The Effects of Exenatide, a GLP-1 Agonist, on Alcohol Self-Administration in Heavy Drinkers
Phase: PHASE1
Conditions: Alcohol Use Disorder
Sponsor: Boston Medical Center

The Effects of Exenatide, a GLP-1 Agonist, on Alcohol Self-Administration in Heavy Drinkers 
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The Effects of Exenatide, a GLP-1 Agonist, on Alcohol Self-Administration in Heavy Drinkers 
 
ClinicalTrials.gov number: NCT03645408 
Protocol Version Number: 1.8 
Protocol Version Date: 10/05/2020 
Sponsor:  NIAAA/NIH 
Principal Investigator:  Eric G. Devine, Ph.D. 
 
Phone: 617-638-7888 
 
E-mail: eric.devine@bmc.org 
 
CONFIDENTIAL 
 
This document is confidential and the property of Boston Medical Center.   No part of it 
may be transmitted, reproduced, published, or used by other persons without prior 
written authorization from the study sponsor. 

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TABLE OF CONTENTS 
1 List of Abbreviations ........................................................................................................... 3 
2 Protocol Summary .............................................................................................................. 4 
3 Background/Rationale & Purpose ..................................................................................... 5 
3.1 Background Information ............................................................................................ 5 
3.2 Rationale and Purpose ............................................................................................. 7 
4 Objectives ............................................................................................................................ 7 
4.1 Study Objectives ........................................................................................................ 7 
4.2 Study Outcome Measures ........................................................................................ 7 
4.2.1 
Primary Outcome Measures ....................................................................... 7 
4.2.2 
Secondary Outcome Measures .................................................................. 7 
5 Study Design ....................................................................................................................... 8 
6 Potential Risks and Benefits .............................................................................................. 8 
6.1 Risks ........................................................................................................................... 8 
6.2 Potential Benefits..................................................................................................... 13 
6.3 Analysis of Risks in Relation to Benefits ............................................................... 13 
7 Study Subject Selection ................................................................................................... 13 
7.1 Subject Inclusion Criteria ........................................................................................ 13 
7.2 Subject Exclusion Criteria ....................................................................................... 13 
8 Study Intervention ............................................................................................................. 14 
9 Study Procedures ............................................................................................................. 15 
10 Assessment of Safety and Data Safety Monitoring Plan (DSMP) ............................... 18 
10.1 Definitions ................................................................................................................ 18 
10.2 Safety Review .......................................................................................................... 19 
10.3 Reporting Plans ....................................................................................................... 20 
10.4 Stopping Rules ........................................................................................................ 20 
11 Data Handling and Record Keeping ............................................................................... 21 
11.1 Confidentiality .......................................................................................................... 21 
11.2 Source Documents .................................................................................................. 21 
11.3 Case Report Forms ................................................................................................. 21 
11.4 Study Records Retention ........................................................................................ 22 
12 Statistical Plan .................................................................................................................. 22 
12.1 Study Hypotheses and Proposed Analyses .......................................................... 22 
12.2 Sample Size Determination .................................................................................... 23 
13 Ethics/Protection of Human Subjects ............................................................................. 24 
14 Literature References ....................................................................................................... 25 
15.  Appendix A: Schedule of Events ................................................................................... 30 

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1 
List of Abbreviations 
 
Abbreviation 
Abbreviation definition 
ABV 
Alcohol By Volume 
AE 
Adverse Events 
AUD 
Alcohol Use Disorder 
AUQ 
Alcohol Urge Questionnaire 
BAC 
Blood Alcohol Concentration 
BAL 
Blood Alcohol Level 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CIWA 
Clinical Institute Withdrawal Assessment 
CIWA-AR 
Clinical Institute Withdrawal Assessment for Alcohol–Revised 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSMP 
Data Safety Monitoring Plan 
ECG 
Electrocardiogram 
GFR 
Glomerular Filtration Rate 
GLP-1 
Glucose-Dependent Insulinotropic Peptide  
GLP1-R 
Glucagon-Like Peptide-1 Receptor 
MINI 
Mini International Neuropsychiatric Interview 
mRNA 
Messenger Ribonucleic Acid 
NTS 
Nucleus of the Solitary Tract 
OCDS 
Obsessive Compulsive Drinking Scale 
SAE 
Serious Adverse Events 
SDU 
Standard Drink Units 
SNP 
Single Nucleotide Polymorphisms 
SSL 
Secure Sockets Layer 
TLFB 
Time-Line Follow-Back 
VAS 
Visual Analogue Scale 
 

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2 
Protocol Summary 
Title: 
The Effects of Exenatide, a GLP-1 Agonist, on Alcohol Self-
Administration in Heavy Drinkers 
Population: 
The present study will involve 72 men and women aged 21 to 
55 who exceed safe levels of drinking.  Women and minorities 
who meet the study criteria will be eligible to participate. No 
vulnerable populations are being targeted for inclusion in this 
study 
Intervention: 
We propose to undertake a double-blind, randomized, 
placebo-controlled, crossover design trial that will test the 
effect of exenatide on alcohol self-administration and craving 
following a priming dose of alcohol.  Subjects will receive 
either a 5 mcg dose of immediate release exenatide or a sham 
injection 30 minutes prior to completing a drinking challenge.  
Subjects will receive alcohol in the laboratory.  Subjects will be 
presented with a priming drink mixed to raise their BAL 0.03 
g/dl. Subjects will be presented with eight drinks, each mixed 
to raise their BAL 0.0125g/dl over a two-hour period.  They will 
be told that they can either consume the desired number of 
drinks over the following 60 minutes or they will receive the 
equivalent in a cash reward.  Subjects will serve as their own 
controls.  The intervention will be repeated with a Sham 
injection/exenatide after a washout period.  
Objectives: 
The specific objective of this study is to test the effects of 
exenatide on alcohol self-administration and craving among 
heavy drinkers. This medication is a promising candidate that 
has unique actions on GLP-1 receptor systems that have been 
implicated in the regulation of alcohol consumption.  Testing 
the effects of exenatide on drinking is a compelling opportunity 
that is consistent with the mission of NIAAA to evaluate the 
efficacy of re-purposed compounds with novel mechanisms 
that have the potential to treat AUD.  If successful, this study 
could lead to a phase II randomized controlled trial to test 
exenatide as a treatment for AUD.   
Design/Methodology: This is a double-blind, randomized, placebo-controlled, 
crossover design trial that will test the effect of exenatide on 
alcohol self-administration and craving following a priming 
dose of alcohol.  An established human laboratory self-
administration procedure will be followed.  Each subject will 
complete up to 4 clinic visits over a period of up to 38 days of 
participation.  Study participation is comprised of a baseline 
assessment, alcohol self administration Trial 1, and alcohol 
self administration Trial 2.  The volume of alcohol consumed 
during alcohol challenge trials 1 and 2 will be used to test the 
effect of exenatide on alcohol consumption.  Craving 
measures (AUQ and VAS) collected during the self-
administration trials will be used to test the effect of exenatide 
on alcohol craving.   
Total Study Duration: The entire study will take 24 months to complete. 

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Subject Participation 
Duration: 
Each subject’s length of participation will be up to 38 days.   
 
3 
Background/Rationale & Purpose 
 
3.1 
Background Information 
Current models of care for treating Alcohol Use Disorder (AUD) include both behavioral 
therapies and pharmacotherapy1.  Although pharmacotherapy for AUD in the US has been 
available since 1948 when disulfiram was approved, options for treatment are limited as there 
are only four medications which have been approved by the FDA for treating AUD.  Disulfiram, 
naltrexone, acamprosate, and long-acting naltrexone have all shown promise as agents to treat 
AUD2 but no single medication has proven to be effective across the heterogeneous groups of 
people with AUD3. Movement towards models of personalized care and pharmacogenetic 
treatment matching4-5 hold some promise for improving AUD treatment outcomes, but the limited 
number of unique mechanisms of action of the currently approved drugs presents a challenge to 
implementing this model of care.  Unfortunately, few novel compounds to treat AUD progress to 
phase II trials, and developing novel compounds is both costly and time-consuming6.  One 
pathway of drug development efforts has been focused on re-purposing FDA approved 
medications that have promising mechanistic effects7 and some success has been achieved in 
using this strategy with anticonvulsants8.  Identification of additional drugs with unique 
mechanisms of action that are found to reduce alcohol consumption could expand the treatment 
options and further the goal of personalized care for AUD.  The overarching goal of our research 
is to identify agents with unique mechanisms that hold promise for treating AUD.  The specific 
objective of this study is to determine whether exenatide, a GLP-1 receptor agonist that is FDA-
approved for treating diabetes, has effects on alcohol craving and consumption.     
Alcohol Use Disorder as a national health problem 
More than 16 million adults suffer from Alcohol Use Disorder (AUD) in the United States8.  The 
economic burden of this is estimated to be 249 billion dollars and approximately 88,000 
Americans die from alcohol-related causes each year9.  Untreated AUD is associated with an 
increased risk of accidents, injuries, suicide, and worsening of other health comorbidities10 and it 
is the fourth most preventable cause of death in the US9.  Treating addiction more effectively 
has become a priority of national importance and the Surgeon General has urged researchers 
to undertake testing of new treatments to combat addiction11.  The present study is intended to 
answer the call for accelerating drug development for AUD by exploring the potential to re-
purpose an existing drug as a treatment for AUD6-7.    
 
