Pharmacogenetic Study of Ondansetron in Alcohol Use Disorder

Alcohol use disorder (AUD) is a heterogeneous and chronic relapsing disorder that includes
both acute (binge drinking) and chronic (frequent heavy drinking) dimensions. Perhaps because
of this heterogeneity, the therapeutic effect size of the approved medicines for the
treatment of AUD has been small. In an effort to overcome the heterogeneity of response to a
particular medication, recent studies have instituted a personalized approach to therapy.
Major breakthroughs in pharmacogenetics have made it possible to identify discrete subgroups
of the AUD population according to genetic profiles in order to target the subjects who are
most likely to respond to treatment with a particular agent. In addition, genetic variation
contributing to the risk of alcohol dependence may be differentially associated with
treatment response Thus a successful personalized medicinal approach should ensure that
targeted subgroups achieve an optimal treatment response with high predictability. Such an
approach holds the potential to identify not only robust responders to treatment but also
those who might have minimal or modest adverse effects from the putative therapeutic
medication. From a practical clinical standpoint, a personalized medicine approach starts
with a genetic screen to identify the "right" subject, who can then be treated with the
appropriate medication, with a high probability of a positive treatment outcome and,
therefore, a substantial impact on public health.

Inclusion Criteria:

- Men and women who have given written informed consent

- Aged 18 to 70

- The subject has a breath alcohol concentration (BrAC) = 0.00% at the screening visit
and < or = 0.02% at all visits after the screening visit

- Diagnosis of alcohol use disorder (AUD) using Diagnostic and Statistical Manual of
Mental Disorders, 5th Edition (DSM-5) criteria

- Able to provide TLFB alcohol consumption information for the 90-day period prior to
the Screen Visit.

- During the 4 weeks preceding the Baseline Visit, the subject reports:

- ≥6 Heavy Drinking Days (HDDs) - defined as a day with alcohol consumption of ≥5
standard drinks (i.e., 12 g of ethanol) for men, and ≥ 4 standard drinks for
women

- ≤14 consecutive abstinent days

- Total alcohol consumption of an average of ≥21 standard drinks/week for men and
≥14 standard drinks/week for women in past 28 days and have met these criteria
during the 7 days prior to randomization

- An expressed wish to reduce or stop drinking

- Willingness to participate in behavioral and medicinal treatments for Alcohol Use
Disorder

- Stable residence in the 28 days prior to the Baseline Visit and no plans to move in
the next 9 months. A stable residence is a domicile in which an individual can operate
as if it were his or her own homestead and does not include shelters or halfway
houses.

- Provides contact information for 1 or 2 "locators" who can be used to contact the
subject

- Able to read and understand English and complete the rating scales and questionnaires
accurately, follow instructions, and make use of the behavioral treatments. This will
be assessed with the Slosson Oral Reading Test-Revised, on which the subject must
demonstrate at least a 6th grade reading level.

- If the subject is a woman of child-bearing age, she must:

- Agree not to try to become pregnant during the study, and use adequate contraception
(defined as oral/ systemic contraception, intrauterine device, diaphragm in
combination with spermicide, or condom for male partner in combination with
spermicide) or

- Be postmenopausal, (i.e., have had her last natural menstruation at least 24 months
prior to baseline) or

- Have had a hysterectomy or been surgically sterilized prior to the Baseline Visit, or

- Plan not to be sexually active vaginally with men during the entire duration of the
trial.

Exclusion Criteria:

- A subject presenting with any of the following at the Baseline Visit will be excluded
from the study:

- The subject has fewer than 6 heavy drinking days (HDD) (defined as ≥5 standard
drinks for men and ≥4 or greater standard drinks for women) in the 4 weeks
preceding the Baseline Visit.

- The subject has greater than 14 consecutive abstinent days in the 4 weeks
preceding the Baseline Visit.

- The subject has a Clinical Institute Withdrawal Assessment for Alcohol Scale
(CIWA-Ar), Revised, score ≥10

- The subject has a current diagnosis of schizophrenia, bipolar disorder, or other
psychotic disorder, or a non-psychotic diagnosis such as major depressive
disorder, post-traumatic stress disorder, panic disorder, eating disorder, or
substance use disorder (except alcohol, tobacco, or cannabis) that is judged by
the PI or designee as exclusionary.

