Pharmacogenetic Study of Ondansetron in Alcohol Use Disorder
Condition: Alcohol Use Disorder
MeSH terms: Alcoholism; Alcohol Drinking
Intervention: Ondansetron; Placebo
Intervention description: Ondansetron (0.33 mg) bid+ BBCET counseling; Placebo + BBCET counseling
Intervention MeSH terms: Ondansetron
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Factorial Assignment
Intervention model description: 2 x 2 factorial design: treatment intervention (active, placebo) x genotype (responsive, non-responsive)
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: treatment assignment and genotype classification known only to research pharmacist and study biostatistician who performed randomization.
Enrollment: 293.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: alcoholism, treatment, serotonin transporter

Summary:

      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.
    

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)