD participants are ethically justified, and can provide important data on 
medication effects and safety in the target clinical population [52]. Additionally, focusing on participants 
with <8 of out 11 AUD symptoms endorsed) can ensure maximal safety when studying this population 
by eliminating the likelihood of clinically significant withdrawal or alcohol-related medical complications. 
Our team has ample prior experience with alcohol administration procedures in both clinical and non-
clinical populations; we will utilize these methods to study the potential efficacy of semaglutide in 
participants with AUD. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
Semaglutide (Ozempic®) received FDA approval in 2017 for use as an adjunct to diet and exercise to 
achieve glycemic control in adults with type 2 diabetes mellitus (T2D). Semaglutide received FDA 
approval based on the results of 25 completed trials with the goal of providing results that would be 
applicable to a broad type II diabetes (T2D) population, including the elderly, patients with renal 
impairment, and patients at high cardiovascular risk. These trials involved > 9,300 participants, of whom 
>5,700 were treated with semaglutide. In these trials, treatment with semaglutide alone was efficacious 
for reduction in hemoglobin A1C (HbA1c) below 7% (e.g., 73% of participants had HbA1c <7% at week 
30, compared to 28% of placebo-treated patients). Significant body weight reductions were also 
reported, with the weight loss achieved at end-of-treatment ranging from -1.43 to -4.28 kg 
(corresponding to 2.3−4.9%). Weight reductions were evident after 4 weeks of treatment, and persisted 
up to 104 weeks [75]. The peak plasma concentration of semaglutide is reached 1-3 days post-dose. 
Steady-state exposure is achieved following 4-5 weeks of once-weekly administration, and elimination 
half-life is approximately 1 week. 
Risks related to medication. The most commonly reported side effects/adverse events (AEs) are 
gastrointestinal, with nausea being the most frequently reported symptom. The majority of reports of 
nausea (0.5 mg dose vs placebo; 15.3 vs. 6.1%), vomiting (5.0 vs 2.3%), and/or diarrhea (8.5 vs 1.9%) 
occur shortly following a dose escalation. Abdominal pain (7.3 vs 4.6%) and constipation (5.0 vs 1.5%) 
were also reported [76]. In studies ranging from 30-56 weeks in duration, the discontinuation rate due 

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to these gastrointestinal AEs was ranged from 5-13%, with this number increasing during longer 
treatment durations [77].  
Rarer AEs (occurring at a frequency of <5%) included symptomatic hypoglycemia (≤70 mg/dL glucose 
threshold), which occurred in 1.6% of semaglutide-treated participants versus 0% placebo participants; 
dyspepsia (3.5 vs 1.9%); eructation (2.7 vs 0%); and gastroesophageal reflux disease (1.9 vs 0%). In 
placebo-controlled trials, injection site reactions (e.g., discomfort, erythema) were reported in only 0.2% 
of semaglutide-treated patients, suggesting good tolerability of subcutaneous administration. Patients 
exposed to semaglutide had a mean increase from baseline in amylase of 13% and lipase of 22%. 
Cholelithiasis was reported in 1.5% of treated patients. The 0.5 mg dose resulted in a mean increase in 
heart rate of 2 to 3 beats per minute, while there was a mean decrease in heart rate of 0.3 beats per 
minute in placebo-treated patients. Hypersensitivity reactions (e.g., anaphylaxis, angioedema) have 
been reported with GLP-1 receptor agonists. [76]. Other adverse reactions with a frequency of >0.4% 
associated with semaglutide include fatigue, dysgeusia and dizziness [76].  
Rodent studies have shown an increase in the incidence of thyroid C-cell tumors after lifetime exposure 
of semaglutide at clinically relevant plasma levels. However, several studies in T2D patients taking GLP-
1R agonists have shown no increase in neoplasm risk, even after several years of use [78]. Nevertheless, 
a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 2B is 
considered a potential risk factor for taking the medication, and will be an exclusionary criterion.  
In a 2-year trial, acute pancreatitis was observed in 8 semaglutide-treated patients (0.27 cases per 100 
patient years) and 10 placebo-treated patients (0.33 cases per 100 patient years). One case of chronic 
pancreatitis was confirmed in a semaglutide-treated patient. History of pancreatitis will be an exclusion 
factor, and study participants receiving semaglutide will be observed for signs and symptoms of 
pancreatitis (via blood monitoring of serum amylase and lipase). If pancreatitis is suspected, semaglutide 
will be discontinued, and appropriate management recommended.  
Other rare events include postmarketing reports of acute kidney injury and worsening of chronic renal 
failure, which may sometimes require hemodialysis, in patients receiving long-term treatment with GLP-
1 receptor agonists. Some of these events have been reported in patients without known underlying 
renal disease. Most of these events occurred in patients who had experienced nausea, vomiting, 
diarrhea, or dehydration. Therefore, we will monitor renal function by including a measure of serum 
creatinine at baseline and at subsequent visits involving blood samples.  
Although most safety data on semaglutide comes from trials with T2D participants, there are now a 
number of randomized trials underway examining GLP-1 receptor agonists in participants with 
substance use disorder, including trials on tobacco, cocaine, alcohol, cannabis, and opioids. A full list of 
registered randomized trials can be found by searching for “GLP-1” at ClinicalTrials.gov. This study will 
be the first to our knowledge to focus specifically on heavy-drinking smokers. The use of a short-term 
medication screening protocol (lasting roughly 10 weeks) will provide an opportunity to demonstrate 
tolerability and generate data on side effect profiles in this population while minimizing any risks 
associated with longer-term medication exposure. 
Risks Related to Questionnaire and Interview Assessments. There may be potential risks associated with 
assessment procedures. Participants may find the battery of psychiatric and psychological assessments 
tedious or intrusive. Participants may experience discomfort resulting from questions about personal 
histories or substance use patterns.  

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Participation in Alcohol Administration Sessions. Other potential risks include typical risks related to 
participation in alcohol administration studies. For example, it is possible that participants may 
experience dizziness/nausea from drinking during these visits, or symptoms the following day (e.g., 
headache). Our group has considerable experience with alcohol administration and self- administration 
procedures [80-84], and the safety precautions required in these studies. Across these studies, the 
incidence of adverse events such as vomiting has been exceptionally low. Our procedures will follow the 
NIAAA recommended guidelines for administering alcohol to human subjects 
(https://www.niaaa.nih.gov/Resources/ResearchResources/job22.htm). Briefly, the NIAAA guidelines 
include recommendations for administering alcohol to participants who meet criteria for AUD. In 
particular, we have taken measures to protect against ethical concerns by excluding treatment-seekers 
(or those engaged in an active quit attempt), as per the NIAAA recommended guidelines. Additionally, 
we will screen out participants with severe AUD (defined as 6 or more of 11 symptoms). This approach 
allows us to generate data relevant to a clinical population while minimizing risks.  
Risks Related to DNA Collection. The purpose of collecting saliva for DNA in this study is to allow 
secondary analyses to examine whether medication effects might be different according to certain 
genetic factors. These analyses may also focus on genetic factors potentially associated with drug use or 
related behaviors, such as nicotine and alcohol metabolism, dopaminergic function, or impulsivity. 
Potential risks associated with DNA collection involve potential identification, and there may be risks 
with genetic (DNA) tests that are as yet unknown. Genes may be shown at some point in the future to 
be related to mental illnesses or tendency to addiction. Samples will be labeled with participant ID only, 
and analyzed at an outside laboratory. Samples will be de-identified and links with participant identifiers 
will be broken upon completion of the analyses. We will not conduct any whole genome sequencing of 
the DNA samples. Additionally, the consent form will state that participants have the option to opt out 
of DNA collection, and to request that their samples are destroyed at any time during the study. 
Participants will not receive any feedback from any of the genetic tests from study staff. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
The participants in this study are not expected to benefit directly from their participation. However, the 
knowledge gained from this study could lead to a better understanding of a medication with potential to 
treat alcohol and nicotine addiction, and potentially other substance use disorders.  
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
Given the vast health implications of substance use disorder and the currently limited array of effective 
medications, it is imperative to pursue novel pharmacotherapeutic options. A key strategy in this regard 
is to “repurpose” medications that are already approved (and have proven safe) in the context of other 
health conditions. Given the sizable amount of research on GLP-1 receptor agonists in other clinical 
populations, coupled with preclinical evidence that these medications reduce motivation for alcohol, 
nicotine, and other drugs, evaluating this medication class in the proposed population is warranted. 
Given no available pharmacotherapies for the indication of concurrent alcohol and nicotine addiction, 
any evidence for potential efficacy in heavy-drinking smokers could have substantial implications. From 
this standpoint, the risk/benefit profile for testing semaglutide in a population of non-diabetic 
participants is favorable.  

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Although we anticipate the risk of adverse events to be low based on the safety profile of the 
medication, gradual dose escalation, and relatively short duration of treatment, several steps will be 
taken to track and report medication-related side effects. As described further in later sections of this 
application, participants will be monitored regularly by virtue of attending weekly lab visits for 
medication delivery, at which side effects will be assessed and clinical lab results monitored. Participants 
will be given a contact number for study staff in case of emergent side effects (and instructed to seek 
medical attention in the event of any serious side effects), and participants will be contacted by phone 
shortly after dose escalations to monitor symptoms. We expect some participants to experience nausea 
shortly following dose escalations, but that these symptoms will usually be transient.  
Given the focus on a non-obese population, we will be particularly vigilant in monitoring changes in 
body weight and blood glucose, and will exclude participants at the outset with body weight or blood 
glucose levels below normal range, based on physician judgement. We will carefully monitor 
participants with glucose tests and weight measurements at regular study visits (see schedule of 
activities table), and will instruct participants to be vigilant for potential symptoms of hypoglycemia. 
Periodic blood tests to measure fasting glucose, fasting insulin, serum lipase and amylase, serum 
creatinine, and serum calcitonin will occur at baseline and regularly thereafter (i.e., at visits prior to dose 
escalations). All adverse events will be documented and reported in accordance with relevant policies, 
and the regulations of NIH. We have enlisted the TraCS DSMB to assist with safety monitoring of the 
study. The board will convene at the beginning of the study and at scheduled points to review study 
progress and safety data, and to review any SAEs and considerations related to stopping rules (described 
further below). 
Considering the use of an FDA approved medication that has been deemed safe in the context of chronic 
administration for glycemic control, the risks related to medication use in this short-term screening trial 
are acceptable in comparison to the potential benefits of the proposed research (i.e., demonstrating 
potential efficacy of a new medication for substance use disorder). 
Risks Related to Alcohol Administration Sessions. Alcohol administration procedures are commonly used 
to study risk factors for alcohol use disorder (AUD), and have proven capable of identifying successful 
pharmacotherapies [40]. As per the NIAAA guidelines for administration of alcohol in human studies, 
such studies are typically restricted to non-treatment-seeking participants in order to minimize ethical 
concerns, as will be the approach in this study. Further details on safety procedures are provided later in 
this document. 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
 
 
To examine effects of semaglutide vs. 
placebo on alcohol self-administration 
under laboratory conditions.  
 
 
 
 
 
Amount of alcohol consumed 
and breath alcohol 
concentration (co-primary 
endpoints) during a validated 
laboratory alcohol self-
administration protocol. In 
this procedure, participants 
are provided the option of 
choosing between drinks and 
Primary: This outcome is a 
laboratory assay of alcohol intake, 
and has been used in prior human 
laboratory studies to screen 
candidate medications, allowing 
comparisons with effect sizes for 
other medications. This session will 
be conducted during the standard 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
monetary reward. The 
comparison of interest is the 
difference between 
medication and placebo 
groups in the change in 
laboratory consumption 
between baseline and the 
maintenance dose of 0.5mg. 
 
 
maintenance dose (0.5mg) to mimic 
the common clinical scenario. 
 