Rationale for developing exenatide as an agent to treat AUD 
GLP-1 is an endogenous peptide that regulates blood glucose by decreasing the rate of 
gastric emptying, promoting pancreatic beta cell activity if blood glucose levels are elevated, 
reducing glucagon release, and producing satiety for food13.  Peptides that share structural 
similarities to GLP-1 have been synthesized including exenatide (synthetic Exendin-4) and 
liraglutide that are resistant to the GLP-1 metabolizing enzyme dipeptidyl peptidase IV13-14. 
There is now substantial preclinical evidence that these GLP-1 agonists can attenuate 
behaviors that model both the consumption and seeking of several commonly abused 
substances including alcohol7-8,10-11, cocaine15, and nicotine16. Consistent with the idea that 
GLP-1 agonists are acting on overlapping pathways that regulate both food and drug intake, 
these compounds have been found to  attenuate the reinforcing actions of food6,17-18. Both 
Exendin-4 and liraglutide have been shown to reduce alcohol consumption by rodents7,8-11. The 
administration of these drugs attenuates alcohol-induced place preference7,10 indicating that 
they reduce the rewarding effects of alcohol. Treatment with Exendin-4 blocks increases in 

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alcohol intake following periods of alcohol deprivation, suggesting that this drug may decrease 
the likelihood of relapse during periods of abstinence19. Exendin-4 induced reductions in alcohol 
consumption were not observed in mutant mice who were missing central nervous system GLP-
1 receptors, providing some evidence that the effects of this drug on alcohol consumption are 
specifically mediated by brain GLP-1 receptors11.  These effects in rodents may involve GLP-1 
agonist attenuation of alcohol-induced release of mesolimbic dopamine, which is implicated in 
regulating the rewarding effects of alcohol7,10. 
 The primary goal of this study is to determine whether findings from rodent studies of 
the inhibitory effects of GLP-1 agonists on behaviors related to alcohol consumption will 
translate into similar results in heavy drinking humans. In this proposed study we will examine 
the effects of the GLP-1 agonist exenatide on alcohol self-administration and cravings among 
heavy drinkers.  Exenatide binds to the human GPL-1 receptor with an affinity equivalent to that 
of human GLP-1 peptide20-21. This medication is approved for use in type 2 diabetes to help 
normalize blood glucose levels and has been tested in non-diabetic patients as a medication for 
the treatment of Parkinson’s disease22. It should also be noted that the GLP-1 agonist liraglutide 
has received FDA approval as a medication for the promotion of weight loss23. 
At present, the most direct evidence implicating involvement of GLP-1 receptor systems 
in the regulation of alcohol consumption in humans is the finding that significant associations 
exist between select GLP1-R single nucleotide polymorphisms (SNP) and the occurrence of 
AUD24. Suchankova et al. found that social drinkers who had the 168Ser/Ser variant for the 
rs6923761 SNP for the GLP-R1 gene consumed more alcohol in a self-administration task than 
subjects with the other variants of this SNP.   
In the human brain, GLP-1 positive neurons have been found in the medullary tissue that 
contain the nucleus of the solitary tract (NTS)25. This may be of significance because in rodents 
the NTS projects to key areas implicated in mediating food and alcohol reward including the 
ventral tegmental area and the nucleus accumbens26-29. GLP-1 receptor mRNA has been 
detected in mesolimbic regions of the primate (Rhesus monkey) brain30.  These findings 
suggest that exenatide may influence alcohol consumption in primates and, therefore possibly 
humans by acting through pathways that regulate drinking that are connected to the NTS.   
More evidence, however, is needed regarding the localization of GLP-1 neuron pathways within 
the human brain to support this hypothesis. 
GLP-1 receptors, thus far, have been demonstrated to be present in several areas of the 
human brain including the hypothalamus, caudate-putamen, globus pallidus, temporal cortex, 
frontal cortex, parietal lobe, and orbitofrontal cortex31-32.  Evidence concerning the functional 
consequences of acute administration of GLP-1 agonists, such as exenatide, on regional human 
brain activity has been presented in a few imaging studies. Injection of a 5 mcg dose of 
exenatide resulted in an increase in regional cerebral glucose metabolism in prediabetic 
subjects following glucose ingestion.  This increase occurred in the overall mean in the 
collective regions that regulate glucose homeostasis (including frontal lobes, limbic system, 
insula, and putamen) and in those associated areas associated with food reward systems 
(including the orbital frontal cortex and anterior cingulate)33. The acute intravenous 
administration of exenatide to obese subjects was found by one group of investigators to reduce 
the activation of brain structures including the amygdala, insula, orbitofrontal cortex, and 
putamen that were produced by the presentation of food related cues34-35. Other investigators 
have found that exenatide administration decreased the activation of brain structures (including 
the amygdala, insula, hippocampus, and frontal cortex) during food cue exposure in healthy 
obese subjects, but had no effect on these structures in lean subjects36. These findings suggest 
that the acute administration of exenatide has effects on brain regions that have been shown to 
be associated with responses to alcohol cues (amygdala, temporal cortex, insula, anterior 
cingulate)37-39 and alcohol administration (amygdala, anterior cingulate; insula, orbital frontal 

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cortex, putamen) in social and heavy drinkers40-41. Given the demonstrated effects of exenatide 
on regional brain function associated with both food and alcohol reward, we expect that this 
drug will modulate alcohol craving and consumption.   
 
This study will be conducted in compliance with the protocol, applicable regulatory 
requirements, and BMC/BU Medical Campus Human Research Protection policies and 
procedures. 
 
3.2 
Rationale and Purpose  
 
This proposal holds significant innovation as there is strong evidence that medications that act 
as agonists at the GLP-1 receptor decrease alcohol consumption and its rewarding effects. 
There are currently no published clinical studies concerning the effects of GLP-1 agonists on 
alcohol consumption. This proposed study answers the call for accelerating the development of 
medications for AUD by testing a commercially-available and well-tolerated agent at a fraction of 
the cost of developing novel therapies.  Currently there is one placebo controlled double-blind 
study of the effects of sustained release formulation of exenatide on alcohol consumption by 
alcohol dependent subjects (NCT03232112).   
 
4 
Objectives 
 
4.1 
Study Objectives 
 
The specific objective of this proposal is to determine whether the GLP-1 agonist 
exenatide has effects on alcohol consumption and craving that identify it as a candidate 
medication for the treatment of AUD.  This medication, which is approved by the FDA for the 
treatment of Type 2 diabetes, has been shown in preclinical studies to be a promising candidate 
as an AUD treatment medication because of its actions on GLP-1 receptor systems. These 
systems have been implicated in the regulation of alcohol consumption7-11. Testing the effects of 
exenatide on drinking is a compelling opportunity that is consistent with the mission of NIAAA to 
evaluate the efficacy of re-purposed compounds with novel mechanisms that have the potential 
to treat AUD.   If successful, this study would provide proof of concept that the administration of 
a GLP-1 agonist could reduce alcohol consumption in human subjects, and thereby provide 
support for the conduct of phase II randomized controlled trials to test one or more of the many 
currently FDA approved GLP-1 agonists as a treatment for AUD.  
 
4.2 
Study Outcome Measures 
 
4.2.1 
Primary Outcome Measures 
 
The primary outcomes are alcohol consumption and cravings during the alcohol self-
administration trials.  Drinking volume during the alcohol self-administration will be measured to 
evaluate the effects of exenatide vs. sham injection on the rate of alcohol consumption after a 
priming drink.  Alcohol craving will be measured using the Visual Analog Scale (VAS) and the 
Alcohol Urge Questionnaire (AUQ)30 during the exenatide self-administration trial.  These self-
report measures of craving will be used to evaluate the effect of exenatide on craving vs. 
placebo.   
 