- Current or recent (within 4 weeks prior to Baseline Visit) treatment with
antipsychotics or any medication likely to interact with ondansetron to produce
an adverse effect, as judged by a study physician.

- Treatment with any investigational medicinal product within 30 days or 5
half-lives (whichever is longer) prior to Randomization.

- Currently participating or has recently (4 weeks prior to Randomization)
participated in a treatment program for alcohol use disorders.

- MINI 6.0 Suicide Risk Assessment module B will be used to assess subjects' risk
of suicide. A score of > or = 9 will be evaluated by the PI or designee to
determine eligibility. Subjects who are deemed by the PI or designee to be at
risk of suicide will be excluded.

- Clinically significant, unstable physical illness (e.g., hematologic, hepatic or
renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine,
neurological, infectious, neoplastic, or metabolic disturbance), as judged by the
PI or designee to be exclusionary

- Clinically significant abnormal vital signs, as judged by the PI or designee

- Clinically significant abnormal 12-lead ECG at the Screen Visit, clinically
significant cardiovascular disease requiring regular or intensive clinical
monitoring, a current history of arrhythmias, or a current or past history of
clinically significant QT prolongation, including: QTcF > 450 ms (average of 3
12-lead measurements)

- Serum potassium, magnesium or calcium levels outside the central
laboratory's reference range that are deemed clinically significant by the
PI or designee.

- Taking medications (within the last 7 days prior to the Baseline Visit) that
have the potential to prolong the QT interval, as judged by a study
physician, or may require such medications during the course of the study.
For patients taking these medications, a study physician will evaluate the
potential for ondansetron to interact with the medication to produce a
clinically significant risk for the participant.

- Clinically unstable cardiac disease, including unstable atrial fibrillation,
symptomatic bradycardia, unstable congestive heart failure, active
myocardial ischemia or indwelling cardiac pacemaker

- Complete left bundle branch block

- History of Long QT Syndrome or a first-degree biological family member with
this condition

- Evidence of hepatic failure and/or ascites, prolonged prothrombin time
(International Normalized Ratio [INR] > or = 1.7), bilirubin >10% above the upper
limit of the central lab's normal range and/or esophageal variceal disease

- Active hepatitis and/or serum glutamic oxaloacetic transaminase (SGOT), serum
glutamic pyruvic transaminase (SGPT) or lactacte dehydrogenase (LDH) > 3x the
upper limit of normal

- Treatment, either current or within 28 days prior to Randomization, with any
medications having a potential effect on alcohol consumption and related
behaviors or mood. These include opioid antagonists (e.g., naltrexone, Vivitrol®,
Selincro®), glutamate antagonists (e.g., acamprosate), anticonvulsants (e.g.,
topiramate, gabapentin), serotonin reuptake inhibitors (e.g., fluoxetine),
serotonin antagonists (e.g., buspirone), other antidepressants (e.g., tricyclic
antidepressants or monoamine oxidase inhibitors), dopamine antagonists (e.g.,
haloperidol), and disulfiram (Antabuse®)

- At the Screen Visit, the subject's urine contains opiates, cocaine, amphetamines,
barbiturates, or benzodiazepines that cannot be explained by appropriate use of
prescribed medication

- History of severe or life-threatening adverse reactions to ondansetron

- Female subjects of childbearing potential who have a positive pregnancy test at
Baseline Visit or are pregnant, breast feeding, not adhering to an acceptable
form of contraception at screening or any time during the study, or unwilling to
maintain an acceptable form of contraception throughout the study

- Prior to Randomization, the subject is compelled to participate in an alcohol
treatment program to maintain his/her liberty

- As of Screen Visit, the subject is sharing a household with a subject randomized
to any investigational trial of ondansetron

- Any other condition or therapy that, in the investigator's opinion, may pose a
risk to the subject, prevent the subject from completing the required study
procedures or interfere with the study objectives • Less than 75% European
ancestry proportions or African-American ancestry porportions

- Body weight greater than or equal to 110 kg (242 lb)