Secondary: Subjective alcohol 
responses and alcohol/cigarette 
demand are validated measures of 
drug reward/motivation, and are 
known to be sensitive to medication 
effects. Given substantial individual 
differences in alcohol 
pharmacokinetics, a within-subjects 
analysis is preferable for these 
endpoints (such that each 
participant will serve as their own 
control). Laboratory sessions will 
take place at two time points: 
baseline and 0.5mg maintenance 
dose. 
Secondary 
 
 
To examine group differences in 1) 
alcohol/cigarette demand and 
subjective responses to alcohol during 
alcohol administration, and 2) 
naturalistic drinking and smoking 
behaviors over the course of the 10-
week treatment period. 
Laboratory measures of 
subjective responses to 
alcohol, alcohol demand, and 
cigarette demand during 
controlled laboratory alcohol 
administration (lab sessions 
will take place at baseline and 
again after achieving the 
maintenance dose).  
 
Number of standard drinks 
consumed and number of 
cigarettes consumed per day 
during the treatment phase 
(Weeks 0-10), as measured by 
a daily diary report. 
 
Similar to the primary 
outcome, secondary outcome 
analyses will examine 
medication vs. placebo group 
differences in within-subjects 
changes in these outcomes 
over time (baseline to 0.5mg). 
 
Laboratory measures of alcohol 
response and alcohol/cigarette 
demand are clinically valid indicators 
of drug motivation, and are 
demonstrated to be sensitive to 
medication effects. Investigating 
these outcomes under controlled 
conditions will allow us to test for a 
medication “signal” on measures of 
alcohol and nicotine motivation. 
 
Daily measures of alcohol 
consumption (standard drinks per 
day) and cigarettes per day are 
selected to afford greater power for 
modeling change in consumption 
over the treatment period. Note that 
these outcomes are considered 
secondary because this Phase II trial 
involves non-treatment-seeking 
participants who are not attempting 
to reduce alcohol or use or cigarette 
smoking. 
Tertiary/Exploratory  
 
 
Body weight, HbA1c, alcohol 
elimination. 
Changes in body weight, 
HbA1c, and alcohol 
elimination will be examined 
as exploratory endpoints 
based on potential clinical 
relevance. 
GLP-1 receptor agonists lower 
HbA1c and body weight in indicated 
populations (e.g., Type II diabetes, 
obesity). Given high co-occurrence 
of obesity and alcohol use disorder, 
reporting whether medication is 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
 
associated with these reductions in 
the present sample is clinically 
relevant. Data from the alcohol 
administration sessions will be used 
to estimate whether medication 
predicts changes in alcohol 
elimination during treatment, and 
whether changes in body weight 
account for any such differences. 
These outcomes are exploratory.  
 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
Overview of Study Design. 
 
The aim of this protocol is to translate preclinical findings on GLP-1 agonists by conducting an early-
Phase II investigation of semaglutide in non-treatment-seeking participants with AUD, with a focus on 
human laboratory outcomes. Given preclinical evidence for the potential efficacy of GLP-1 agonists for 
reducing both alcohol and nicotine intake, and the need for treatments targeting both alcohol and 
nicotine addiction, this proposal focuses on cigarette smokers with AUD.  
 
This is a single-site, Phase II, two-arm, double-blind (participants, outcome assessors), randomized, 
placebo-controlled, dose-ranging study. Following a baseline assessment eligible participants will be 
randomized to medication or placebo conditions by the IDS staff at a 1:1 ratio. The treatment period will 
be approximately 10 weeks, taking into account the dose escalation necessary for this medication. 
Those randomized to semaglutide will receive 0.25mg/week for 4 weeks (Weeks 1-4), and 0.5mg/week 
for 4 weeks (Weeks 5-8). Provided that participants have tolerated the medication , participants will 
receive a final dose of 1.0mg (Week 9), and will return for a discharge lab visit with repeat lab tests at 
Week 10, followed by a final monitoring assessment by phone scheduled approximately 6 weeks after 
the last medication dose (Week 15). Those in the placebo condition will receive sham placebo 
administration at each visit (described in further detail in later sections). Participants will attend weekly 
visits at Eastowne CRU or CTRC to receive medication or placebo doses. 
 
In addition to the medication visits, participants will be asked to attend four laboratory visits: two 
involving alcohol self-administration (one prior to the first medication visit and one during the 0.5mg 
treatment phase) and two involving alcohol challenge (one prior to the first medication visit and one 
during the 0.5mg treatment phase). These sessions are designed to assess changes in alcohol responses 
over the course of the treatment period. Laboratory sessions are described in further detail below. 
Measurements of naturalistic alcohol and cigarette use will also be recorded throughout the treatment 
period. These assessments will be captured using a daily diary that will be provided to participants. 
Participants will receive an automated text message daily via Phone.com as a reminder to complete the 
diary. Additional self-report measures of substance use will be collected at study visits.  
 

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As summarized above, the primary objectives are to examine whether treatment with semaglutide 
alters alcohol self-administration (primary outcome) and laboratory measures of alcohol response and 
motivation (i.e., demand and responses to alcohol, secondary outcomes) during alcohol administration. 
We hypothesize that the semaglutide treatment (versus placebo) will be associated with reduced 
alcohol self-administration during a laboratory session conducted at the maintenance dose of 0.5mg. 
We further hypothesize that semaglutide will lead to reductions in alcohol demand, cigarette demand, 
and subjective responses to alcohol (e.g., reduced stimulation) during alcohol administration sessions.  
 
The primary and secondary outcomes for this trial will be assessed during exposure to the standard 
maintenance dose (.5mg). While an extended treatment phase at the 1.0mg dose is beyond the scope of 
this small-scale trial, the inclusion of a brief (1-week) phase at 1.0mg is designed to provide initial data 
on tolerability and any changes on selected secondary outcomes (i.e., drinks per day and cigarettes per 
day) in this population. Capturing these data will help to support feasibility and pilot data for 
subsequent funding proposals with longer treatment intervals. 
 
Secondary objectives include examining changes in naturalistic alcohol consumption and cigarette 
smoking during the treatment period. Although participants will not be attempting to reduce drinking or 
smoking in this trial, it is hypothesized that treatment with semaglutide will result in reductions in 
alcohol consumption (drinks per day) and cigarettes per day over the course of the treatment period. 
Tertiary/exploratory outcomes include examining changes in body weight, HbA1c, and alcohol 
elimination during the trial. 
 
In total, participation in this study is estimated to take a maximum of up to 50 hours of combined time 
over a period of up to approximately 16 weeks beginning with initial screening. This includes a screening 
and baseline visit (up to 4 hours), up to 9 subsequent laboratory visits for medication administration and 
side effects monitoring (up to 1 hour each), a final discharge visit (Week 10), and final telephone check-
in (Week 15). If necessary for safety reasons, (e.g., based on lab results), participants may be asked to 
attend (unplanned) visit(s) for follow-up labs at the discretion of the study physician. Participants will 
also complete four visits involving alcohol administration over the course of Weeks 0-10; these sessions 
may last up to 7-8 hours each. Participants also will receive calls from staff 2-3 days after each 
medication phase begins (placebo, 0.25mg, 0.5mg, 1.0mg) to check in on side effects (10 minutes per 
call), and will be asked to complete brief daily questionnaires via a daily diary with reminders sent via 
daily text message prompt (1-2 minutes per day). 
 
A detailed summary of study procedures is provided below. 
 
Detailed Study Procedures. 
 
Following initial recruitment (described in section 5.5), participants will be asked to complete the 
following procedures: 
a) Telephone screen 
Initial screening will be conducted by telephone by trained research staff and will assess participant 
alcohol, cigarette, and drug use, medications, and basic medical inclusion/exclusion factors. 
Potential participants will be given a brief description of the study. The initial telephone screen is 
estimated to take roughly 15-30 minutes. Contact information will be collected from interested 
callers who pass the initial screen. Following the initial screen, participants will proceed to be 
booked for an informed consent and baseline interview session. The informed consent procedures 

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will be conducted remotely using a HIPAA-compliant virtual meeting platform (e.g., Webex, Zoom) 
and Docusign. Depending on participant and staff availability, the phone screening and informed 
consent/baseline interview can happen on the same day (after the screening call) or at a future 
date. 
b) Screening and Baseline Data Collection Visits 
At the informed consent session, a member of the research staff will review the study 
procedures and carry out informed consent procedures (including electronic signature via 
Docusign) prior to proceeding to the baseline interview. Following informed consent, the staff 
member will conduct a semi-structured interview to assess inclusion/exclusion criteria. A 
research assistant will use a structured interview to measure diagnostic and substance use 
screening criteria, including symptoms of alcohol use disorder; inclusion/exclusion factors 
related to medical history will also be assessed (see criteria listed above). The Structured Clinical 
Interview for DSM-V [53] will be used to assess AUD and substance use disorder symptoms. 
History of other psychiatric diagnoses and medication use will be assessed via self-report. The 
research assistant will also collect information on demographic factors, criteria related to 
current medical status and medications, current alcohol, tobacco and other substance use (see 
“Phone Screen” document), as well as substance use disorder symptoms (via select modules 
from the SCID interview) and symptoms other psychiatric symptoms (using the MINI screening 
module). Participants who appear eligible will be booked for an in-person visit, which will take 
place at the laboratory site (Medical Wings C), with some procedures (e.g., blood draw) booked 
at CTRC as necessary. 
The in-person screening/baseline visit will include a brief review of informed consent to answer 
any additional questions, and a brief review of self-report and interview questions from the 
remote screening session. The Timeline Follow-Back (TLFB) [54] will be used to assess alcohol, 
cigarette and other drug use in the 90 days prior. The participant will also provide a breathalyzer 
screen. Participants who have a positive BAC (greater than 0.00) will be monitored until their 
BAC is reduced to a safe level (BAC<.03g%), in accordance with NIAAA guidelines (or to 0.00g% 
in the event that the participant drove to the session). 
Participants who remain eligible after the interview will complete vitals and measurements (HR, 
BP, height, weight, temp), and a measure of expired alveolar carbon monoxide (CO). A baseline 
saliva sample for DNA analysis will also be collected. Additionally, participants will provide a 
urine sample and complete a blood draw (up to 70-80 ml) for a comprehensive metabolic panel 
(e.g., Na, K, Cl, CO2, BUN, Creatinine, Glucose, Calcium, Albumin, Total protein, Total bilirubin, 
AST, ALT, Alk Phos), baseline measure of HbA1c, baseline measure of nicotine metabolites (e.g., 
3HC, COT), serum amylase and lipase, and complete blood count (e.g., Auto WBC, Corrected 
WBC, RBC, HGB, HCT, MCV, MCH, MCHC, RDW, MPV, Platelet). These procedures will be 
conducted by the research assistant, and the baseline blood draw will be taken by a team 
member with phlebotomy training. If there is no team member with phlebotomy training 
available that day, the blood draw may also be booked at CTRC. If needed, the blood draw and 
other baseline procedures may be booked as separate visits. On the day of the visit that includes 
the blood draw, participants will be instructed to arrive fasting for 12 hours (to allow for 
assessment of baseline HbA1c and lipids). If participants are not able to arrive fasting for the 
baseline session, the fasting lipids sample may be deferred or completed at the next possible 
visit. Blood samples will be sent to McClendon laboratory for testing. A portion of the blood 
sample (de-identified) will also be stored (Thurston Bowles building and Neurosciences Research 