4.2.2 
Secondary Outcome Measures 
 
A secondary aim of the present study is to examine the effects of exenatide on the absorption of 

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alcohol in a sample of heavy drinkers. It is hypothesized that areas under the breath alcohol 
concentration curves in heavy drinkers obtained during the first 40 minutes after ingestion of the 
priming drink of alcohol will be significantly lower in subjects when they receive exenatide as 
compared to when they are given sham injections.  Another secondary goal of this study will be 
to determine whether blood glucose levels enter into the hypoglycemic range in any of the study 
subjects receiving the combination of alcohol and exenatide. It is hypothesized that the 
proportion of subjects with post-trial blood glucose levels in the hypoglycemic range will not 
differ significantly between the sham injection and exenatide treatment trials. 
 
 
5 
Study Design 
 
This is a double-blind, randomized, placebo-controlled, crossover design trial that will test the 
effect of exenatide on alcohol self-administration and craving following a priming dose of 
alcohol.  An established human laboratory self-administration procedure will be followed30. The 
O’Malley self-administration procedure entails the administration of a priming drink followed by 
the presentation of four drinks on a tray which subjects may drink, or receive compensation for 
the drinks not consumed. After one hour the first tray of drinks is removed and subjects are then 
given the opportunity to consume a second tray of drinks. Confirmation of the validity of this 
approach as a method for screening for medications to treat AUD include the finding that pre-
treatment with naltrexone, which is an approved medication for treating AUD, significantly 
reduced alcohol consumption when the O’Malley self-administration procedure was used36.  
Using this procedure, our group has found that the anticonvulsant zonisamide reduces alcohol 
consumption in non-treatment seeking social drinkers34.  We later confirmed that the 
administration of zonisamide decreases alcohol consumption in subjects with AUD in a double-
blind randomized clinical trial23 as have other investigators34.  Testing exenatide using 
O’Malley’s self-administration procedure is the next logical step in drug development following 
positive findings that exenatide reduces drinking in animal models.  The human laboratory-
based alcohol self-administration procedure is a cost effective and time-efficient method for 
testing novel drug candidates for AUD treatment6.  
 
Subjects: Heavy-drinking subjects will be enrolled to increase the potential generalizability of 
these findings to a clinical AUD population.  Subjects will be recruited through advertising, study 
flyers, internet postings, by community recruiters, and an established subject registry at Boston 
Medical Center.  Interested subjects will be screened by telephone to determine initial eligibility 
prior to the baseline assessment. 
 
Community Recruiters: Two to three community recruiters will be hired to display/distribute 
approved study recruitment materials for a trial period of 2-3 months.  The estimated payment 
for this service will be $50-100 per month but this may be increased to meet market conditions 
for this recruitment service. After a period of 2-3 months recruiter services may be “renewed” for 
an additional 2-3 months.  Additional recruiters may be hired to display or distribute approved 
recruitment materials as needed to increase the rate of recruitment.  Recruiting services may be 
utilized until recruitment goals have been met.   
 
6 
Potential Risks and Benefits 
 
6.1 
Risks 

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To minimize the risk of adverse health events we will instruct subjects to contact study staff with 
any questions or concerns about changes in health effects after initiating study 
medication/placebo. Trained medical staff will evaluate any reported adverse effects and make 
a clinical determination about management.   Subjects will be given a wallet card that includes a 
phone number with 24/7 coverage for medical emergencies.  
C) Potential Risks 
Risks of study medication 
The following adverse reactions were observed in subjects treated with 10-20 mcg of exenatide 
per day.  The package insert for the exenatide immediate release formulations lists the 
incidence of the following adverse reactions versus placebo as follows for patients receiving 
monotherapy with exenatide in diabetic subjects: Nausea (8% versus 0%), Vomiting (4% vs 
0%), and dyspepsia (3% versus 0%)56.  Between  
one and two percent of Type II diabetic subjects receiving exenatide monotherapy experienced 
decreased appetite, diarrhea and/or dizziness. Type II diabetic subjects receiving combined 
therapy of exenatide with metformin (and/or 
sulfonylureas) experienced a higher incidence 
of adverse effects than did subjects receiving 
exenatide monotherapy. The incidence of 
adverse effects in patients receiving exenatide 
in combination with metformin or sulfonylurea 
versus those treated with placebo and these 
antidiabetic agents is shown in table 3.   
 
There is a warning that post-marketing 
data indicate that acute pancreatitis including 
necrotizing pancreatitis and hemorrhagic 
pancreatitis (fatal and non-fatal) have 
occurred in association with exenatide 
administration. A precaution exists stating that 
there is an increased risk of hypoglycemia 
occurring in patients taking exenatide in 
combination with sulfonylureas. The administration of pharmacologic doses of GLP-1 were not 
found to increase the incidence of occurrence of hypoglycemia in fasting healthy subjects57. 
Exenatide may produce nausea and vomiting that can be problematic in patients with impaired 
renal function. This drug was not well tolerated in patients with end-stage renal disease who 
were undergoing dialysis. It is advised that exenatide be used with caution in patients with 
severe renal impairment. Some reports of allergic reactions have been reported during post-
approval use of exenatide including injection-site reactions, generalized pruritus and/or urticaria, 
macular or papular rash, angioedema, anaphylactic reaction.   
In a study of the effects of monotherapy with exenatide 10 mcg twice daily over a period 
of 24 weeks, 10% of subjects experienced nausea vs 0% of those who received placebo.  Three 
percent of subjects vomited vs. 0% of those who received placebo58.  In one study 65% of 
healthy subjects developed nausea following injection of 10 mcg dose exenatide when they 
were allowed to eat a standardized meal 60 minutes after the administration of this drug59. In a 
dose ranging study of exenatide monotherapy with type-2 diabetics, nausea was reported by 
13% of subjects receiving .1 mcg/kg dose, 0% of subjects receiving .2 mcg/kg dose, 29% of 
subjects receiving .3 mcg/kg dose, 60% of subjects receiving .4 mcg/kg dose, and 14% of 
subjects receiving placebo60. There is a warning that thyroid C-cell tumors have been observed 
to occur in female rats receiving extended release treatment with exenatide.  Also, exenatide 
has produced developmental toxicity when administered to pregnant rats.  
Table 3. Combination therapy vs. placebo 
Adverse effect 
Placebo 
Combination 
Therapy 
Nausea 
18% 
44% 
Vomiting 
4% 
13% 
Diarrhea 
6% 
13% 
Feeling jittery  
4% 
9% 
 Dizziness  
6% 
9% 
Headache 
6% 
9% 
Dyspepsia 
3% 
6% 
Asthenia  
2% 
4% 
Gastric Reflux  
1% 
3% 
Hyperhidrosis 
1% 
3% 

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Risks of Phlebotomy, medication injection, and pinprick for blood glucose test 
These procedures may cause pain, bruising, lightheadedness, fainting and on rare occasions, 
infection.  
 
Risks of alcohol self-administration 
There is a potential risk of increased alcohol consumption following the alcohol self-
administration experiment, but studies of subjects who have completed the alcohol self-
administration procedure indicate that this is rare.  Social drinkers who completed an alcohol 
self-administration study were not found to have increased risk for problem drinking 6 weeks 
after completing the self-administration study61.  Similar results were found for alcohol 
dependent subjects 3 months after participation in a study testing the effects of naltrexone on 
alcohol self-administration62. Young social adult drinkers also did not exhibit an increase in real 
life drinking 6 weeks after the completion of intravenous alcohol self-administration 
experiments63.    
 
Subjects may reach a level of intoxication that is uncomfortable to them.  If a subject consumed 
all eight drinks that were available to them during the two one-hour alcohol Challenge Trials, 
there is a possibility that they could reach an estimated peak BAC of 0.09 to 0.13g/dl taking into 
account the rate of metabolism of 0.010 to 0.020 g/dl per hour64.  This risk is unlikely to be a 
problem because we are recruiting subjects who routinely engage in binge drinking and have 
likely developed some tolerance to alcohol.  The alcohol self-administration paradigm that we 
have chosen does not include any coercion, inducements, or pressure to consume more alcohol 
than subjects feel comfortable consuming.  There are no experimental manipulations that would 
increase drinking (e.g., heavy-drinking confederate, anxiety manipulation).  In fact, in this study 
design there are inducements for subjects to not drink beyond the initial priming dose.  Subjects 
will receive monetary incentives for each drink that they do not consume.  To reduce the risk of 
injury or harm after the subject has been discharged from self-administration laboratory, we will 
require that subjects have a plan for transportation that does not involve the subject driving.  
Subjects must have a BAC below 0.04 g/dl prior to discharge from the alcohol self-
administration trials.   
 
