Buproprion for Binge Drinking

The design is a 1:1 random assignment to placebo or bupropion XL (extended release)
(300mg/d). The study biostatistician, will prepare the randomization schedule and include
blocking by gender and nicotine dependence. Randomization will be based on a stratified block
design, with gender and nicotine dependence as the stratification variables with
medication/placebo randomly assigned in blocks of four.

Bupropion XL will be initiated at 150 mg/d on Days 1-4 and increased to 300 mg/d for Days
5-84. The University of North Carolina (UNC) Hospital's Investigational Drug Services (IDS)
will prepare opaque capsules containing bupropion XL 150/300 mg and matching placebo.
Capsules will be inserted into blister packs with each pack containing 1 week of medication.
The IDS will receive the randomization schedule from our statistician and prepare the blister
packs according to the blocked schedule with blocking for gender/nicotine dependence.

Recruitment, Telephone Screen, and Full Eligibility Screening: Subjects will initially be
prescreened by phone and then at full screening read and sign the informed consent. A
breathalyzer test will be administered (must be 0.00 gms/dl to give informed consent),
height, weight and BMI recorded and a medical history and examination completed.
Over-the-counter and prescription medication use will be recorded and nicotine use
documented. Complete Blood Count (CBC) with differential; serum bilirubin, Aspartate
Aminotransferase (AST), Alanine Aminotransferase (ALT), Gamma-Glutamyl Transferase (GGT,)
sodium, potassium, chloride, blood urea nitrogen, creatinine, glucose; and urinalysis and
urine toxicology completed. A carbohydrate deficient transferrin (CDT) sample will be drawn.
CDT samples will be stored frozen and then shipped in batches to Charleston, South Carolina
for assay. Women will be given a urine pregnancy test (Ub-HCG) at screening and at weeks 4,
8, and 12. Trained interviewers will conduct the psychiatric screening interview using the
M.I.N.I. . The Structured Clinical Interview (SCID) Substance Use Disorders Module to
establish Diagnostic and Statistical Manual (DSM-V) criteria for alcohol use disorders will
be administered by one of the study doctors. The study coordinator will conduct the
pretreatment 90-day Timeline Followback (TLFB) interview to identify amount of alcohol
consumed and timeframe of consumption. A binge drinking episode requires a minimum of 5/4
(men/women) standard drinks consumed over about a two hour period, i.e. consuming a bottle of
wine over five hours would not be coded as a binge drinking day. The Penn Alcohol Craving
Scale (PACS) and the University of Rhode Island Change Assessment (URICA) will be completed
and treatment goal—abstinence vs. reduction— recorded.

Initial Treatment Visit (within 21 days screening): Eligible individuals will not be required
to abstain from drinking alcohol prior to randomization. The study coordinator will
administer a breathalyzer test (BAC must be ≤0.04 gms/d) and complete assessments as outlined
in Table 1, Protection of Human Subjects. A salivary cotinine sample will be taken A 1-week
blister pack of bupropion-XL or placebo with written instructions will be dispensed from the
Investigational Drug Services according to the randomization block along with a 1-week
back-up blister pack in case of delayed appointments or lost doses. Bupropion-XL will be
titrated with 150 mg given daily for 4 days followed by 300 mg/d. Participants will be given
a calendar style diary to track pill taking, drinking quantity/timing, intoxication and any
side effects. Finally, participants will receive Medical Management from a trained clinician.

Subsequent Treatment Visits: TLFB and PACS are gathered each visit, cotinine samples at weeks
4, 8 and 12 and URICA at week 8. Medical monitoring will be conducted by study physicians and
will consist of review of vital signs, concomitant medication use, and general inquiries into
side effects. The physician may recommend that medication be held for a period of time to
deal with an adverse event, e.g. nausea. One month and three months following the last visit
subjects will be contacted by phone to update drinking (TLFB), adverse effects and
medications.

Medical Management Intervention: The psychosocial support for the study will be Medical
Management (MM). MM sessions average 10-15 minutes and focus on three main areas: (1)
feedback on consequences of drinking; (2) encouraging compliance with medication/addressing
compliance problems and (3) encouraging progress towards drinking goal— reduction or
abstinence are acceptable. 10% of sessions will be audiotaped and reviewed to enhance
fidelity.

Medication Compliance Monitoring: Participants will record their pill taking in
calendar-style diaries that will be provided and collected at each visit. Pills will be
distributed in blister packs that will be returned to the study coordinator to reconcile any
unused medication from the returned blister packs with participants' diary records.

Inclusion Criteria:

1. Men and women between the ages of 21 and 44 years.

2. A minimum of 5/3 (men/women) or more binge drinking episodes per month over the past
three months. A binge drinking episode is defined as the consumption of 5/4
(men/women) standard drinks (~12 gms ethanol) in about a two hour period. Subjects may
meet DSM-V criteria for mild or moderate alcohol use disorder.

3. Ability to understand and sign written informed consent.

4. Must have a 0.0 gms/dl breathalyzer reading on the day of screening and 0.0 gms/dl on
the day of randomization.

5. BMI ≥18.5 (normal weight or above)

6. Express a desire to achieve abstinence or to reduce alcohol consumption

7. Must have a stable residence and be able to identify an individual who could contact
participant if needed.

Exclusion Criteria:

1. Presence of physical dependence on alcohol as assessed by clear tolerance to alcohol
or alcohol withdrawal symptoms based on SCID interview or a Severe Alcohol Use
Disorder (>5 SCID DSM-V symptoms).

2. Bupropion is contraindicated in individuals with a history of bulimia or a seizure
disorder

3. Clinically significant medical disease that might interfere with the evaluation of the
study medication or present a safety concern (e.g., renal insufficiency, cirrhosis,
unstable hypertension, diabetes mellitus, seizure disorder). Clinically significant
psychiatric illness including any psychotic disorder, bipolar disorder,
anorexia/bulimia, severe depression, or suicidal ideation.

4. Other substance abuse or dependence disorder other than nicotine or cannabis abuse.

5. Concurrent use of anticonvulsants. Concurrent use of any psychotropic medication
including antidepressants, mood stabilizers, antipsychotics, anxiolytics, stimulants,
or hypnotics with the exception of stable doses of antidepressants for one month.
Bupropion is commonly added to antidepressants for augmentation so the use of another
antidepressant does not represent a safety concern. .Prior history of adverse reaction
to bupropion.

6. AST or ALT > 3.5 times Upper Limit of Normal (ULN) or bilirubin > 1.5 X ULN.

7. Positive urine toxicology screen with the exception of cannabis. Individuals with
positive cannabis screens will be excluded only if they have a history of cannabis
dependence.

8. Pregnant women and women of childbearing potential who do not practice a medically
acceptable form of birth control (oral or depot contraceptive, or barrier methods such
as diaphragm or condom with spermicidal).

9. Women who are breastfeeding.

10. Individuals requiring inpatient treatment or more intense outpatient treatment for
their alcohol problems.

11. Participation in any clinical trial within the past 60 days that would have safety
concerns for the trial.

12. Court-mandated participation in alcohol treatment or pending incarceration.