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Building) for subsequent analysis (e.g., nicotine metabolites and blood neutrophils, which are 
affected by cigarette smoking). Neutrophil analyses will be conducted by Dr. Robert Tarran’s lab. 
The saliva sample will also be stored at Thurston Bowles building. The urine sample will be used 
to test for the presence of several drugs (for example, heroin, cocaine, methamphetamines, 
opiates). (For females, the test will include a pregnancy screen.) If a participant tests positive for 
drugs other than cannabis (or if females screen positive for pregnancy), the participant will be 
excluded from the study. 
Participants will complete baseline questionnaires, which will be collected on paper. A 
Demographic Screening Questionnaire will assess basic demographic factors (e.g., age, 
education, income). A Locator form will collect contact information for three individuals who 
can be contacted if a participant is unable to be reached by study staff for follow-up visits. Other 
baseline measures will include the Alcohol Use Disorders Identification Test (AUDIT) [55], Self-
Report of the Effects of Alcohol Questionnaire (SRE) [56, 57], Fagerström Test of Nicotine 
Dependence (FTND) [58], and the Nicotine Dependence Syndrome Scale (NDSS) [59], Barratt 
Impulsivity Scale (BIS-11) [60], UPPS Impulsive Behavior Scale (UPPS) [61], Impaired Control 
Scale (ICS) [62], Center for Epidemiological Studies Depression Scale (CES-D) [63], Toronto 
Alexithymia Scale (TAS-20) [64], the Reward Probability Index (RPI) and the Environmental 
Reward Observation Scale (EROS) [65]. Baseline measures that will be repeated at subsequent 
visits will include the Timeline Followback (TLFB), the Penn Alcohol Craving Scale (PACS) and 
Tiffany Questionnaire of Smoking Urges (TQSU) [66], and the Wisconsin Smoking Withdrawal 
Scale (WSWS) [67]. To assess potential medication effects on changes in motivation and self-
efficacy for resisting alcohol/cigarettes, we will use alcohol and smoking Contemplation Ladder 
items, Alcohol and Cigarette Abstinence Self-Efficacy (AASE/CASE) (these scales will be repeated 
at each visit) and the Inventory of Drinking Situations (IDS) scales [68-70]. Appetite and eating 
behavior will be assessed with the Simplified Nutritional Appetite Questionnaire (SNAQ) [71], 
Control of Eating Questionnaire (CEQ) [72], the Three Factor Eating Questionnaire (TFEQ) [73] 
and the Reward-Based Eating Drive Scale (R-BEDS) [74]. During the medication phases, side 
effects will be assessed with the SAFTEE questionnaire [75], a standard tool for alcohol clinical 
trials. Participants will also complete previously validated Purchase Tasks for alcohol, cigarettes, 
and food, and delay discounting will be assessed with the Monetary Choice Questionnaire 
(MCQ) [76-79]. These brief behavioral economic tasks assess perceived value of reinforcers by 
presenting hypothetical scenarios involving choices between the reinforcer (alcohol, cigarette, 
food) and monetary rewards; these measures will be completed at each visit. Finally a previously 
validated sweet taste preference test will be administered at baseline and again on the final 
visit, since this phenotype has been shown to be implicated in both food and alcohol reward, 
and may be modulated by a GLP-1 agonist. This test involves participants tasting solutions of 
sugar water prepared to reach .05, .1, .2, .42, and .83 molar sucrose, and then rating preference 
and intensity of the taste. The sweet taste test will be overseen by a research assistant using 
previously published protocols from prior projects at UNC [80, Error! Hyperlink reference not 
valid.]. 
The baseline questionnaires and interview assessments are projected to take approximately 3-4 
hours combined. To accommodate potential scheduling/time constraints or delays at the 
baseline visit, some questionnaires that are not time-sensitive (for instance, personality 
questionnaires) may be deferred until a later lab visit as needed, at the discretion of the study 
team. All interview records and paper questionnaires will be stored in study binders in a secure 
location for subsequent entry into an electronic database for analysis. Patients will be given 

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breaks as needed. Following the blood draw, participants will be offered a snack and bottled 
water (given the instructions to arrive fasting). If results of the baseline screening/medical 
assessment indicate that the participant is tentatively eligible, they will be given a 
comprehensive orientation to the next phases of study, including the follow-up medication 
visits, the laboratory alcohol administration visits, and the daily surveys. Locator/collateral 
contact information will also be obtained. A Locator form will collect contact information for 
three individuals who can be contacted if a participant is unable to be reached by study staff for 
follow-up visits. Following the completed baseline assessments, the participant’s screening 
summary will be reviewed for eligibility, including review of medical criteria and any 
medications that the participant is taking by the study physician. Lab results will be uploaded to 
the EMR and reviewed by the study physician prior to prescribing the medication. Potential 
interactions with semaglutide will be verified using an established online database such as 
Epocrates or Lexicomp. In the event of any uncertainties about medication interactions, 
participants will be asked to contact their primary care physician to confirm no concerns with 
taking semaglutide.  
For eligible participants, the study physician will provide sign-off on all medical criteria (e.g., 
medical history, medications, lab results), and the PI will provide sign-off on other baseline 
criteria. Once participants have been confirmed as eligible, the physician will submit an order to 
start medication or placebo. Medication and placebo will be dispensed at CTRC (Week 1 visit) at 
a date coordinated with the participant. Participants will be advised to be vigilant for symptoms 
of hypoglycemia at the medical visit, and instructed to contact the study team to review any 
symptoms that emerge (regular glucose tests will also be obtained at follow-up visits, as noted 
in the schedule of assessments). If necessary, the medication review will take place via 
telephone or telemedicine, depending on medical team availability.  
Participants’ Week 1 visit will be scheduled with enough lead time to review lab results and 
exclude participants (if needed) prior to administering the study medication. Additionally, if 
clarification of medical criteria is needed at any point during or following the phone or in-person 
screening process, or at any subsequent stage of the study, the study physician may meet with 
the participant via a remote contact method (e.g., phone, Webex/Zoom, or telehealth) to clarify 
medical questions or discuss test results. 
c) Daily Assessments.  
Throughout the study, participants will be asked to complete a brief self-report survey each day that 
includes measures of 1) prior-day number drinks consumed; 2) number of cigarettes smoked; and 3) 
prior day peak craving/demand for alcohol and cigarettes. Participants will be provided with a paper 
booklet in which to enter responses and will be asked to bring the booklet to each visit. At each visit 
the research staff will collect the interim daily surveys for retention in the participant’s study binder. 
Participants will be texted an automated text message each day during their participation in the 
study as a reminder to complete the daily survey. If preferred, participants can opt to receive an 
email link. (No daily survey data will be collected from participants via text or email.) At each study 
visit, a staff member will provide compensation for the prior week’s surveys, and will review survey 
adherence and progress towards compensation for good adherence (described later), as a means of 
motivating adherence to self-report assessments. In the event a participant completes the daily 
assessments but forgets to bring the packet to a given visit, they will be asked to bring their packet 
to the following session. Participants will be asked to either a) complete the measures in person at 
the current lab visit, or b) to schedule a brief meeting with a research team member via Zoom or 

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Webex in order to complete the questions (depending on scheduling and availability). These 
approaches will be used in specific circumstances if needed (e.g., if the participants forgets to 
complete the daily assessments altogether, or will be unable to bring it to the next session). 
d) Weekly Laboratory Visits.  
Medication administration visits will occur at either the Eastowne Clinical Research Unit (CRU) or the 
CTRC.  Following the baseline (Week 0) visit, participants will visit CRU or UNC Hospital/CTRC once 
weekly (Weeks 1-9), for subsequent medication or placebo doses, and for a final follow-
up/discharge visit at Week 10. (In addition, the study physician may request an additional follow-up 
lab visit(s) at any point in the study to monitor side effects.) In addition, to accommodate events 
such as missed lab visits or scheduling difficulties, assessment procedures at a given weekly visit 
(e.g., questionnaires, lab tests) may be conducted within a 7-day window of the original target date, 
as necessary, to avoid unnecessary missing data.  In addition to medication/placebo administration, 
follow-up visits will include 1) vitals, weight measurements, and a brief side-effects assessment, 2) a 
finger-stick glucose test (or fasting blood draw depending on the week, see study flow chart), 3) a 
brief calendar-based self-report assessment of interim alcohol and cigarette use (TLFB), and 4) a 
repeat CO measurement. These procedures are expected to take roughly 30-60 minutes in total, and 
will be conducted by a trained study team member and/or a member of the CRU/CTRC team (e.g., 
RN). All side effects reports, labs, and other medical test results (e.g., glucose tests) will be uploaded 
in Epic (e.g., lab tests) or sent electronically (e.g., self-reported medication changes) for review by 
the study physician. If side effects or lab results suggest that further assessment is indicated, a 
member of the medical team will advise the study team (and if necessary, contact the participant) to 
provide direction. At the Week 4, Week 8, and final discharge visits, participants will be asked to 
arrive fasting to allow for a blood draw for follow-up lab assays (identical to those described in the 
baseline procedures above). As with the baseline sample, a portion of each sample will be stored for 
follow-up analyses (e.g., nicotine metabolites). 
 
e) Alcohol Sessions.  
 
To evaluate effects of medication phase on laboratory measures of alcohol response and self-
administration, participants will be asked to complete four laboratory visits over the course of the 
study. Two visits will occur between the Week 0 and 1 visits (baseline phase), and two will occur 
between the Week 8 and 9 visits (0.5 mg phase). Minor scheduling deviations will be accommodated 
as needed, provided that the participant has completed at least three weeks of the .5mg phase at 
the time of the second set of laboratory sessions. 
 
During each of these sessions participants will be asked to report to the lab having received 
instructions to abstain from alcohol and recreational drugs for 24h, and not to consume food for 4 
hours prior to arrival. Participants will also be advised not to drive to these study appointments. 
Participants will also be asked to schedule a smoking break just prior to arrival (to ensure that 
participants are not nicotine-deprived during testing) [16]. Upon arrival participants will provide 
breathalyzer and expired CO readings, as well as measures of body weight and vitals (HR, BP) and a 
finger-stick blood glucose test. Participants will also receive the Short Alcohol Withdrawal Scale 
(SAWS) to ensure that no significant withdrawal symptoms are present. Evidence of withdrawal 
symptoms will require a consultation with an addiction medicine physician (Dr. Tow or Dr. Jordan) 
prior to proceeding. (We except a low likelihood that this will happen because participants with 

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severe AUD or history of withdrawal symptoms will be excluded). Female participants will also be 
asked to repeat the urine pregnancy screen at each alcohol session.  
 
In the interim, participants will complete self-report questionnaires (e.g., Timeline Follow-Back to 
assess recent substance use). Participants will be seated in a comfortable recliner chair for the 
alcohol administration procedures. Participants will first complete baseline physiological readings 
(systolic and diastolic blood pressure, heart rate), and baseline measurements of self-report 
questionnaires (see below). Next, participants will complete one of two procedures (alcohol 
challenge, alcohol self-administration), dependent on the visit week. Specifically, the first alcohol 
challenge session (AC1) and the first self-administration session (SA1) will be scheduled to take place 
between Week 0 and 1. The second alcohol challenge session (AC2) and the first self-administration 
session (SA2) will be scheduled to take place between Week 8 and 9 (0.5mg treatment phase), 
allowing for minor scheduling adjustments as noted above. Prior to the self-administration session 
only (which is longer in duration), participants will consume a standardized, isocaloric meal in 
advance of the alcohol self-administration procedures, with a standardized wait time between 
completion of the meal and onset of beverage consumption. The two session types will be 
scheduled with at least one interim day scheduled between sessions when possible. For both 
sessions, participants will be instructed to expect to remain in the lab for a full day (e.g., 8 hours). 
 
Alcohol Challenge Sessions (AC1, AC2) 
The AC sessions are designed to generate data to estimate within-person changes in acute 
responses to alcohol as a function of medication phase (baseline vs. 0.5mg). Following baseline 
assessments (described above), participants will be asked to consume a pre-determined dose of 
alcohol calculated to achieve a target peak breath alcohol concentration (BrAC) of .06g%. This BrAC 
level reflects a moderate alcohol dose. Individualized doses will be calculated using established 
formulas [83] that account for determinants of total body water (e.g., height, weight, sex, age). 
Beverages will consist of 80-proof vodka combined with a non-alcoholic, sugar-free mixer at a 1:5 
ratio. Beverages will be allocated to three equal portions in separate cups. Participants will be asked 
to consume the beverages at an even pace over 10 minutes. A separate placebo session is not 
incorporated for the AC sessions, because our primary interest is in examining within-person 
changes in laboratory alcohol responses as a function of medication dose (baseline vs. 0.5mg), and 
because our primary outcome is self-administration (described below). Although a limitation of this 
approach is the inability to dissociate expectancy from pharmacological effects in measuring 
subjective responses to alcohol, increasing the number of sessions to dissociate expectancy effects 
is not a major aim for this preliminary project.  
 
After completion of the beverages, participants will wait 10 minutes (to allow an absorption period), 
then will complete an initial breath alcohol concentration (BrAC) reading. BrAC readings will be 
repeated at 10-minute intervals during the first hour of the session (peak BrAC is anticipated to 
occur around 30-40 minutes, on average, with variability across subjects). Participants will repeat 
the battery of self-report questionnaires (outlined below) and physiological assessments at three 
points on the ascending limb of the blood alcohol curve: upon the first BrAC reading that meets or 
surpasses .02g%, .04g%, .06g%. To account for the fact that some participants may not reach the 
.06g% target, the latter assessment will be conducted if/when it appears the participant will not 
reach the .06g% target (as evidenced by two consecutive descending BrAC readings after surpassing 
the .05g% mark).  
 