Risk of loss of confidentiality  
There is some risk that health information collected as part of this study could be seen by 
unauthorized individuals.  Every effort will be made to minimize this risk and protect subject 
confidentiality. 
 
Adequacy of Protection against Risks 
A) Recruitment and Informed Consent 
All study procedures will be conducted at the Clinical Studies Unit at Boston Medical Center and 
the General Clinical Research Unit at Boston University Medical Campus.  At the first screening 
visit a research assistant will greet the prospective subject and provide a copy of the consent 
form to read prior to meeting with a study physician.  After reviewing the consent, candidates 
will meet with study physician and receive an explanation of the study purpose and 
requirements. If still interested after receiving an explanation of the study, the candidate will be 
given an opportunity to review, inquire about, and sign the study informed consent form. A 
consent questionnaire quiz will be administered to ensure that the subject understands the 
study procedures.  Any incorrect answers will be reviewed until the consenting physician is 
satisfied that the subject comprehends the misunderstood information.  Subjects’ BAC will be 
measured immediately after signing consent to ensure that consent was given while not 

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intoxicated.  BAC must be 0.000 when signing the informed consent document. The consenting 
physician will document the consent process in a progress note in the subject’s source binder.   
Subjects who are deemed to lack decisional capacity will not be enrolled in this study.   
 
B) Protections against Risks 
Risks of study medication 
To minimize the risk of adverse health events we will instruct subjects to contact study staff with 
any questions or concerns about changes in health effects after initiating study medication/sham 
injection. Trained medical staff will evaluate any reported adverse effects and make a clinical 
determination about continuation in the trial and referral for medical care. Subjects will be given 
a wallet card that includes a phone number with 24/7 coverage for medical emergencies.  
Because of evidence that exenatide can adversely affect fetal development in rats, 
women will be excluded from study entry if they have a positive urine pregnancy test or if they 
are of childbearing age and are either not using appropriate methods of contraception or 
practicing abstinence.  
Subjects will be excluded from this study who have renal impairment because of 
potential risks associated with the use of exenatide in patients with this problem. Subjects will 
be enrolled into this study only if the values for renal tests (Creatinine, BUN) are within normal 
limits. Given the warning concerning the association of exenatide treatment with pancreatitis, 
subjects will not be enrolled into this study if they have a history of pancreatitis or lipase above 
the upper normal limit.  Subjects with a history of thyroid cancer or other thyroid disease will be 
excluded from this study because of studies showing that exenatide increases the risk of the 
occurrence of thyroid cancer in animals. Subjects taking warfarin will be excluded to minimize 
the risk of a drug interaction.   
Diabetic patients will be excluded from this study because the use of antidiabetic 
medications including the sulfonylureas and metformin may increase the incidence of adverse 
effects associated with the use of exenatide. Of particular concern is the possibility that the use 
of antidiabetic agents may increase the risk of hypoglycemia occurring in individuals receiving 
injections of exenatide. Finally, the administration of exenatide to a diabetic patient would be a 
therapeutic intervention that should occur only in coordination their other health care providers. 
The effects of the interaction of GLP-1 agonists and alcohol on blood glucose levels has 
not been adequately studied in humans. The administration of exenatide will decrease plasma 
glucagon in Type 2 diabetic patients and also may increase insulin release if blood glucose 
levels are elevated13.  In fasting elderly Type 2 diabetic patients receiving the antidiabetic 
sulfonylurea glyburide, alcohol ingestion produced a greater decrease in blood glucose levels 
than did placebo65. Also, ethanol has also been shown to inhibit gluconeogenesis in Type 2 
diabetes, although it did not produce alterations in total liver glucose output12. The consumption 
of alcohol in healthy subjects receiving the sulfonylurea glipizide did not result in a greater 
reduction in glucose blood levels than when this drug was taken alone, but did prolong the 
length of time during these reductions occurred66.  As a precaution against subjects 
experiencing hypoglycemia in this study, alcoholic drinks will be administered to subjects with a 
sugary mixer (e.g. juice, soda). As a protection for the risk of allergic reaction, injections will be 
preformed in the GCRU.   
 
Risks of Phlebotomy 
To minimize the risk of pain, bruising, lightheadedness, fainting, and on rare occasions, infection 
from a blood draw, we will used trained phlebotomists. 
 
Risks of alcohol self-administration 
To minimize the risk of subjects reaching a level of intoxication that is uncomfortable to them, 

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we will remind subjects that they can discontinue study participation at any time.  Subjects will 
be monitored during the course of the study, both through direct assessment with study staff 
and by observation through a video camera in the alcohol laboratory.  Medical staff will evaluate 
subjects and may make a determination to halt study participation if the subject becomes too 
behaviorally impaired or if there are emergent safety issues.  Subjects who have a BAC greater 
than 0.04 g/dl or who appear to be too behaviorally impaired to leave our research center will be 
asked to remain in the clinic until their intoxication is reduced to a level that it is safe to 
discharge them from the research laboratory.     
 
Risk of loss of confidentiality  
There is some risk that health information collected as part of this study could be seen by 
unauthorized individuals.  Every effort will be made to minimize this risk and protect subject 
confidentiality.  Electronic data will be housed in the REDCap data management system.  
REDCap is protected via Secure Sockets Layer (SSL) encryption that provides access 
restriction options.  Exported data from REDCap will be stored on a secure password-protected 
server behind the BMC firewall. Source and CRF binders will be stored in a double-locked area 
that is accessible to only study staff.  Subjects will be assigned a study identification number 
and this will be used to code any forms that do not require the subject’s direct identifiers (e.g., 
consent form, laboratory results, and contact information).  A linking key that associates study 
ID with direct identifiers will be stored in a double-locked cabinet accessible to only by study 
team members.  Data will be stored on a password-protected computer accessible only to the 
study team.  All study staff will receive appropriate training for the protection of human subjects 
(NIH Protecting Human Research Participants). Study records that include direct identifiers will 
be destroyed in accordance with the institutional policy at Boston Medical Center. A certificate of 
confidentiality will be used to protect subjects from compelled disclosure under court order or 
subpoena.      
  
Protection of vulnerable populations  
Women who are pregnant should not be exposed to exenatide13.  Women who are pregnant, 
who think they may be pregnant, or who are trying to conceive will be excluded from the study.  
Women of childbearing age will complete a urine pregnancy test upon entry into the study and 
will be excluded for a positive finding. Women of childbearing potential must agree to use a 
barrier (diaphragm or condom with spermicide), oral contraceptives, non-ferrous intrauterine 
contraceptive system, levonorgestrel implant, medroxyprogesterone acetate contraceptive 
injection, surgical sterilization, or complete abstinence from sexual intercourse. Prisoners will 
not be enrolled in this study.  Due to the potential risk to children and the minimum legal drinking 
age in the United States, children will not be included in this study.  
 
Monitoring for suicidality risk 
We will screen for suicidality using the Columbia-Suicide Severity Rating Scale and the 
MINI Neuropsychiatric Interview.  Subjects with a MINI suicidality score greater than 8 
(low risk) will be excluded.  Subjects who report any active suicidal thoughts or behavior 
as measured the C-SSRS will be excluded from participation.  In addition to excluding 
active suicidality, the MINI will be used to rule out subjects who have psychiatric 
conditions that may increase the risk of the occurrence of suicidal thoughts or behavior 
(e.g., major depression, bipolar disorder).  Assessment and scoring of suicide rating 
scales will be conducted in real-time while the subject is present.  Suicidality will be 
assessed by trained clinical staff including study MDs, a psychologist, a nurse, and a 

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mental health counselor.  If subjects are found to be at risk for self harm, study staff will 
work with the subject to develop a safety plan that could include escorting the subject to 
the BMC ED or calling BEST.   
 
