Human Laboratory Study of Varenicline for Alcohol Use Disorder

This study is a double-blind, randomized, placebo-controlled, parallel group, two-site study
designed to assess the effects of varenicline as compared with placebo on responses to in
vivo alcohol cue exposure in the human laboratory setting. After signing informed consent,
subjects will be screened for eligibility including medical history, physical examination,
vital signs, electrocardiogram (ECG), drinking history by the timeline follow-back (TLFB)
method, alcohol breathalyzer test, Clinical Institute Withdrawal Assessment for
Alcohol-revised (CIWA), medication use, MINI neuropsychiatric interview, urine toxicology
screen, clinical chemistry, response to cue reactivity, and Columbia Suicide Severity Rating
Scale (CSSR-S). Women of child-bearting potential will have a pregnancy test. If eligible for
the study, subjects will be randomized using a stratified permuted block randomization
procedure in an approximate 1:1 ratio (targeting 24 subjects per group - 12 subjects per
group per site) to receive either varenicline or placebo for 6 weeks. Any nicotine use versus
no use (cigarettes, cigars, chewing tobacco, electronic cigarettes, etc.) in the week before
randomization is the stratification variable.

Varenicline or matched placebo will be titrated over the first week of the study up the
maintenance dose of 1 mg (active) or two capsules (placebo) taken orally BID for an
additional 5 weeks. Subjects will be seen in the clinic at screening, at randomization and 6
other times during the study. A final follow-up telephone interview will occur during Week 9
(2 weeks after the end of study visit).

After the first two weeks and after five weeks of investigational product administration at
Study Week 3 and Study Week 6, respectively, subjects will undergo a cue reactivity paradigm
session (HLAB) including 4 individual visual analog scale (VAS) items assessing alcohol
craving, 2 VAS items assessing emotional reactivity to picture stimuli, and 2 items assessing
emotional manipulation. Immediately after the HLAB session, subjects will view each picture
again and record the emotion felt using the Self-Manikin Assessment (SAM). Other assessments
at baseline (prior to the first dose of investigational product) and/or during the
maintenance period include clinical chemistry, mood/behavior/thinking questions, blood for
medication compliance, vital signs, ECG, concomitant medications, CIWA-AR, pregnancy test and
birth control methods, drinking goal, adverse events (AEs), Alcohol Craving Questionnaire -
Short Form (ACQ-SF-R), Penn Alcohol Craving Scale (PACS), Fagerström Test for Nicotine
Dependence, smoking quantity/frequency, Pittsburg Sleep Quality Index (PSQI), and Profile Of
Moods State (POMS).

Inclusion Criteria:

To be eligible, the subject must:

- Be at least 21 years of age.

- Meet the DSM 5 criteria for alcohol use disorder of a least moderate severity
(AUD-MS).

- Be seeking treatment for AUD and desire a reduction or cessation of drinking.

- Be able to verbalize an understanding of the consent form, able to provide written
informed consent, verbalize willingness to complete study procedures, able to
understand written and oral instructions in English and able to complete the
questionnaires required by the protocol.

- Agree (if the subject is female and of child bearing potential) to use at least one of
the following methods of birth control, unless she is surgically sterile, partner is
surgically sterile or she is postmenopausal:

1. oral contraceptives,

2. contraceptive sponge,

3. patch,

4. double barrier (diaphragm/spermicidal or condom/spermicidal),

5. intrauterine contraceptive system,

6. levonorgestrel implant,

7. medroxyprogesterone acetate contraceptive injection,

8. complete abstinence from sexual intercourse, and/or

9. hormonal vaginal contraceptive ring.

- Be able to take oral medication and be willing to adhere to the medication regimen.

- Complete all assessments required at screening and baseline.

- Have a place to live in the 2 weeks prior to randomization and not be at risk that
s/he will lose his/her housing in the next 2 months.

- Not anticipate any significant problems with transportation arrangements or available
time to travel to the study site over the next 2 months.

- Not have any unresolved legal problems that could jeopardize continuation or
completion of the study.

- And others.

Exclusion Criteria:

- Contact site for additional information