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Following completion of the last set of measures (.06g%), participants will then be escorted to a 
private room to begin the recovery phase, during which they will receive water and will be 
monitored, and take bathroom breaks as needed. During this time, BrAC measurements will 
continue every 15 minutes. On the descending limb of the blood alcohol concentration curve, 
participants will complete follow-up measures and physiological readings at the first BrAC readings 
that meet or fall below .04g% and .02g%. Prior to discharge, participants will be asked to provide an 
additional blood glucose sample (via fingerpick) to assess any differential changes in glucose levels 
following alcohol administration as a function of medication phase. Participants will also complete 
the Food Purchase Task to assess motivation for food following alcohol administration. After this 
point, participants will be provided with a lunch and snacks to consume during the recovery period. 
Participants will be compensated and discharged once BrAC reading reaches .00g% (to allow for 
estimating alcohol elimination rate across sessions AC1 and AC2 as a function of medication group).  
 
Subjective Measures. At baseline (prior to alcohol ingestion) and each subsequent assessment point 
noted above, participants will complete several measures. Measures of subjective alcohol effects 
will include the Biphasic Alcohol Effects Scale (BAES) [84], the Alcohol Urge Questionnaire (AUQ) 
[85] and Drug Effects Questionnaire (DEQ) [86]; the latter will be supplemented with additional 
items to assess potential effects related to medication (e.g., “tired”, “confused”, “nauseous”, 
“dizzy”, “sick”, “drunk/intoxicated”) [16]. The Alcohol Purchase Task [45] Cigarette Purchase Task 
[87] Food Purchase Task [78] and Monetary Choice Questionnaire [76]will be also administered at 
the corresponding intervals noted above. Changes in mood will be assessed using the Profile of 
Mood States – Short Form (POMS-SF) [88]. During the recovery period, participants will complete 
another battery (all measures noted above) once reaching .04g% and .02g% on the descending slope 
of the blood alcohol curve. 
Alcohol Self-Administration Sessions (SA1, SA2).  
Medication effects on laboratory alcohol consumption will be examined using a validated oral self-
administration procedure. Pre-session instructions and arrival procedures/tests will be identical to those 
noted above. After completing baseline physiological and baseline questionnaires, participants will be 
presented with their preferred beverage (beer, wine, or mixed drink). Participants will elect when to 
begin drinking and will then complete a 2-hour ad libitum self-administration period. Participants will 
have access to their beverage at a volume calculated (based on the person’s sex, weight, height, and age 
using established formulas) intended not to exceed a maximum predicted peak blood alcohol 
concentration .12g% over the consumption period of two hours (should the participant consume all of 
the beverages). Participants will be instructed to consume the amount of alcohol they wish (i.e., they are 
not required to drink all of the beverages). Participants will be seated in a comfortable chair/sofa and 
will view a neutral video (e.g., nature documentary) during the session. Beverages will be presented to 
the participant at the onset of the two-hour period, along with ice if requested. Participants will repeat  
rounds of self-report assessments (described above) at 30-minute intervals during the ad libitum phase 
(i.e., at 60, 90, and 120 min. after the end of the priming phase), with physiological assessments and 
BrAC readings taken at these intervals (or more frequently if indicated). The primary outcomes for this 
session are peak BrAC and volume of alcohol consumed.  
Participants will then be escorted to a private room for the recovery period. Assessments during the 
recovery period will be identical to those described above. Participants will be monitored until being 
discharged when BrAC declines below .03% for two consecutive readings, consistent with NIAAA 
recommended guidelines. [52] As noted, participants will be instructed not to drive, and will be asked to 
arrange for a ride home from the study site. If a participant cannot arrange a ride home, they will be 
provided with reimbursement for a ride home via a rideshare service (e.g., Uber or Lyft) up to $25. If a 
participant reports having driven to a session, they will be required to remain at the site until BrAC is 

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measured at 0mg% for two consecutive readings. At alcohol sessions, participants may also be provided 
with a wristband transdermal alcohol monitor (BACTrack Skyn) to wear during the session, which will 
provide a continuous readout of estimated alcohol concentration (measured as total alcohol 
concentration in sweat). Estimated transdermal alcohol concentration will not be a primary outcome - 
as it is not an accurate measure of blood alcohol concentration - but will be collected for purposes of 
secondary data analyses. Specifically, we will record readouts from the transdermal device at regular 
intervals to compare to BrAC readings, which will inform our use of this device in future studies. Because 
we will only have one transdermal device available, it may not be used in all sessions (depending on 
availability).  
List of Study Assessment Measures (See Section 1.3 for assessment time points) 
1. Demographics form 
2. Timeline Follow-Back (TLFB) 
3. Structured Clinical Interview for DSM-5 Mental Disorders (select modules) 
4. MINI Neuropsychiatric Interview (select modules) 
5. Sweet Taste Preference Test 
6. Alcohol Use Disorder Identification Test (AUDIT) 
7. Self-Report of the Effects of Alcohol Questionnaire (SRE) 
8. Center for Epidemiological Studies Depression Scale (CES-D) 
9. Toronto Alexithymia Scale (TAS-20) 
10. Barratt Impulsivity Scale (BIS-11) 
11. UPPS Impulsive Behavior Scale (UPPS) 
12. Reward Probability Index – Environmental Reward Observation Scale (RPI-EROS) 
13. Impaired Control Scale (ICS) 
14. Fagerstrom Test for Nicotine Dependence (FTND) 
15. Nicotine Dependence Syndrome Scale (NDSS) 
16. Penn Alcohol Craving Scale (PACS) 
17. Tiffany Questionnaire of Smoking Urges (TQSU) 
18. Wisconsin Smoking Withdrawal Scale (WSWS) 
19. Wisconsin Inventory of Smoking Dependence Motives (WISDM) 
20. Alcohol and Smoking Contemplation Ladder 
21. Three Factor Eating Questionnaire (TFEQ) 
22. Reward-Based Eating Drive Scale (R-BEDS) 
23. Control of Eating Questionnaire (CEQ) 
24. Simplified Nutritional Appetite Questionnaire (SNAQ) 
25. Monetary Choice Questionnaire (MCQ) 
26. Cigarette Abstinence Self-Efficacy (CASE) 
27. Alcohol Abstinence Self-Efficacy (AASE) 
28. Inventory of Drinking Situations (IDS) 
29. Biphasic Alcohol Effects Scale (BAES) 
30. Alcohol Urge Questionnaire (AUQ) 
31. Drug Effects Questionnaire (DEQ) 
32. Alcohol Purchase Task (APT) 
33. Cigarette Purchase Task (CPT) 
34. Food Purchase Task (FPT) 
35. Profile of Mood States – Short Form (POMS-SF) 
36. Systematic Assessment for Treatment Emergent Effects (SAFTEE) 
37. Prediction of Alcohol Withdrawal Severity Scale (PAWS) 

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38. Short Alcohol Withdrawal Scale (SAWS) 
39. Obsessive Compulsive Drinking Scale 
40. Graded Pain Scale 
 
 
Analysis schedule. Analyses of side effect frequency and AE/SAE frequency will be conducted prior to 
scheduled DSMB meetings. Other analyses will be conducted following the completion of the trial, or as 
otherwise required to fulfill DSMB requests or other reporting requirements.  
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
This short-term trial is intended to produce initial data on the effects of semaglutide in non-treatment-
seeking participants with AUD, with an emphasis on human laboratory outcomes. The dose escalation 
schedule is based on the standard clinical regimen, which is intended to minimize side effects common 
to GLP-1 agonists (i.e., nausea). Participants in the placebo group will complete an identical sequence 
while receiving sham subcutaneous injections (a small needle stick using a micro-needle of the same 
size, without an injection). This placebo condition is selected due to the absence of an available 
matching placebo cartridge from the manufacturer (see section 4.3). All participants will complete 
laboratory alcohol administration sessions at two time points, corresponding with the baseline and 
0.5mg phases. This design allow for within-subjects analyses for laboratory outcomes that are best 
examined at the within-subject level (owing to high inter-individual variability in alcohol 
pharmacokinetics). Overall, this design is intended to maximize feasibility and sample size while also 
accommodating the extended dosage titration period required of GLP-1 agonists. Findings from this trial 
will be used to justify a larger, placebo-controlled Phase II clinical trial application via the R01 
mechanism. 
 
4.3 
JUSTIFICATION FOR DOSE 
Semaglutide (Ozempic®) will be administered according to the FDA-approved schedule, which begins 
with a starting dose of 0.25mg (for titration purposes) once per week for four weeks. At week five, 
dosage is increased to 0.5mg/week (the initial first maintenance dose) for a subsequent four weeks, at 
which point dosage can be increased further (1.0mg) if indicated (and presuming that the 0.5mg dose 
has been tolerated). The intent for this initial trial is to mimic the typical clinical scenario over the first 
several weeks of medication titration. Although primary analyses will focus on the 0.5mg dosage, 
participants will receive one week of 1.0mg treatment at the conclusion of the 0.5mg phase, in order to 
collect initial data on side effects and naturalistic drinking/cigarette use at this dosage in the current 
population. Participants will be monitored carefully and will not be escalated to the next dose if 
experiencing persistent side effects indicative of poor tolerability.  
Given the lack of a true placebo (i.e., no manufacturer-developed placebo Ozempic® pen/cartridge), this 
study will use a placebo condition that consists of weekly sham doses. Sham doses will involve a brief 
needle prick using a very small (e.g., 32 gauge) needle. These procedures are described in more detail 
later in this protocol. By necessity, medical staff administering the medication cannot be blind to 
condition. However, other experimenters and outcomes assessors will remain blind to condition. 
Participants will be instructed during the informed consent and study orientation that they have a 50/50 
chance of being randomized to medication and placebo groups.  
 

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4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit shown in the Schedule of Activities (SoA), Section 1.3. The end of the study 
is defined as completion of the last visit shown in the SoA in the trial overall. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet the following criteria: 
• 
Age 21-65 
• 
Meeting DSM-5 criteria for current (past year) AUD, with between 2-7 symptoms endorsed, and 
NIAAA criteria for current at-risk drinking (i.e., >7/14 drinks in one week for women/men, with 
at least two episodes of 4+/5+ drinks in the past 30 days) 
• 
Willingness/availability to take study medication and complete study procedures, including 
attending weekly visits for medication administration, side effect assessments, and glucose 
monitoring 
• 
Willingness to complete laboratory sessions involving alcohol administration 
• 
Ability to communicate and read in English 
 
5.2 
EXCLUSION CRITERIA 
 
• 
Reporting past 30-day use of illicit drugs other than cannabis at baseline, or having a positive 
toxicology screen for illicit drugs other than cannabis at baseline 
• 
Meeting past-year criteria for a substance use disorder (with the exception of alcohol, tobacco 
or mild cannabis use disorder) 
• 
Current engagement in alcohol treatments, or currently engaged in intentional efforts to quit 
alcohol use  
• 
Past 30-day use of: Sincalide, Sulfonylureas, insulin and insulin products or other medications 
that may interact with semaglutide;, or weight control medications   
• 
Prior use of semaglutide or other GLP-1 agonists  
• 
Known or suspected hypersensitivity to study medication or related products  
• 
Lifetime diagnosis of severe mental illness (including schizophrenia and bipolar disorder)  
• 
History of suicide attempt, or recent (past 30 day) suicidal ideation, or psychiatric hospitalization 
in the last 6 months  
• 
Current significant medical or neurological illness (based on self-report or medical record) 
including severe hepatic impairment or cirrhosis, impaired renal function (eGFR <50ml/min), 
acute or chronic pancreatitis, gastroparesis, gallbladder disease or cholelithiasis, other severe 
gastrointestinal disease, heart failure, coronary artery disease, stroke, seizure disorder, or other 