Incidental findings 
There is a possibility for clinically significant abnormal findings on the ECG and blood laboratory 
tests.  Clinically significant abnormal findings will be communicated to study subjects with a 
recommendation to follow-up with primary care or specialized care.      
6.2 
Potential Benefits 
 
There is no potential direct benefit to participation in this study.  This study presents a very 
strong potential for benefit to science.  Drug development for treating AUD is costly and few 
pharmaceutical companies are testing novel compounds as agents to treat AUD.  Re-purposing 
compounds with FDA approval for other indications is the most promising route for rapid and 
cost-effective development of medications to treat AUD.   This study will bridge the gap in drug 
development by providing a test of exenatide to see if it may be a candidate drug for treating 
AUD.  If successful, this could lead to the expansion of pharmacotherapy options to treat AUD 
and a broadening of our understanding of the mechanistic approach to treating AUD.  
 
6.3 
Analysis of Risks in Relation to Benefits 
 
Given that exenatide has FDA approval for another indication and is well-tolerated in other 
populations, the risk of this medication to human subjects has been established through pre- 
and post-marketing data. With the protections we have in place for all the potential risks in this 
study, we believe the risks of this study are well minimized.  The study holds significant promise 
for informing new models of care given the novel mechanism of exenatide.  We believe the 
risk/benefit ratio is favorable. 
 
7 
Study Subject Selection 
 
7.1 
Subject Inclusion Criteria 
Subject Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1.  21-55 years of age. 
2.  Able to verify age with a state or federal picture ID. 
3.  Exceeds safe weekly drinking limits (14 SDUs for women or 21 SDUs for men per week) 
4.  Reports at least one episode of binge drinking (>3 SDUs for women, >4 SDUs for men) an 
average of once per week in the four weeks prior to baseline screening. 
5.  Meets DSM-5 criteria for mild alcohol use disorder or greater severity.     
 
7.2 
Subject Exclusion 
7.3 
 Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 
An individual who meets any of the following criteria will be excluded from participation in this 

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study: 
1.  Seeking treatment for alcohol problems. 
2.  Clinical Institute Withdrawal Assessment at ≥10  
3.  DSM-5 diagnosis of current major depression, bipolar disorder, schizophrenia, 
bulimia/anorexia, dementia, or a substance use disorder other than alcohol, nicotine, 
marijuana or caffeine. 
4.  If female, pregnant, nursing, have plans to become pregnant. 
5.  If female, does not agree to use an accepted form of birth control. 
6.  Has a medical contraindication to the use of exenatide. 
7.  Has medical or mental condition for which further alcohol exposure at the planned dose 
     range would be contraindicated. 
8.  Current risk of suicidality  (MINI suicidality score greater than 8 (low risk) or Yes to the 
     ideation question #4 of the C-SSRS). 
9.  BMI is less than 18 or greater than or equal to 30. 
10.  History of diabetes. 
11.  Baseline hemoglobin A1c ≥ 6.5% 
12.  Baseline nonfasting glucose >200 
13.  Significantly elevated serum lipase levels. 
14.  Impaired renal function (GFR <80 mL/min). 
15.  Pancreatitis, gastroparesis or other severe gastrointestinal disease. 
16.  Has had gastric bypass surgery 
17.  Subject is currently taking warfarin. 
18.  Has received alcohol counseling or other non-pharmacologic intervention to treat AUD in 
the past 90 days. 
19.  Has taken medications that are used to treat AUD in the past 90 days. 
20.  Subjects with a history of thyroid cancer or other thyroid disease.  
21.  Has urine toxicology results positive for cocaine, opioids, amphetamines, buprenorphine, 
methadone, or methamphetamines.  
22.  Prior history of anaphylaxis or angioedema with another GLP-1 receptor agonist. 
23.  Prior use of exenatide 
24.  Liver function values AST or ALT are twice the normal limit 
25.  Unable to comfortably abstain from nicotine for a period of 8 hours.   
26. Has COPD, history of solid organ transplant, sickle cell disease, severe heart disease or 
other health condition for which exposure to COVID-19 represents an unreasonable risk as 
determined by the study staff physician using accepted COVID-19 guidance (e.g. Centers for 
Disease Control, etc.). 
27.  Subject has prior history of Drug-induced thrombocytopenia 
 
8 
Study Intervention 
Study Medication 
Study medication will be purchased by the BMC Investigational Pharmacy Service.  Medication 
will be administered using a 250mcg/mL, 5mcg/dose, 60 doses/pen, 1.2mL prefilled pen.  
Subjects will receive either a 5 mcg dose of immediate release exenatide or a sham injection.  
The 5mcg dose of exenatide is approved as the first dose to be administered to patients at the 
start of their treatment with this drug for FDA-approved indications.  The sham injection will be a 
needle stick insulin syringes with pre-affixed needles as a sham syringe. No fluid will be injected 
as a protection for maintaining the blind.  Note that the volume of fluid injected for a 5mcg dose 
is only 0.02ml.  We do not expect that subjects will sense this volume of fluid (or lack thereof) 
during the injection.  Subjects will be shielded from seeing the injection to maintain the blind.  
The individual who administers medication will not participate in subject evaluation to maintain 

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the study blind.  The study medication will be administered subcutaneously 30 minutes prior to 
the priming dose of alcohol.  
 
Dosing 
Subjects will receive either a 5 mcg dose of immediate release exenatide or a sham injection on 
both alcohol challenge days.   
 
Medication Storage 
Medication will be stored in the Investigational Pharmacy under refrigerated conditions and may 
be stored at room temperature for up to 30-days following dispensing.  Medication will be stored 
in a secured area until the time that medication is needed for study subjects.  Stability and 
expiry will be monitored by IPS according to the labelling of the medication from the 
manufacturer.   
 
Randomization 
Study randomization will be performed by IPS using a stratified block randomization procedure.  
The study statistician will provide IPS with a randomization log.  On the day of randomization, 
study staff will provide IPS with a randomization number based on the stratifying variable (heavy 
vs very heavy drinking) and IPS will determine the order of drug vs. sham exposure based on 
the randomization log. 
 
Medication Labeling 
The study number will be preprinted on each injection pen. The label will include the drug name 
the subject number,  storage conditions, the 24/7 phone number of the clinical site, and places 
to record the subject number and the date dispensed.  Additional fields may be added to this 
label to meet any regulatory requirements as determined by IPS.   
 
Medication Blinding/unblinding  
Study medication will not be blinded.  Medication will be administered by GCRUstaff who are 
not part of study staff who perform data collection.  The Study PI and study staff will be blinded 
to study medication.  The PI and study physician(s) will make the decision to un-blind the 
identity of the study medication in the event that the study blind needs to be broken to make 
medical decisions regarding subject treatment. 
 
Medication accountability 
The site principal investigator (PI) or designated study personnel will maintain a log of all study 
medication and record of dispensing of all medication to the subject.  
 
9 
Study Procedures 
Study Overview: Each subject will complete 3 clinic visits over a period of up to 28 days of 
participation.  Study participation is comprised of a baseline assessment, alcohol challenge Trial 
#1, and alcohol challenge Trial #2.    
 
Baseline assessment:  Prior to the visit, subjects will complete a COVID-19 symptom 
screening questionnaire following standard of care procedures. If the subject does not complete 
the screening questionnaire before arriving in clinic, study staff will administer the questionnaire 
outside of the clinic at a 6-foot distance. If the subject answers ‘yes’ to any question about 
known COVID symptoms, their in-clinic visit will be cancelled and they will be advised to contact 
their PCP and/or get tested at a testing center. Consenting subjects will undergo a general 
medical screen, physical examination, and electrocardiogram.  Drinking will be assessed using 

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the Time-Line Follow-Back (TLFB)45, and alcohol withdrawal using the Clinical Institute 
Withdrawal Assessment (CIWA)46.  Exclusionary mental health conditions will be assessed 
using the MINI Neuropsychiatric Interview for DSM-547.  Subjects will undergo laboratory testing 
that includes liver and renal function tests, glucose, serum lipase, complete blood count, urine 
toxicology and a urine pregnancy test for women of child bearing potential.  
 
