Pharmacogenetic Study of Ondansetron in Alcohol Use Disorder

The primary study objective is to determine the efficacy of ondansetron (0.33 mg twice daily) administered orally for a period of 16 weeks in reducing risky drinking among currently drinking subjects with alcohol use disorder who have selected genotypes at the serotonin transporter and receptor genes. The secondary objective is to assess the safety and tolerability of ondansetron in subjects with alcohol use disorder who have selected genotypes at the serotonin transporter and receptor genes.

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.

Eligibility Criteria:
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 Time-Line Follow-Back (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 AUD
* 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-International Neuropsychiatric Interview (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 lactate 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 proportions

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