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medical condition that poses a risk for the medication or alcohol administration components of 
the study (as determined by the MD)  
• 
A personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 
2B  
• 
Calcitonin greater than or equal to 50 ng/L  
• 
Uncontrolled thyroid disease at screening  
• 
History of major surgical procedures involving the stomach potentially affecting absorption of 
trial product (e.g., subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery)  
• 
History of Type 1 or Type 2 diabetes, or HbA1c >6.5% measured at screening  
• 
History of diabetic retinopathy, proliferative retinopathy, or maculopathy  
• 
History of diabetic ketoacidosis  
• 
History or presence of malignant neoplasms within the last 5 years (except basal and squamous 
cell skin cancer and carcinoma in situ)  
• 
Currently nursing, pregnant, anticipating pregnancy in the next 6 months, or not using a highly 
effective contraceptive method as judged by the MD, and defined as:   
a. combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, transdermal)  
b. progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, implantable)  
c. intrauterine device  
d. intrauterine hormone-releasing system  
e. bilateral tubal occlusion  
f. vasectomized partner  
g. sexual abstinence  
• 
Elevation of serum lipase, amylase, direct (conjugated) bilirubin, or alkaline phosphatase (ALP), 
ALT, or AST) more than 3X the upper limit of normal on baseline bloodwork 
• 
Baseline body mass index (BMI) <23kg/m2  
• 
Uncontrolled hypertension or systolic BP >180 mmHg and/or diastolic BP >105 mmHg, averaged 
from three measurements 
• 
Plans for travel outside of the local area in the upcoming 12 weeks that would interfere with lab 
visits during the study period (or other logistic factors that would make it difficult to commit to 
entire duration of study)  
 
 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
Specific lifestyle instructions will include: 
 
• 
Refrain from alcohol consumption or other drug use for 24 hours prior to alcohol administration 
sessions  
• 
Arrive fasting at sessions scheduled for blood draws as needed  

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• 
Refrain from consuming food for 4 hours prior to alcohol sessions. Participants will receive a 
standardized snack on arrival for alcohol sessions.) 
• 
Refrain from driving to the lab on the day of alcohol sessions. (Participants will be asked to 
arrange for transportation, or will be provided with transportation home via taxi or Uber) 
• 
Refrain from operating other vehicles or machinery for the duration of day upon discharge from 
alcohol sessions 
• 
Women participating in the study must report being willing to use a reliable birth control 
method during the trial (if sexually active), and must report no plans for pregnancy in the next 6 
months.  
• 
Participants will also understand that they may be excluded if they test positive for drugs other 
than cannabis during the time of scheduled drug screens (repeat drug tests will take place 
during weeks 4 and 8). 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
 
Examples of screen failures would include participants excluded following baseline laboratory work, or 
those excluded based on a change in treatment-seeking status at the time of the baseline assessment. 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a 
specific modifiable factor (e.g., upcoming travel) may be rescreened at a later date. Rescreened 
participants will be assigned the same participant number as for the initial screening. Data pertaining to 
screening failures will be tabulated in an anonymized fashion.  
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Participants will be recruited from the community through advertisements, which may include ads in 
local online or print newspapers, advertisements in buses, print flyers placed in community or hospital 
settings, business cards, campus listservs, and online postings (e.g. Craigslist (ads will not be placed in 
employment section)), and social media ads (Facebook, Twitter, Instagram) that direct potential 
participants toward a study website/landing page (hosted on Research for Me). Participants may also be 
recruited from local medical clinics (e.g., primary care clinics) that grant approval for assisting with 
recruitment (e.g., by placing study advertisements in clinics). Flyers and online advertisements will 
include study contact information and a web link and/or QR code leading to the landing page.  
 
In addition to these “passive” methods of recruitment, we will also include “active” recruitment 
methods. These methods will include members of the study team setting up recruitment booths and 
passing out business cards at public events (e.g., festivals) or public venues. Once initial contact with 
participants is made (e.g., via email or in person), research staff will schedule the participant for a phone 
call to explain the study and conduct a screening interview.  

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Participants will receive compensation. The payments will be allocated as follows (please see 1.2 for a 
summary of all scheduled sessions): 
• 
$50 for completing the consent/screening/baseline sequence (Week 0) 
• 
$75 for alcohol challenge session 1 (To be scheduled between Weeks 0-1) 
• 
$75 for alcohol self-administration session 1 (To be scheduled between Weeks 0-1) 
• 
$100 for alcohol challenge session 2 (To be scheduled between Weeks 9-10) 
• 
$100 for alcohol self-administration session 2 (To be scheduled between Weeks 9-10) 
• 
$30 per visit for each follow-up/medication administration visit during Weeks 1-10 (10 visits 
x$30 per visit = $300) 
• 
Up to $150 for completing and returning daily questionnaires over the study period ($15 per 
weekly set of surveys x 10 weekly visits), which includes the week following the 1.0mg dose, to 
be paid at weekly medication visits) 
• 
A $50 bonus for completing at least 9 of 10 weekly assessments  
• 
Participants will receive a final bonus of $100 for completing the study through Week 10 (to be 
paid at the final discharge visit). 
Therefore, the total maximum compensation over 10 weeks for study visits is $1000. Compensation for 
each pair of the alcohol sessions will occur at the end of the second of the session pair. The final 
payment (including bonuses) will be paid at the Week 10 discharge visit. Overall, these payments are 
structured to maximize retention in the study (given the long dose escalation period and time-intensive 
laboratory sessions). Additionally, an incentive-based structure that includes weekly incentives is 
important to reinforce engagement with daily surveys, and to minimize missing data. Participants will be 
updated at each visit with their progress toward the bonus incentives for adherence (e.g., weekly bonus 
of $10 and progress toward final adherence bonuses). In the event participants are not able to pick their 
final payments in person, we will offer the option of issuing the final payment via electronic gift card to 
the participant’s email address, with their permission. 
We anticipate phone screening up to 400 individuals and randomizing up to 48 participants to 
medication or placebo conditions, in order to obtain a final sample of at least 36 eligible participants 
who complete the full course of the 0.5mg phase (allowing for 25% attrition). If attrition is higher than 
anticipated, we will submit an amendment to enroll additional participants to arrive at a final sample of 
at least 36 participants who complete study procedures through the end of the 0.5mg dosage phase 
(i.e., through the end of Week 9). 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
Semaglutide is a relatively new (approved in 2017) GLP-1 receptor agonist. A new oral formulation of 
semaglutide was approved by the FDA in 2019, making semaglutide the first drug in its class to be 
available in both subcutaneous and oral formulations. GLP-1 agonist medications were designed to 
mimic the function of the endogenous GLP-1 peptide, with the benefit of a much longer half-life than 
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were developed as anti-diabetic therapies. Several GLP-1 agonists (e.g., exenatide, liraglutide, 
lixisenatide, albiglutide, dulaglutide and semaglutide,) are now in widespread use as treatments for type 
II diabetes (T2D); these medications have also proven efficacious for weight loss, reducing glycated 
hemoglobin (HbA1c), and reducing risk for some cardiovascular events [29]. Although the primary 
indication of GLP-1 agonists is T2D, these therapies are increasingly being studied for other indications in 
non-diabetic patients, including obesity/weight management. In June 2021, the FDA approved 
semaglutide at a higher dosage (2.4mg/week) for the indication of weight management, under the 
brand name Wegovy.  
6.1.2 DOSING AND ADMINISTRATION 
Semaglutide will be administered according to the FDA-approved schedule, which begins with a starting 
dose of 0.25mg once per week for four weeks. At week five, dosage is increased to 0.5mg for a 
subsequent four weeks (initial maintenance dose), after which point dosage can be increased further (to 
1.0mg), presuming the medication is well tolerated.  
Although semaglutide can be self-administered in the home setting, medication and placebo 
administration will be delivered by a research nurse or other medical team member at Eastowne CRU or 
CTRC in order to execute the placebo manipulation and ensure adherence to medication. This approach 
also allows us to collect safety outcomes on a regular basis, further ensuring that participants will be 
monitored carefully. Semaglutide is administered subcutaneously (in the abdomen, thigh, or upper arm). 
Doses are delivered via the Ozempic® pen, a cartridge-based device that calibrates medication delivery 
based on the desired dose. An extremely small needle (4mm, 32-gauge needle – the size of 2 human 
hairs) is used to deposit the medication subcutaneously. Because each pen contains 2mg of medication, 
each participant in the medication group will be allocated one pen to cover the first six weeks (i.e., 
0.25mg/week for 4 weeks, followed by 0.5mg/week for 2 weeks), and a second pen for that will supply 
medication for the remaining three weeks (2 weeks at 0.5mg, and 1 week at 1.0mg). This schedule 
results in 9 medication administration sessions. At the week 9 visit, the 1.0mg dose will be delivered as 2 
x 0.5 mg doses given in succession. This is because the medication pens being used for this study deliver 
dosages of 0.25 and 0.5mg, and participants are not being maintained on the 1.0mg dose after week 9. 
This timeframe also allows sufficient time to reach steady-state plasma concentration levels (achieved 
within 4-5 weeks of initiating the starting dose).  
At the present time, we do not have access to a manufacturer-developed placebo (the medication relies 
on the proprietary Ozempic® pen for delivery). Therefore, this study will use weekly sham injections for 
the placebo group. Sham doses will involve a brief needle prick using a very small (e.g., 32 gauge) 
needle, identical to the one used in the Ozempic® pen (NovoFine), or a needle of similar gauge (e.g., an 
insulin needle). Given the extremely small volume of medication delivered in the treatment condition, 
we will not utilize saline or another inert substance for the placebo administration. During medication 
and placebo administration, participants’ view will be shielded from the injection site to prevent 
unblinding. Medication will be delivered in the upper arm, abdomen, or thigh. Given the extremely small 
volume of the injections, we will not utilize saline or another inert substance for the placebo 
administration; rather, the sham doses will consist of briefly inserting the micro-needle.  
Due to the nature of the placebo condition, it will not be possible to blind the staff RNs administering 
the medication. However, we will provide training to study staff to minimize the likelihood of 
contaminating the blinding procedures. We will also develop procedures to minimize contact between 

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the RNs and outcome assessors. All other staff members (including research assistants and outcomes 
assessors) will remain blind to condition, unless unblinding is necessary (e.g., due to an adverse event). 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
The team will collaborate with IDS to source the medication (and NovoFine or insulin needles for the 
placebo condition), which will be sourced and stored at the IDS pharmacy prior to dispensing. 
Participants assigned to medication will be prescribed one Ozempic® pen following randomization. As 
per IDS requirements, in between study visits participants will be given their assigned medication pen 
and asked to bring their pen back to each follow-up visit. In between visits, pens will be placed in a small 
plastic container and then encased opaque, tamper-proof bag in order to prevent unblinding. (For 
participants in the placebo condition, a plastic object of roughly equal size and weight will be placed in 
the plastic container and medication bag.)  Participants will be instructed not to open the bag in 
between visits. A refill pen will be prescribed prior to the Week 7 visit, once the doses from the first pen 
have been allocated. Any unused doses from individual pens (e.g., in the event of participant drop-out) 
will be discarded/destroyed by IDS, as will any pens that expire during the course of the trial. In the 
event a pen expires before a participant completes the study, a replacement pen will be prescribed at 
the discretion of the study physicians. 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Ozempic® is manufactured by Novo Nordisk. As described above, the medication is dispensed from a 
proprietary device, the Ozempic® pen. Each pen contains 2mg of medication, requiring that each 
participant is prescribed two pens over the course of the study. A full description and visuals can be 
found at the following site: 
https://www.Ozempic®pro.com/how-to-prescribe/Ozempic®-pen.html 
 
The placebo group will receive sham injections that involve a brief needle-prick without dispensing a 
substance. The needles used for the sham injections will be the NovoFine 32G needle, the same needle 
in the Ozempic® pen (https://www.novoneedles.com/novofine.html) or a comparable needle of a 
similar gauge (e.g., an insulin needle). In no case will any fluid be injected during placebo sessions. 
To mimic the active medication administration, the medical staff member will insert the microneedle 
briefly and then remove it while the participant’s view is shielded.  
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
Pens will be dispensed from IDS. For drug dispensing visits at CRU (Eastowne), scheduled for Weeks 1 
and 7, pens will be delivered the day of the visit by courier. Ozempic pens will be kept in the 
participant’s possession (sealed in a tamper-proof bag) between visits. According to the manufacturer, 
following the first use, the Ozempic® pen can be stored for up to 56 days at room temperature (59 to 86 
F) or refrigerated at 36 to 46 F. As per our plan developed in collaboration with IDS, participants will be 
instructed to keep the medication bag at room temperature for simplicity. Each participant’s pen will be 
labeled with the study ID number and pens will not be shared across participants. Placebo needles will 
remain packaged until use, and will be stored at room temperature in a secure location. 
 