Study randomization: Subjects will be randomized to a crossover sequence of drug exposure.  
Subjects will be assigned to one of two groups, with one group receiving exenatide in the 
alcohol challenge Trial #1 and the other receiving exenatide prior in the alcohol challenge Trial 
#2.  Randomization of subjects will be accomplished using a stratified randomization procedure 
that will allow for between-group balance for drinking status (heavy vs. very heavy).  Heavy 
drinking is defined as ≥ 21 and < 35 standard drinks per week for men, and ≥ 14 and < 28 
standard drinks per week for women.  Very heavy drinking is defined as ≥ 35 standard drinks 
per week for men, and ≥ 28 standard drinks per week for women.  This stratified randomization 
will minimize the possibility that the order of study drug administration seems to influence 
outcomes when order effects are actually related to differences in severity of drinking between 
the two groups of subjects who are receiving the study medication in a different order. On the 
day of randomization, subjects will undergo an alcohol breath test, urine drug screening, 
assessment of concomitant medications, and the TLFB.  Subjects who have purposefully 
abstained from drinking and achieved 14 days of abstinence prior to the challenge will be 
discontinued from participation for ethical reasons49.  
 
Alcohol Challenge Trials 1 & 2:  Subjects will return to the laboratory within 14 days of the 
baseline assessment to complete the alcohol Challenge Trial #1. Prior to the visit, subjects will 
complete a COVID-19 symptom screening questionnaire following standard of care procedures. 
If the subject does not complete the screening questionnaire before arriving in clinic, study staff 
will administer the questionnaire outside of the clinic at a 6-foot distance. If the subject answers 
‘yes’ to any question about known COVID symptoms, their in-clinic visit will be cancelled and 
they will be advised to contact their PCP and/or get tested at a testing center. Concomitant 
medications, urine drug screening, Blood Alcohol Concentration (BAC) will be assessed to 
determine eligibility to proceed with the challenge.  A BAC reading of 0.000 is required at each 
visit to continue with the study procedures.  For safety reasons, subjects will be asked to 
arrange transportation plans that does not include driving themselves home.   
Subjects will receive either a 5 mcg dose of immediate release exenatide or a sham 
injection.  The 5mcg dose of exenatide is approved as the first dose to be administered to 
patients at the start of their treatment with this drug for FDA-approved indications.  The sham 
injection will be a needle stick insulin syringes with pre-affixed needles as a sham syringe. Note 
that the volume of fluid injected for a 5mcg dose is only 0.02ml.  We do not expect that subjects 
will sense this volume of fluid (or lack thereof) during the injection. Subjects will be shielded 
from seeing the injection to maintain the blind.  The individual who administers medication will 
not participate in subject evaluation to maintain the study blind.  The study medication will be 
administered subcutaneously 30 minutes prior to the priming dose of alcohol.  Peak plasma 
concentrations of exenatide injected as 5 mcg dose are seen at about 90-120 minutes after 
subcutaneous administration of this drug and its terminal half-life is 2.4 hours13,50.  A 5 mcg dose 
of exenatide injected prior to the administration of oral glucose was found to enhance cerebral 
glucose metabolic rate in brain regions implicated in the regulation of appetite and food reward 
among subjects with impaired glucose metabolism33. These effects were observed 90 minutes 
after the administration exenatide. The 5 mcg dose of exenatide was found to prevent elevation 
in blood glucose levels and the rate of glucose absorption after the administration of oral 
glucose33.   

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Figure 2: Alcohol Self-Administration Procedure 
 
Priming Dose 
5 minutes  
Drink mixed to 
achieve BAC= 
0.03g/dl 
Absorption  
40 minutes 
BAC measured 
in 10-minute 
intervals 
 
Self-Administration 
Blocks 1 & 2 
60 minutes each 
4 drinks per block 
Each drink mixed to 
raise BAC 0.0125 
g/dl 
Study drug  
Study drug 
administered 30 
minutes prior to 
priming dose 
The priming drink will be given no more than 30 minutes after study drug is administered 
(see Figure 2 for alcohol challenge timeline).  Subjects will have five minutes to consume a 
single priming dose of alcohol. After a 40-minute observation period, subjects will begin the 
alcohol self-administration Blocks 1 and 2.  The alcohol self-administration trials will be 
conducted in a human laboratory designed to simulate a typical living room.  The human 
laboratory is a room furnished with a lounge chair, side table, and television which allows 
access to popular streaming entertainment (e.g., Netflix, YouTube). A small unobtrusive camera 
is in the room 
to allow for 
monitoring 
and video 
recording 
without study 
staff being 
present.   
 
Priming dose.  
Subjects will be given a priming drink designed to increase the subject’s blood alcohol level 
(BAL) to 0.03g/dl, using the alcohol of their choice that is 24% Alcohol By Volume (ABV) or 
greater.  Drinks will be mixed with a sugary mixer (3:1 Mixer:Alcohol) to preclude the occurrence 
of hypoglycemia. The volume of alcohol will be calculated using an online tool developed by 
UW-Madison (http://dionysus.psych.wisc.edu/WebCMS/baccalc.htm) based on a formula 
described by Watson51. The subjects will be asked to drink the priming drink over a period of 5 
minutes. The purpose of the priming drink is to normalize drinking in the laboratory.  
 
Absorption period. Subjects will be observed for 40 minutes following the priming dose of 
alcohol.  This period will provide ample time for subjects to reach the target BAC. Breathalyzer 
readings will be completed at 10 minutes intervals.  
 
Alcohol self-administration Blocks 1 and 2.  In each of the alcohol self-administration Blocks, 
subjects will be presented with four drinks, each mixed to raise their BAC by 0.0125g/dl. They 
will be told that they can either consume the desired number of drinks over the following 60 
minutes, or they will receive the equivalent dollar amount of the cost of each drink ($3.00) they 
did not consume.  At the end of each 1-hour session the drinks will be removed and the volume 
of alcohol remaining will be measured with a graduated cylinder.  Cravings will be assessed 
using the AUQ and VAS every 30 min during the self-administration blocks. BAC levels will be 
obtained at the end of the Block 2 session as will blood glucose levels. Blood glucose levels will 
be measured at the end of Block 2 using a glucometer and blood obtained from a pinprick 
sample. If the subject is found to be hypoglycemic (glucose < 70 mg/dL), staff will give the 
subject orange juice and re-test in 30 minutes.  If the subject is found to be hyperglycemic 
(glucose > 300 mg/dl), staff will escort the subject to the BMC emergency department for 
evaluation.  At the end of this session subjects will also be asked to rate their experience of 
nausea using a visual analog scale developed to assess nausea in in an emergency 
department52. Subjects will be assessed for safety prior to subjects leaving the laboratory. 
Subjects will not be released until their BAC is below 0.04 g/dl and they are not behaviorally 
impaired.   
There will be a 7-14 day washout period between alcohol Challenge Trial #1 and Trial 
#2. Based on the known half-life of exenatide, all of the medication will be cleared within 2 days.  
The washout may extend up to 14 days to provide flexibility in scheduling of Trial #2. After the 
second alcohol self-administration trial has been completed subjects will receive a copy of the 

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NIAAA publication Rethinking Drinking48 and will be encouraged to review rethinking drinking 
materials online.  Subjects will be compensated up to $448 for completion of all study activities.  
Subjects will receive a reimbursement of $50 for the screening visit, $150 for alcohol Challenge 
Trial #1, $150 for alcohol Challenge Trial #2.  Subjects will receive a $50 bonus for completing 
both alcohol Challenge Trials.   Subjects may receive up to $48 dollars in payments for drinks 
not consumed during the two alcohol self-administration Trials.  Subjects who report no 
recreational drug use other than marijuana at the time of phone screening but then test positive 
for recreational drug use other than marijuana at the first in-clinic visit will not be reimbursed.  
Subjects will be informed of this policy at the time of telephone screening.  This measure is in 
place to prevent subjects from lying about no recreational drug use in order to receive 
compensation for a single visit in this study.   
 
10 Assessment of Safety and Data Safety Monitoring Plan (DSMP) 
 
10.1 
Definitions 
 
The following definitions will be used in the assessment of safety: 
 
Adverse Event (AE) is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the research, 
whether or not considered related to the subject’s participation in the research. 
 
Serious Adverse Event (SAE) is any adverse event that  
(1) results in death; 
(2) is life-threatening; 
(3) results in inpatient hospitalization or prolongation of existing hospitalization; 
(4) results in a persistent or significant disability/incapacity; 
(5) results in a congenital anomaly/birth defect; or 
(6) based upon appropriate medical judgment, may jeopardize the subject's health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition (examples of such events include allergic bronchospasm requiring intensive 
treatment in the emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse).  
 
Life-threatening means that the event places the subject at immediate risk of death from the 
event as it occurred.  
 
Unanticipated Problem is defined as an event, experience or outcome that meets all three of 
the following criteria:  
 
is unexpected; AND 
 
is related or possibly related to participation in the research; AND 
 
suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.  
 
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 
 
Unexpected means the nature, severity, or frequency of the event is not consistent with either: 

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 
the known or foreseeable risk of adverse events associated with the procedures involved 
in the research that are described in (a) the protocol–related documents, such as the IRB-
approved research protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document, and (b) other relevant sources of information, such 
as product labeling and package inserts; or 
 
the expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile 
for the adverse event. 
 
10.2 
Safety Review 
 
Both the risks listed in Section 6.1 and unknown risks will be monitored as follows:  
 
Adverse events will be monitored from the time of study enrollment until the end of participation.  
Adverse events will be monitored by medical staff using the “adverse events” CRF.  Adverse 
event monitoring will be conducted at each study visit from the time of consent.  Subjects will be 
given a wallet card with a 24/7 telephone number in the event that there are adverse effects 
which the subject would like to consult with medical staff prior to the next scheduled visit.  
Adverse events will be assessed if at any point in the study a subject uses this 24/7 emergency 
phone contact. If a subject has an ongoing SAE or unanticipated problem at the time that the 
subject completes all study procedures, Adverse Event assessment will continue until 
satisfactory resolution (either resolved or stabilized and is not expected to resolve in the near 
term) of the event or problem. 
 
For each recorded AE or SAE, the study MD staff or study nurse will assess expectedness 
based on the known published side effect profile for exenatide.  The study MD staff or study 
nurse will also assess severity based on the following criteria: 
Mild: 
An event that is usually transient, requiring no special treatment, and 
does not generally interfere with the subject’s daily activities. 
Moderate: 
An event that interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the 
subject. The event is usually ameliorated with additional specific 
therapeutic intervention.  
Severe: 
 
An event that interrupts usual activities of daily living or significantly 
affects clinical status. The event poses a significant risk of harm to the 
subject and hospitalization may be required, and typically requires 
intensive therapeutic intervention. 
Life-threatening 
An event that puts the subject into imminent risk of death without 
intervention. 
 
The study MD staff or study nurse will assess AE/SAE relationship to the investigational product 
based on the following criteria: 
 
Unrelated: 
The subject did not receive the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is not reasonable, or there is another obvious cause of the AE/SAE. 

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Unlikely: 
There is evidence of exposure to the investigational product or there is 
another more likely cause of the AE/SAE. 
Possible: 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is reasonable, but the AE/SAE could have been due to another 
equally likely cause. 
Probable: 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is reasonable, and the AE/SAE is more likely explained by the 
investigational product than by any other cause. 
Definite 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is reasonable, the AE/SAE is more likely explained by the 
investigational product than by any other cause, and the AE/SAE shows a 
pattern consistent with previous knowledge of the investigational product or 
investigational product class. 
 
10.3 
Reporting Plans 
 
The Principal Investigator at BMC/BU Medical Campus will report Unanticipated Problems, 
safety monitors’ reports, and Adverse Events to the BMC/BU Medical Center IRB in accordance 
with IRB policies: 
 
Unanticipated Problems occurring at BMC/BU Medical Campus involving a fatal or life-
threatening event will be reported to the IRB within 2 days of the investigator learning of 
the event. 
 
Unanticipated Problems occurring at BMC/BU Medical Campus not involving a fatal or life-
threatening event will be reported to the IRB within 7 days of the investigator learning of 
the event. 
 
Reports from safety monitors with recommended changes will be reported to the IRB 
within 7 days of the investigator receiving the report.  
 
Adverse Events (including Serious Adverse Events) will be reported in summary at the 
time of continuing review, along with a statement that the pattern of adverse events, in 
total, does not suggest that the research places subjects or others at a greater risk of harm 
than was previously known. 
 
Reports from safety monitors with no recommended changes will be reported to the IRB at 
the time of continuing review.  
 
10.4 
Stopping Rules 
 
There are no interim analyses planned that would allow for a determination of futility or 
overwhelming benefit.  Study enrollment will be suspended under the following circumstances: 
 
1.  Serious Adverse Events.  Study enrollment will be suspended in the event of a single serious 
adverse event that is determined to be unexpected and at least possibly related.  If suspended, 
study recruitment will not continue until a determination has been made about whether the 
known risks of participation have changed and the BU Medical Campus/Boston Medical 

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Center IRB has made a finding that the risk/benefit ratio remains favorable given the possible 
newly identified risk.   
 
2.  Risk of intoxication.  Subject recruitment will also be suspended if more than one subject of 
the first ten subjects enrolled is discontinued by the investigator due to intoxication during the 
alcohol self administration trial.  Due to differences in alcohol tolerance, BAL is not a reliable 
measure of subjects potentially posing a safety risk.  Study staff will make a subjective 
determination of risk based on the subject’s behavior.  After 10 subjects have been enrolled, the 
trial will be suspended if there are more than 10% of subjects whose participation has been 
halted by the study team due to concerns about physical safety because of intoxication during 
the alcohol self-administration trial. If suspended for this reason, the study team will consider 
design changes to reduce the likelihood of this as a potential risk to study subjects.  Recruitment 
would resume when the BU Medical Campus/Boston Medical Center IRB has made a 
determination that proposed changes to the study design have an acceptable risk/benefit ratio. 
 
11 Data Handling and Record Keeping 
 
11.1 
Confidentiality 
 
All staff will be fully trained in the procedures for protection confidential health information.  To 
maintain subject confidentiality, study data will be coded on CRFs that are identified by a 
subject number only. Source records with identifying information and CRFs will be stored in 
double-locked space with access only by authorized staff.  Data stored in the REDcap system 
have strong protections including file encryption and password access.  Subject information will 
not be released without written permission.  Upon approval of the study by an IRB, an 
application will be filed with NIAAA for a Certificate of Confidentiality.  
 
11.2 
Source Documents 
 
Source documents in this study include: 
Laboratory test results 
Photocopies of the urine drug screening test result 
ECG tracings 
Subject locator form 
Subject contact form 
 
Data generated by the methods described in the protocol will be recorded in the subjects' 
source binder. Data may be transcribed legibly on CRFs for each subject or directly inputted into 
an electronic system or any combination thereof. 
 
11.3 
Case Report Forms 
 
The study case report form (CRF) will be the primary data collection instrument for the study. All 
data requested on the CRF will be recorded. All missing data will be explained. If a space on the 
CRF is left blank because the procedure was not done or the question was not asked, a written 
explanation will be included to detail why the data was not recorded.  If the item is not applicable 
to the individual case, a notation will be made.  All entries on will be printed legibly in black ink. 

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If any entry error has been made, to correct such an error, a single straight line will be drawn 
through the incorrect entry and the correct data will be entered closely to the original data. All 
such changes will be initialed and dated.  There will be no erasures or white-out on CRFs.  For 
clarification of illegible or uncertain entries, the clarification will be printed near the item, then 
initialed and dated. Electronic CRFs in the REDcap system will include an audit trail.   
 
The CRFs that will be used in this study are: 
Demographics 
Concomitant Medications 
Adverse Events 
Birth Control Assessment 
Urine Drug Screening  
Vital Signs 
Blood Alcohol Level 
Laboratory summary sheet 
Time-line Follow-back 
Pregnancy test 
Birth control assessment 
Medical History 
Blood Glucose 
Nausea VAS 
Physical Examination 
MINI diagnoses summary 
Medication Compliance log 
Eligibility 
ECG 
C-SSRS 
CIWA-AR 
OCDS 
AUQ 
VAS 
 
11.4 
Study Records Retention 
Study records will be retained for at least seven years after completion of the study.  
 
12 Statistical Plan 
 
12.1 
Study Hypotheses and Planned Analyses 
 
For our primary outcomes, data from subjects who experience moderate to severe nausea 
during the alcohol self-administration trials will be excluded from our statistical analysis. 
Although the dosing chosen for this study minimizes the potential for nausea as a medication 
side effect, this may occur in some subjects.  These subjects will be excluded from analyses as 
medication-induced nausea could confound the drinking outcomes.  The presence of nausea 
will be established by a rating greater than 30 on a VAS scale that rates nausea from no nausea 
to unbearable nausea53.  
Hypothesis 
Proposed Analyses 
1. Subjects will consume less 
alcohol during an alcohol Challenge 
Trial when receiving exenatide 
The volume of alcohol consumed during alcohol 
challenge trials 1 and 2 will be used to test the effect of 
exenatide on alcohol consumption.  We will use a mixed 