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6.2.4 PREPARATION 
 
Semaglutide does not require advance preparation; cartridges are pre-filled and doses are calibrated 
using the pen device. The RN or medical staff member will select the correct dosage and administer the 
medication as per manufacturer guidelines.  
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Following the baseline assessment, participants will be randomized to medication or placebo conditions 
at a 1:1 ratio by a member of the IDS team using a pre-determined randomization scheme. Medication 
and placebo administration will be carried out by a staff RN at CRU or CTRC. Due to the nature of the 
placebo condition, it will not be possible to blind the RNs to condition. However, all other staff members 
will remain blind to condition, and the staff members administering medication will be trained in 
protecting the blind (e.g., redirecting the conversation if the participant comments about medication 
condition; minimizing contact with experimenters.) To maintain blinding of participants, participants’ 
view will be shielded and they will be asked to face away from the injection site during all placebo and 
medication administrations. Aside from the staff members administering medication, no study team 
members interacting with participants will be aware of participants’ assignments. At the stage of interim 
analyses (e.g., in preparing safety reports for DSMB meetings) and final analyses, the study statistician 
will be provided with the assignment log. None of the study personnel involved in recruitment or 
enrollment will have knowledge of the details of the randomization table that will be used by the IDS 
pharmacy. 
 
At the completion of the trial, participants will be provided with a questionnaire asking about perceived 
medication assignment (to assess the success of maintaining the blind). Due to common side effects of 
semaglutide (in particular nausea), we do not expect blinding to be successful in all cases.  
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Medication will be administered by CRU or CTRC staff to assure compliance and reduce potential 
sources of non-adherence. A missed session will constitute a missed medication dose. As per 
manufacturer directions, any missed doses/appointments will be corrected by asking the participant to 
come in for the dose as soon as possible within 5 days of the missed dose. After the 5-day mark has 
passed, the dose will be skipped, and the participant will resume with the next scheduled dose. Study 
medication logs will serve as the primary source document for tracking medication and placebo 
administration. Participants will be coded as non-adherent if they miss more than 2 scheduled doses 
between Weeks 1-9. In the event of missed medication doses or missed appointments, the physician will 
have the discretion to adjust the appointment date (within the manufacturer or standard practice 
guidelines), or to prescribe a replacement pen if needed to accommodate the target medication 
schedule. 
 
6.5 
CONCOMITANT THERAPY 
 
Participants may be taking medications for other conditions (provided those treatments are not 
included in the list of exclusion criteria). For this protocol, a prescription medication is defined as a 
medication that can be prescribed only by a properly authorized/licensed clinician. Medications to be 

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reported in the Case Report Form (CRF) are concomitant prescription medications, over-the-counter 
medications and supplements. Changes to medication status or other treatments will be assessed at 
each in-person visit, with any changes reviewed by a study physician. Should a concomitant therapy 
preclude further participation for safety or scientific reasons (for instance, if a participant starts a 
therapy that constitutes an exclusion factor), this issue will be discussed by the study leads and the 
participant will be excused from further participation, if required to ensure safety. By definition, 
participants will not be seeking treatment for alcohol use or smoking cessation. If a participant makes 
the decision to seek treatment for alcohol or smoking during the study, s/he will be referred to 
appropriate treatment resources and excused from further participation. 
 
 
6.5.1 RESCUE MEDICINE 
 
Not applicable 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Study discontinuation: The study may be halted if deemed necessary by the lead investigators, DSMB, or 
IRB. Examples of reasons for study discontinuation include unexpectedly high frequency of serious 
adverse events, or significant increases in alcohol use during treatment, leading to the conclusion that 
the medication is not safe in this population. In addition to the participant discontinuation rules noted 
below, the following study stopping rules will trigger halting the study pending a DSMB evaluation: 1) 
Occurrence of any hospitalization or any SAE rated at Grade 4-5 (CTCAE) in a medication-treated 
participant (and deemed likely to be medication-attributable); 2) Documentation of SAEs in >3 
medication-treated participants that are deemed likely attributable to medication; 3) Removal of >5 
subjects due to adverse events deemed attributable to study-related procedures, inclusive of SAE 
and/or medical stopping rules (e.g., weight, alcohol consumption, disease progression), as defined in 7.2 
below. In order to classify events as medication-attributable, the PI will request that IDS breaks the blind 
and provides a file containing condition assignment to the study physician(s). If any of the 
aforementioned events trigger a DSMB meeting, the full randomization table will be provided to a 
statistician, so that group differences can be fully evaluated at the meeting. Given the safety profile of 
semaglutide for other clinical conditions, as well as preclinical evidence that GLP-1 receptor agonists 
reduce drug intake, these scenarios are expected to be unlikely. 
 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. The 
investigators may discontinue or withdraw a participant from the study if clinically or otherwise 
indicated. Examples of reasons removing a participant include: 
 
• 
Significant study intervention non-compliance  
• 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
that indicates that continued participation in the study would be unsafe  

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• 
Pregnancy 
• 
Diagnosis of significant disease or disease progression which requires discontinuation of the 
study intervention 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant relocates from the local area, or is otherwise unable to attend visits 
• 
Significant or persistent side effects that pose significant discomfort or preclude escalation to 
the 0.5mg dose (e.g., persistent significant nausea, or  hypoglycemia, as indicated by 
repeated fasting glucose values below normal 54 mg/dL 
• 
Changes in lab tests or clinical status from baseline that render the participant ineligible 
to continue in the judgement of the physician(s) (e.g., elevated liver enzymes, elevated 
serum amylase or lipase levels, weight loss as defined below) 
• 
Excessive weight loss (defined as loss exceeding 5% of baseline weight or BMI < 20) 
• 
A change in treatment-seeking status (i.e., the participant expresses a desire to enter 
treatment for alcohol or smoking cessation). 
• 
A significant increase in alcohol consumption, as evidenced by a >50% increase in drinks 
per week (relative to baseline) lasting more than two weeks. Drinks per week in the 30 
days preceding the Week 0 visit (measured by the TLFB) will serve as the baseline 
measure. 
• 
Evidence of significant alcohol withdrawal symptoms  
• 
Any other change in medical status or side effects that is significant enough to warrant 
removal in the judgement of the study physicians 
 
If a participant exhibits changes in symptoms or clinical status that warrant potential removal, the study 
physicians will confer and render a decision as to whether to withdraw the participant. With respect to 
dosage increase, if a participant’s side effects profile or laboratory tests during the initial 4-week phase 
(.25mg) indicate that s/he is unable to safely proceed to the 0.5mg dose, the participant may be 
removed from the study at the discretion of the physicians. If lab tests or side effects during the 
standard maintenance dose of 0.5mg suggest that a participant is unlikely to tolerate a higher dose 
(1mg), they may be excluded from the 1.0mg dose escalation at the discretion of the physicians. In this 
case, participants will be given the option of one additional week at the standard therapeutic dose of 
0.5mg (i.e., highest tolerated dose). Reasons for participant discontinuation or withdrawal from the 
study will be recorded on the Case Report Form (CRF). Participants who sign the informed consent form 
but do not receive the study intervention (e.g., fail to attend the Week 1 visit for randomization) may be 
replaced.  Participants who sign the informed consent form, and are randomized and receive the study 
intervention, and subsequently withdraw, or are withdrawn or discontinued from the study, may be 
replaced. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for 2 consecutive scheduled 
medication visits and is unable to confirm attendance at the following visit (or is unable to be contacted 
by the study staff 

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The following actions will be taken if a participant fails to return to a required study visit: 
• 
The team will attempt to contact the participant and reschedule the missed visit within one 
week, and counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wishes to and/or should continue in the study. 
• 
The team will attempt to contact the individuals that the participant had listed on the Locator 
Form at baseline (maximum of three attempted contacts per individual). 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, up to 3 telephone messages, up to 
3 email messages, and if necessary, a letter to the participant’s last known mailing address or 
local equivalent methods). These contact attempts will be documented in the participant’s 
medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
The efficacy assessments/outcomes are noted in summary form in section 3. The ascertainment of these 
outcomes is described in further detail in section 4 (study design). Briefly, the endpoints are human 
laboratory measures of alcohol consumption and alcohol response; self-reported alcohol consumption 
and cigarette use over the course of the trial; and changes in weight, HbA1c, and alcohol elimination. 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Safety and assessments are summarized in detail in the study design section (Section 4.1). Briefly, safety 
assessments include a baseline assessment, body weight, bloodwork, vitals signs, and clinical interview 
to assess substance use and psychiatric symptoms. Follow-up medical visits will include repeat 
assessments of bloodwork and scheduled time points, as well as follow-up measurements of body 
weight and vitals signs. Medication side effects will be assessed at each visit, and a study team member 
will contact participants within 2-3 days of each dosage increase to evaluate potential side effects. Other 
assessments (questionnaires, interviews) are noted in Section 4.1. 
 
Safety precautions during alcohol administration sessions. Our team has considerable experience with 
alcohol administration procedures. Our procedures follow the NIAAA guidelines for administering 
alcohol in human studies (https://www.niaaa.nih.gov/research/guidelines-and-resources/administering-
alcohol-human-studies). Based on these guidelines, alcohol administration studies with participants who 
meet criteria for AUD are typically restricted to non-treatment-seeking participants in order to avoid 
ethical concerns, as will be the approach in this study. Additionally, our approach in this study is to only 
recruit people who meet criteria for AUD with <8 of out of 11 symptoms endorsed. Regarding the 
alcohol dose for alcohol challenge sessions, we will use sex- and body weight adjusted formulas [70] to 
ensure that dosage is calibrated across participants to achieve the target BrAC (.06g%). Participants will 
have undergone a medical screen prior to participation, and will be excluded if the study medical staff 
has reason to believe that alcohol is contraindicated. Participants will receive a BrAC reading on arrival 
to the alcohol sessions; the session will be rescheduled if the participant presents with a positive BrAC.  

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Following the completion of alcohol sessions, participants will be escorted to a private room designated 
for recovery purposes. During alcohol self-administration sessions, participants will only be discharged 
after their breath alcohol concentration descends below .03g%, which is consistent with NIAAA 
guidelines. During alcohol challenge sessions, participants will be asked to remain in the lab until BrAC 
reaches 0mg% (in order to collect BrAC data until alcohol is fully eliminated, for purposes of 
pharmacokinetic analyses). Participants will also be provided with reimbursement for transportation if 
they do not drive and are not able to locate assistance with transportation (participants will be advised 
not to drive to the alcohol sessions).  If a participant presents with a positive BrAC, the session will be 
rescheduled, and the participant will be asked to remain in the lab until it is safe to leave. 
 
To ensure participant safety, at least two members of the study staff will be present for the duration of 
all alcohol administration sessions. If an urgent medical situation arises at either medication or alcohol 
visits, a team member will contact the physicians on the team to consult, based on a predetermined 
sequence (e.g., contact physician A, followed by physician B, then physician C). Additionally, any 
participants who express a desire to seek treatment during the study will be excused from further 
participation and provided with alcohol or smoking cessation resources. Co-I Dr. Jordan directs 
outpatient addiction treatment at UNC-CH. 
 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include an adverse reaction 
requiring intensive treatment in an emergency room or at home. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
For adverse events (Aes) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  

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• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (Aes) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
8.3.3.3 EXPECTEDNESS  
The study physicians will be responsible for determining whether an adverse event (AE) is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. At weekly medication visits, all participants will review a side effects 
checklist (SAFTEE) with a research assistant, which will then be provided for review by a medical staff 
member at CTRC. The staff member will begin with an open-ended question about side effects or any 
other adverse events, followed by a review of specific side effects using the SAFTEE. Any previously 
reported side effects will be queried to determine any change in status (presence or severity). These 
weekly visits will be a primary method for identifying side effects. Additionally, a research staff member 
will contact participants by phone in the week following the initial dose, as well as the week following 
each dose escalation. Phone calls will be scheduled 2-3 days following these events.  
 
All Aes including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All Aes 
occurring while on study will be documented appropriately regardless of relationship. All Aes will be 
followed to adequate resolution. 
 

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Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. Aes characterized as intermittent require documentation of 
onset and duration of each episode. 
 
Under the direction of the PI, members of the research team will record all reportable events with start 
dates occurring any time after informed consent is obtained until 7 (for non-serious Aes) or 30 days (for 
SAEs) after the last day of study participation. At each study visit, the team member will inquire about 
the occurrence of AE/SAEs since the last visit. Any such events will be followed for outcome information 
until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
All project staff will be trained to identify adverse events (Aes), which must be reported to the PI and 
study physicians within 24 hours. In addition, any unanticipated participant issues will be discussed in 
weekly staff meetings, which will provide another opportunity to identify Aes.  
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
Research staff will be trained to report potential Aes or SAEs to the PI immediately. For any potential 
Aes/SAEs, the study physician will make a determination to distinguish between Aes, SAEs and 
unanticipated problems and provide judgment about attributions. Management and reporting of Aes, 
SAEs, and unanticipated problems will be carried out in accordance with Good Clinical Practice (GCP) 
standards, as outlined by the Food and Drug Administration. Aes will be defined as any negative medical 
event during the trial (whether or not the event is deemed related to the study medication). SAEs are 
defied as events that are potentially life threatening or result in heath; cause congenital malformation; 
result in persistent/significant disability or incapacity; require inpatient hospitalization or prolongation 
of hospitalization; or reflect an otherwise notable medical event in the judgment of the study physician. 
Aes/SAEs will be monitored regularly by the study research team and medical staff, in particular by 
inquiring about adverse events at each weekly visit. Should Aes or SAEs occur, they will be recorded, 
rated as mild/moderate/severe by the study physician, and reported in accordance with UNC IRB 
requirements and GCP standards. Any Aes will be reported to the IRB in progress reports and at the 
conclusion of the study. SAEs and unanticipated events will be reported to the IRB and DSMB within 48 
hours, and to NIAAA if judged as treatment-related. All staff working on this study will be made aware of 
the monitoring and reporting requirements for Aes/SAEs, and will have completed GCP training and 
other trainings required to conduct human subjects research at UNC.  
 
Any Aes, SAEs or unanticipated problems will be followed until resolution by the Pis and/or research 
staff. Participants will be contacted regularly during follow-up and any observations of Aes/SAEs will be 
discussed among the Pis and the study physician at regular meetings (or immediately, in the event of 
SAEs or unanticipated problems). In the event of SAEs or unanticipated problems, the physician and 

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study Pis will be notified immediately, and the participant will be referred to or provided with 
appropriate medical support.  
 
Participants will be advised to seek prompt medical attention in the event of an unanticipated medical 
event. In the event of an SAE, a member of the study medical staff will maintain regular contact with the 
participant until the event is resolved and fully documented. A determination of relatedness to 
medication will be made based on symptoms, timing, and other factors. 
Monitoring will be the primary responsibility of the PI. In addition, a Data and Safety Monitoring Board 
will be established to maximize safety (the TraCS DSMB will be involved for this project, and will review 
progress at scheduled semiannual meetings during the trial). 
 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
If an event is deemed an AE or SAE, participants will receive a phone call from study personnel to inform 
them that the event has been recorded and will be reported as such. Any incidental findings uncovered 
during the baseline medical exam or weekly visits (e.g., via bloodwork or other measurements) will be 
reported to the participant by the study physician, and an appropriate follow-up plan will be 
recommended to the participant.  
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
Not applicable 
 
8.3.9 REPORTING OF PREGNANCY  
 
At the baseline visit and each study visit that involves an alcohol session, female subjects will undergo a 
urine pregnancy test upon arrival to the clinical site. In the case of a positive pregnancy test, the 
participant will be notified immediately, and study intervention will be discontinued while continuing 
safety follow-up. If any follow-up plan is recommended by the study physician, one of the staff members 
will communicate this recommendation to the participant.  
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 

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• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
Any Ups identified by the study team will be discussed amongst the study leadership team, and 
corrective actions will be identified. If applicable, a protocol amendment will be developed and 
submitted to the IRB. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (Ups) to the reviewing Institutional Review Board 
(IRB), and if applicable, the DSMB. The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
In the case of a UP that may impact participants’ safety or alter their experience during the trial (e.g., by 
necessitating a change in protocol), participants will be notified by a study team member at the 
subsequent visit. In the event of any UP that may have an imminent impact on participant safety, a team 
member will contact the participant by phone to inform them of the problem.   
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
• 
Primary Efficacy Endpoint(s):  
 
o Breath alcohol concentration (BrAC) and volume of alcohol consumed during laboratory 
alcohol self-administration procedures. The outcomes are continuous variables. The effect 
of interest is the interaction between medication group (semaglutide vs. placebo) and 
time/dosage (baseline vs. 0.5mg). The baseline session will take place between Weeks 0 and 
1, and the 0.5mg session will take place between weeks 8 and 9. 
 
• 
Secondary Efficacy Endpoint(s): 
 
o Changes in subjective responses to alcohol (stimulation, sedation, craving) and alcohol and 
cigarette demand during laboratory alcohol challenge procedures. The outcomes will be 

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analyzed as continuous variables. The effect of interest is the interaction between 
medication group (semaglutide vs. placebo) and time/dosage (baseline vs. 0.5mg). The 
baseline session will take place between Weeks 0 and 1, and the 0.5mg session will take 
place between weeks 8 and 9. 
o Changes in drinks per day and cigarette consumption over the course of the trial, as 
assessed via daily surveys. The outcome variables will be treated as continuous, however, 
this assumption will be tested and the modeling approach will revised as needed to properly 
account for the nature of the outcome variable (e.g., analyze as count variable with negative 
binomial distribution). The effect of interest is the interaction between medication group 
(semaglutide vs. placebo) and time (Week 1 to Week 10). 
 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
Because no human data on semaglutide’s effects on alcohol consumption outcomes are available, there 
is no a priori effect size estimate to facilitate power calculations. We will seek a final sample size of 36 
participants. Assuming at least 36 enrollees have complete data, our analyses suggest that this allows 
sufficient power (.80) to detect a medium effect size (f = .25) for an interaction between group 
(medication vs. placebo) and dosage (baseline, 0.25mg, 0.5mg). This estimate assumes an alpha level of 
.05 and a within-person correlation ® of 0.5 across time points. Further, because our multilevel model 
(MLM) analyses will involve more time points for certain analyses (e.g., daily assessments), this 
approach will increase power further, which is advantageous in the event that medication effects are in 
the small range. Assuming a 25% attrition rate, we anticipate needing to randomize 48 enrollees to 
arrive at a final sample of 36. 
 
9.3 
POPULATIONS FOR ANALYSES 
 
Primary analyses will include all participants who were randomized and received a medication or 
placebo dose following the Week 0 visit (randomization will occur after the Week 0 visit, just prior to the 
Week 1 visit). MLM analyses can accommodate missing data, allowing inclusion of participants without 
complete data (e.g., missed visits or missed daily survey responses). Reasons for missing data and drop-
out will be documented in the study database and reported in any publications. 
 
A supplementary per-protocol analyses will be conducted using all participants who received 1) at least 
7 of the 9 scheduled doses, and 2) those participants who receive the final (1.0mg) dose. This planned 
analysis will be conducted irrespective of the number of participants in these groups. If the sample 
permits, an exploratory subgroup analysis will examine participants as a function of weight 
(overweight/obese vs. not overweight or obese). 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Primary analyses will rely on multilevel models (MLM), which are well suited to examining within-person 
changes over time, while also accommodating missing data and unequal group sizes, and allowing the 
evaluation of between-subjects moderators (e.g., overweight/obesity status) if necessary. MLM with 

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maximum likelihood estimation can accommodate missing data under the assumption that the data are 
missing at random. Secondary, sensitivity analyses will be conducted to test the robustness of study 
findings for violations of the assumption that data is missing at random. Specifically, we will examine if 
baseline variables are associated with data missingness (for instance, age, sex, level of substance use) 
using t-tests and chi-square analyses (for continuous and dichotomous variables, respectively). Baseline 
variables that are associated with data missingness will be included as covariates in additional adjusted 
models (that adjust for the baseline variables related to missingness). Assumptions for the statistical 
methods being used will be tested. Should there be evidence of violations of these assumptions (e.g., 
presence of outlying and influential cases, distributional concerns for residuals, and so on), appropriate 
corrective actions will be taken. Sensitivity analyses will be used to determine the extent to which the 
main study results are influenced by these violations. We will focus our interpretations on small p-values 
(p < .05) that indicate evidence against the null hypothesis. We will report the number of decimal places 
of the p-value in line with the journal’s guidelines and APA recommendations (usually 2 or 3 decimal 
places). For specific outcomes, the units of measurement and expected ranges of values (or example 
ranges, if the full range is unknown) are noted in the subsequent analysis sections 9.4.2 and 9.4.3. Any 
extreme outliers (defined as >3.0 standard deviations from the mean) will be recoded to one unit 
greater than the next most extreme value, in order to reduce undue influence of extreme outliers. For 
all statistical tests, confidence intervals will be evaluated in combination with tests of statistical 
significance. Assumptions for the statistical methods being used will be tested. Should there be evidence 
of violations of these assumptions (e.g., presence of outlying and influential cases, distributional 
concerns for residuals, and so on), appropriate corrective actions will be taken. Sensitivity analyses will 
be used to determine the extent to which the main study results are influenced by these violations. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
Alcohol self-administration sessions: MLM will be used to examine changes in laboratory self-
administration (defined as peak BAC and quantity of alcohol consumed, co-primary outcomes) as a 
function of medication phase (baseline; 0.5mg). These analyses will use medication phase as the within-
subjects factor and condition (semaglutide vs. placebo) as the between-person factor. Self-
administration will be measured based on recorded breath alcohol concentration (BrAC), measured in 
g% (e.g., .00g% - .08g%). 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Alcohol challenge sessions: MLM will also be used to examine changes in 1) cigarette and alcohol 
demand during alcohol challenge (based on corresponding purchase tasks) (e.g., based on number of 
hypothetical drinks/cigarettes consumed at a given price point), and 2) self-reported stimulation (0-10 
range), sedation (0-10 range), and craving (1-7 range), from BAC = .00 to BAC = .06g%, as a function of 
medication phase (within-person) and drug condition (between person). These analyses will examine 
changes in outcomes from BAC = .00 to .06 using medication phase as the within-subjects factor and 
condition as the between-person factor.  The analyses will be complemented by analyses of peak 
subjective effects (e.g., stimulation, sedation, craving, on the same scales as noted above), across the 
two alcohol administration sessions (AC1 and AC2). 
 
Daily self-report data: We will use MLM to estimate within-person changes in primary outcomes (e.g., 
daily alcohol use [number of drinks consumed per day] and cigarette use [number of cigarettes smoked 
per day] over the trial period), using study week as the within-subjects factor and condition 
(semaglutide, placebo) as the between-person factor.  

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9.4.4 SAFETY ANALYSES 
 
Total side effects reported (e.g., 0-15), and number of severe side effects reported during each 
medication phase will be assessed using MLM with medication phase (baseline, 0.25mg, 0.5mg, 1.0mg) 
as the within-subject factor and condition (semaglutide, placebo) as the between-person factor. . These 
count variables will be analyzed using a negative binomial MLM, however, this assumption will be tested 
and the modeling approach will revised as needed to properly account for the nature of the outcome 
variable (e.g., zero-inflated negative binomial regression).  
 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Descriptive statistics will be used to report relevant demographics such as age, sex, and education.  
 
9.4.6 PLANNED INTERIM ANALYSES  
 
No interim analyses of efficacy will be planned. 
 