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compared to when they receive a 
sham injection.     
models repeated measures approach to test for 
differences between alcohol consumption between the 
exenatide and sham injection self-administration trials54-
55.  This data will be divided into first and second-hour 
blocks of self-administration. Within-subject factors for 
this analysis will include Treatment and Time Block. Trial 
order will be used as covariate in these analyses to allow 
evaluation as to whether the order of treatments had a 
significant effect on the outcome. Appropriate covariance 
structures will be determined using Akaike’s information 
criteria to evaluate the best model fit. Results analysis will 
be examined for both treatment effects and the Treatment 
x Time Block interaction results. 
2.  Subjects will report lower levels 
of craving as measured by the 
Visual Analog Scale (VAS) and the 
Alcohol Urge questionnaire (AUQ) 
during the exenatide Challenge 
Trial compared to the sham 
injection Challenge Trial.   
Craving measures (AUQ and VAS) collected at 30-minute 
intervals during the self-administration trials will be used 
to test the effect of exenatide on alcohol craving.  A mixed 
models approach will be used to test for differences in 
craving between the exenatide and sham injection 
Challenge Trials. Within-subject factors for this analysis 
will include Treatment and Time Block. Trial order will be 
used as covariate in these analyses to allow evaluation 
as to whether the order of treatments has a significant 
effect on the outcome. 
Hypothesis 3: Areas under the 
breath alcohol concentration curves 
(AUC’s) in heavy drinkers obtained 
during the first 40 minutes after 
ingestion of the priming drink of 
alcohol will be significantly lower in 
subjects when they receive 
exenatide as compared to when 
they are given sham injections 
AUC’s for BAC obtained using data obtained during the 
40-minute absorption period will be compared between 
Challenge Trials using a repeated measures mixed 
models approach. In addition, individual BAC values 
obtained at 10-minute intervals after alcohol ingestion of 
the priming drink also will be compared between the 
sham injection and exenatide treatment trials using a 
repeated measures mixed models approach. A significant 
time x trial interaction value also will be taken to indicate 
a significant between trial difference in the rates of 
alcohol absorption. 
Hypothesis 4. The proportion of 
subjects with post-trial blood 
glucose levels in the hypoglycemic 
range will not differ significantly 
between the sham injection and 
exenatide trials. 
 
The proportion of subjects with blood glucose values 
below 50 mg/dl will be compared within subjects using the 
McNemar’s test. We hypothesize that there will be no 
difference in blood glucose levels between the alcohol 
Challenge Trials.   
 
12.2 
Sample Size Determination 
 
A group size of 28 completers was selected for use in this study based on an assumed effect 
size of 0.7 suggested by similar alcohol self-administration studies with amount consumed as 
the primary outcome42,44.  This effect size is in the range we found for the anticonvulsant 
zonisamide used in a similar alcohol self-administration study43.  The sample size for this study 
is based on an estimated reduction of 1.5 standard drinks with an estimated standard deviation 
(2.1) of the between Challenge Trial differences in alcohol self-administration, with an effect size 

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of this magnitude (i.e. 0.7).  This requires a sample size of 28 to allow for detection of a 
significant within-subject difference in alcohol consumption with an alpha value of 0.01 and 
power value of 0.81.  Based on an estimated 15-20% rate of non-completion for randomized 
subjects, we anticipate randomizing 36 subjects to achieve a sample of 28 completers.  Given 
our experience with recruiting AUD populations into clinical trials, we expect a screening 
exclusion rate of roughly 50%.  Approximately 72 subjects will be consented and screened in 
clinic to yield a sample of 36 eligible subjects.   
 
 
Given that this a laboratory based experiment we do not plan to conduct any planned 
interim analyses in this study. 
 
13 Ethics/Protection of Human Subjects 
 
This study is to be conducted according to applicable US federal regulations and institutional 
policies (which are based in federal regulations, guidance, and ICH Good Clinical Practice 
guidelines). 
 
This protocol and any amendments will be submitted to the Boston Medical Center and Boston 
University Medical Campus IRB, for formal approval of the study conduct. The decision of the 
IRB concerning the conduct of the study will be made in writing to the investigator. A copy of the 
initial IRB approval letter will be provided to the sponsor before commencement of this study.  
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. The consent form will be submitted with the protocol for review and approval by the IRB. 
The consent of a subject, using the IRB-approved consent form, must be obtained before that 
subject is submitted to any study procedure. Consent will be documented as required by the 
IRB.   

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14 Literature References 
 
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15.  Appendix A: Schedule of Events 
 
Baseline 
(May be split 
over 2 visits) 
Randomization 
& 
Trial1 
Trial 2 
Clinic Visit # 
0 
1 
2 
COVID-19 Screening 
Questionnaire (pre-visit) 
X 
X 
X 
Informed Consent 
X 
 
 
Urine Drug ScreenA 
X 
X 
X 
Locator Form  
X 
 
 
Demographics 
X 
 
 
Medical History 
X 
 
 
Physical Exam 
X 
 
 
MINI V 6.0 
X 
 
 
CBC w Diff 
AST, ALT, GGT, Tbili,  BUN, 
Ca, CO2, Cl, Cr, G K, Na, 
Triglycerides, Serum lipase, 
Ha1c 
X 
 
 
Vital Signs, weight, Blood 
Alcohol Levelb, c 
X 
X 
X 
ECG 
X 
 
 
Prior and Concomitant Meds 
X 
X 
X 
CIWA-AR 
X 
X 
X 
Eligibility Checklist 
 
X 
 
Confirm Eligibility to continue 
 
X 
X 
Urine Pregnancy Test   
X 
X 
X 
Birth control assessment 
X 
X 
X 
AEs 
X 
X 
X 
C-SSRS 
X 
X 
X 
Treatment Referral 
 
 
X 
TLFB (28 day at baseline) 
X 
X 
X 
Alcohol Craving VASc 
 
X 
X 
OCDSc 
X 
X 
X 
AUQc 
 
X 
X 
Nausea VAS  
 
X 
X 

The Effects of Exenatide, a GLP-1 Agonist, on Alcohol Self-Administration in Heavy Drinkers 
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Baseline 
(May be split 
over 2 visits) 
Randomization 
& 
Trial1 
Trial 2 
Clinic Visit # 
0 
1 
2 
Blood Glucose (at end of 
block2) 
 
X 
X 
 
A)  Test for opioids, cocaine, amphetamines, methamphetamine, tetrahydrocannabinol (THC), 
barbiturates, oxycodone, buprenorphine, methadone and benzodiazepines, and alcohol (Ethyl 
Glucuronide)  
B) if the  baseline visit is split between two days, vitals, breathalyzer, and weight are to be taken at each 
visit.  
c) See Table 2 for specific administration times   
 
Items highlighted in blue will be performed in-clinic remote. The study staff and subject will connect 
through video call while located in separate rooms in the Clinical Studies Unit to avoid unnecessary face-
to-face contact. Forms that must be filled out by the subject will be left on a clipboard in the exam room to 
be occupied by the subject, and study staff will instruct subjects to fill out the forms. Forms filled out by 
study staff through interviewing the subject will be kept in the study staff’s room. The COVID-19 screening 
questionnaire will be administered before the subject arrives for their in-clinic visit. 
 
Items highlighted in yellow will be performed with social distancing. The study staff and subject will be 
located in the same room, but will maintain a 6-foot distance and both persons will wear PPE at all times. 
 
Items highlighted in green require direct contact between study staff and subject. Contact will be limited to 
minimum necessary and PPE will be worn at all times by both study staff and subject. 

The Effects of Exenatide, a GLP-1 Agonist, on Alcohol Self-Administration in Heavy Drinkers 
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16.  Appendix B: Schedule of assessments during drinking lab 
 
 
 
Pre-
challenge 
Observation 
Self-
admin 
Block1 
Self-admin 
Block2 
Assessment 
 
 
 
 
BAC 
Prior to 
drug admin 
Every 10 
minutes 
Every 30 
minutes 
Every 30 
minutes 
VAS-Alcohol Craving 
Prior to 
drug admin 
Every 10 
minutes 
Every 30 
minutes 
Every 30 
minutes 
AUQ  
Prior to 
drug admin 
At end of 
observation 
Every 30 
minutes 
Every 30 
minutes 
OCDS 
Prior to 
drug admin 
None 
None 
None 
VAS-Nausea 
 
 
End of 
block 
End of 
block