9.4.7 SUB-GROUP ANALYSES 
 
Not applicable 
 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Not applicable 
 
9.4.9 EXPLORATORY ANALYSES 
 
Sex will be examined as an exploratory moderator in all analyses. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1 INFORMED CONSENT PROCESS 
 
 
In obtaining and documenting informed consent, the team will comply with applicable regulatory 
requirements (e.g., 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56) and adhere to ICH GCP. Consent will 
be obtained remotely (via web teleconference and Docusign, as described previously) by a qualified 
study staff member in person at the outset of the baseline session. Additional procedures are noted 
below. 
 

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10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
 
Consent forms will describe the study intervention, study procedures, and potential risks. The 
participant’s electronic signature indicating consent is required prior to starting 
intervention/administering study intervention. Participants will also be given an informational sheet 
about the study medication. Additional procedures are described below. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
initial consent process will be conducted remotely using a HIPAA-compliant web platform (e.g., WebEx, 
Zoom, Teams) and Part 11-compliant Docusign to maintain optimal safety. A copy of the consent form 
will be provided to the participant in advance of the scheduled videoconference. A qualified team 
member will explain the research study to the participant and answer any questions that may arise. A 
verbal explanation will be provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants.  Participants will 
have the opportunity to carefully review the consent form and ask questions prior to signing. The 
participants should have the opportunity to discuss the study with their family or surrogates or think 
about it prior to agreeing to participate. The participant will electronically sign the informed consent 
document prior to any procedures being done specifically for the study. Participants must be informed 
that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the signed informed consent document will be given to the participants for their 
records. The informed consent process will be conducted and documented in the source document 
(including the date), and the form signed (via Docusign), before the participant undergoes any study-
specific procedures. The rights and welfare of the participants will be protected by emphasizing to them 
that the study is voluntary and the quality of their medical care will not be adversely affected if they 
decline to participate. While the initial consent form will be conducted electronically, supplementary 
consent forms (e.g., consent to unencrypted communication, HIPAA authorization, and biospecimen 
consent) may be conducted either remotely (via Docusign) in advance of the baseline visit or in person 
(paper form) at the baseline visit, depending on timing.  
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, funding agency, and 
regulatory authorities.  If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will 
provide the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. Circumstances that may warrant 
termination or suspension include, but are not limited to determination of unexpected, significant, or 
unacceptable risk to participants. Study may resume once concerns about safety, protocol compliance, 
and data quality are addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 

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10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party. All research activities will be conducted in as private a setting as possible. 
 
Any computerized data will be password protected and contained on a secure, password-protected 
computer or a secure server. Recruitment data (de-identified) will be stored in a secure, password-
protected file accessible only to the study investigators and personnel. At the end of recruitment, 
eligible subject files will be separated from those failing to meet eligibility criteria, and records of 
ineligible recruitment subjects will be anonymized. Data pertaining to screening failures will be 
tabulated in an anonymized fashion. Data collected in other formats (e.g., medical screening notes) will 
be labeled only by study identifier and stored in binders in secure, locked cabinets while the study is 
taking place. Files will be stored and archived in accordance with Good Clinical Practice (GCP) standards. 
For all questionnaire and interview assessments, participants will be informed that they may decline to 
answer any question if they so choose. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored during the study for purposes of 
maintain contact with participants, and for communicating any safety information or unanticipated 
problems. At the end of the study, all records will continue to be kept in a secure location for as long a 
period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be stored at UNC in the PI’s laboratory and on secure backup servers with password-protected access. 
This will not include the participant’s contact or identifying information. Rather, individual participants 
and their research data will be identified by a unique study identification number. Electronic data are 
stored on a password protected drive only accessible by the research team.  Data obtained on paper will 
be transferred to an electronic data file (Excel, SPSS, REDCap), stored on a secure server, and identified 
by participants ID. For non-computer based forms, the data collection sheets are stored in a locked 
cabinet in a separate locked data storage space at the PI’s laboratory. 
 
At the end of the study, all study databases will be de-identified and archived in the PI’s laboratory and 
backed up on a secure server hosted at UNC. De-identified data resulting from this study may also be 
presented at meetings, published in journals or presentations. In addition, this study will be registered 
at ClinicalTrials.gov, and de-identified information from this study will be submitted to ClinicalTrials.gov. 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  

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Data collected for this study will be analyzed and stored at the PI’s laboratory. The study biostatistician 
will be given access to the data necessary for conducting specified analyses, and data will be de-
identified prior to giving access.  
 
De-identified biological samples will be stored at UNC for the duration of the study, until all biological 
tests are completed and the data transferred to electronic format. De-identified DNA samples will be 
stored indefinitely, provided the participant has given consent for DNA storage, in order to examine 
future questions related to phenotypes of interest for this line of research.  
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed (after specimens are de-identified). 
 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Provide the name and contact information of the Principal Investigator and the Medical Monitor. 
Principal Investigator 
Medical Monitor 
Christian Hendershot, Ph.D., Associate 
Professor 
TBD (The medical monitor and DSMB members 
will be identified and added prior to data 
collection) 
UNC-Chapel Hill  
 
104 Manning Dr.
 
 
Christian_Hendershot@med.unc."  
 
Christian_Hendershot@med.unc.edu 
 
The investigative team is summarized on the face page of this protocol. As noted, a DSMB will be formed 
prior to carrying out the study.  
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB). Members of 
the DSMB will be independent from the study conduct and free of conflict of interest. The DSMB will 
dictate the intervals at which they meet to assess safety and efficacy data. At this time, each data 
element that the DSMB needs to assess will be clearly defined. The DSMB will provide its input to the 
IRB and National Institutes of Health as necessary. 
 
10.1.6 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s). A local study monitor will be appointed to provide on-site monitoring during the course 
of the research study.  
 
 

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10.1.7 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The PI will be responsible for addressing quality control issues and correcting errors or protocol 
deviations. The PI will have oversight over training study staff and ensuring that protocol elements are 
carried out with fidelity. Quality control will be ensured by developing SOPs for protocol elements to 
standardize data collection procedures. The investigational site will provide direct access to all trial 
related sites, source data/documents, and reports for the purpose of monitoring and auditing by the 
sponsor, and inspection by local and regulatory authorities. 
 
 
10.1.8 DATA HANDLING AND RECORD KEEPING  
 
 
10.1.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
As a single-site, small-scale trial, the project will not involve coordinated data collection and 
management responsibilities across sites/teams. Data safety and storage precautions are outlined 
elsewhere in the study protocol.  
 
10.1.8.2 STUDY RECORDS RETENTION  
 
Study records will be retained for a minimum of 7 years following study completion. Paper source 
documents will be archived in accordance with UNC policies. Electronic materials and de-identified 
datasets will be stored securely as outlined above.  
 
10.1.9 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The PI 
will report deviations within 7 working days of identification of the protocol deviation, or within 7 
working days of the scheduled protocol-required activity.  All deviations must be addressed in study 
source documents, reported to NIAAA Program Official and the IRB. Protocol deviations must be sent to 
the reviewing Institutional Review Board (IRB) per their policies. The site investigator is responsible for 
knowing and adhering to the reviewing IRB requirements. Further details about the handling of protocol 
deviations will be included in the MOP. 
 
10.1.10 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 

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This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals. Data from this study may be requested from other researchers after the completion 
of the primary endpoint by contacting the PI. 
 
 
10.1.11 
CONFLICT OF INTEREST POLICY 
 
Any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or 
any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the design and conduct of this trial. All investigators will make a conflict of interest 
declaration at the outset of the study and at regular intervals thereafter in accordance with UNC 
policies. 
 
10.2 ADDITIONAL CONSIDERATIONS 
Not applicable 
10.3 ABBREVIATIONS 
 
AASE 
Alcohol Abstinence Self-Efficacy 
AE 
Adverse Event 
APT 
Alcohol Purchase Task 
AUD 
Alcohol Use Disorder 
AUDIT 
Alcohol Use Disorder Identification Test 
AUQ 
Alcohol Urge Questionnaire 
BAES 
Biphasic Alcohol Effects Scale 
BIS-11 
Barratt Impulsivity Scale 
BMI 
Body Mass Index 
BrAC 
Breath Alcohol Concentration 
CASE 
Cigarette Abstinence Self-Efficacy 
CES-D 
Center for Epidemiological Studies Depression Scale 
CEQ 
Control of Eating Questionnaire 
CFR 
Code of Federal Regulations 
CMP 
Clinical Monitoring Plan 
CO 
Carbon Monoxide 
CPT 
Cigarette Purchase Task 
CRF 
Case Report Form 
CTRC 
Clinical & Translational Research Center 
DEQ 
Drug Effects Questionnaire 
DNA 
Deoxyribonucleic acid 
DSM-5 
Diagnostic and Statistical Manual for Mental Disorders v.5 

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DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
FPT 
Food Purchase Task 
FTND 
Fagerstrom test for Nicotine Dependence 
GCP 
Good Clinical Practice 
GLP-1 
Glucagon-Like Peptide 1 
GLP-1R 
Glucagon-Like Peptide 1 Receptor 
HbA1c 
Glycated hemoglobin 
ICH 
International Conference on Harmonisation  
ICS 
Impaired Control Scale 
IDS 
Inventory of Drinking Situations 
IRB 
Institutional Review Board 
MCQ 
Monetary Choice Questionnaire 
MNWS 
Minnesota Nicotine Withdrawal Scale 
MOP 
Manual of Procedures 
NC Tracs 
North Carolina Translational & Clinical Sciences Institute 
NDSS 
Nicotine Dependence Syndrome Scale 
NIAAA 
National Institute on Alcohol Abuse and Alcoholism 
NIH  
National Institutes of Health 
NRT 
Nicotine Replacement Therapy 
PACS 
Penn Alcohol Craving Scale 
PI 
Principal Investigator 
POMS-SF 
Profile Of Mood States Short Form 
PAWS 
Prediction of Alcohol Withdrawal Severity Scale 
QA 
Quality Assurance 
QC 
Quality Control 
RBEDS 
Reward Based Eating Drive Scale 
RPI-EROS Reward Probability Index – Environmental Reward Observation Scale 
SAE 
Serious Adverse Event 
SAFTEE 
Systematic Assessment for Treatment Emergent Effects 
SAWS 
Short Alcohol Withdrawal Scale 
SNAQ 
Simplified Nutritional Appetite Questionnaire 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
SRE 
Self-Report of the Effects of Alcohol Questionnaire 
SUD 
Substance Use Disorder 
T2D 
Type II Diabetes 
TAS-20 
Toronto Alexithymia Scale 
TFEQ 
Three Factor Eating Questionnaire 
TLFB 
Timeline Follow-Back Interview 
TQSU 
Tiffany Questionnaire of Smoking Urges 
UP 
Unanticipated Problem 
UPPS-P 
UPPS-P Impulsive Behavior Scale 
WISDM 
Wisconsin Inventory of Smoking Dependence Motives 
WSWS 
Wisconsin Smoking Withdrawal Scale 
5-HT2C 
Serotonin 2C Receptor 

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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
1.2 
July 26 2021 
Elaboration on statistical analyses 
and clarification on other 
procedural issues. 
Minor changes requested 
during initial review of the 
protocol. 
1.3 
Feb 28 2021 
Clarification of medication 
dispensing procedures, addition of 
personnel, addition of Docusign 
procedures, other protocol 
modifications. 
Changes addressed issues that 
emerged while preparing for 
recruitment and meeting with 
IDS and study investigators. 
1.4 
June 23 2022 
Minor revisions to select 
assessment instruments, exclusion 
criteria, and clarification of 
medication dosing and DSMB 
meeting plan 
Refinement of study procedures 
and clarification of monitoring 
schedule as requested by 
DSMB and IDS 
1.5 
August 22 
2022 
Updates to medication storage, use 
of Phone.com for text messaging, 
select questionnaire modifications, 
modifications to alcohol self-
administration session 
Medication storage changes 
requested by IDS; Phone.com 
added as per UNC requirements 
for text messaging; other 
changes intended to streamline 
and improve assessment 
procedures 
1.6 
October 31 
2022 
Updated inclusion criteria to allow 
for light smokers and increased 
range of AUD symptoms; added 
analysis for blood neutrophils; 
added additional recruitment flyers. 
Changes made to facilitate 
recruitment and address an 
exploratory research question. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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