Pharmacogenetic Study of Ondansetron in Alcohol Use Disorder

NCT02354703 | Completed Phase 2 Results DMC

• 1 other identifier: HP00061575
• Study Type: interventional
• Target: 293
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Alcohol Use Disorder

Keywords

alcoholism, treatment, serotonin transporter

Outcome Measures

Primary Outcomes (1)

• Drinks Per Drinking Day

  self-reported number of standard drinks of alcohol (14 g alcohol) consumed per drinking day

  16-week treatment period

Secondary Outcomes (2)

• Percent Drinking Days

  16-week treatment period

• Percent Heavy Drinking Days

  16-week treatment period

Study Arms (4)

ondansetron-responsive genotype

EXPERIMENTAL

ondansetron-0.33 mg bid + Brief Behavioral Compliance Enhancement Treatment (BBCET) for 16 weeks and carrying one of the following genotypes: if European ancestry: SLC6A4 gene: 5-HTTLPR:LL, or rs25531:AA, or 5-HTTLPR + rs25531 (LALA genotype) or rs1042173:TT HTR3A gene: rs1150226:AG; or rs1176713:GG HTR3B gene: rs17619942:AC If African ancestry: HTR3B gene: rs176744: CC or CA SLC6A4 gene: 5-HTTLPR:LL, or rs25531:AA, or 5-HTTLPR + rs25531 (LALA genotype) or rs1042173:TT

Drug: Ondansetron

ondansetron--non-responsive genotype

EXPERIMENTAL

ondansetron-0.33 mg bid + Brief Behavioral Compliance Enhancement Treatment (BBCET) for 16 weeks and NOT carrying any of the responsive genotypes

Drug: Ondansetron

placebo--responsive genotype

PLACEBO COMPARATOR

placebo bid + Brief Behavioral Compliance Enhancement Treatment (BBCET) for 16 weeks and carrying one of the following genotypes: if European ancestry: SLC6A4 gene: 5-HTTLPR:LL, or rs25531:AA, or 5-HTTLPR + rs25531 (LALA genotype) or rs1042173:TT HTR3A gene: rs1150226:AG; or rs1176713:GG HTR3B gene: rs17619942:AC If African ancestry: HTR3B gene: rs176744: CC or CA SLC6A4 gene: 5-HTTLPR:LL, or rs25531:AA, or 5-HTTLPR + rs25531 (LALA genotype) or rs1042173:TT

Drug: Placebo

placebo--non-responsive genotype

PLACEBO COMPARATOR

placebo bid + Brief Behavioral Compliance Enhancement Treatment (BBCET) for 16 weeks and NOT carrying any of the responsive genotypes

Drug: Placebo

Interventions

Ondansetron DRUG

Ondansetron (0.33 mg) bid+ BBCET counseling

ondansetron--non-responsive genotype; ondansetron-responsive genotype

Placebo DRUG

Placebo + BBCET counseling

placebo--non-responsive genotype; placebo--responsive genotype

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• 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
• 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 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

Sponsors & Collaborators

• University of Maryland, Baltimore: lead
• University of Pennsylvania: collaborator

Study Sites (3)

MPRC

Baltimore, Maryland, 21228, United States

Location

University of Pennsylvania Treatment Research Center

Philadelphia, Pennsylvania, 19103, United States

Location

Philadelphia VAMC

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Conditions

Alcoholism

Interventions

Ondansetron

Condition Hierarchy (Ancestors)

Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring

Limitations and Caveats

The pre-specified enrollment target of 256 participants starting treatment was calculated to detect a difference in change in drinks per drinking day between ondansetron and placebo groups at an effect size of 0.59 with a power of 0.84. The achieved enrollment of 95 participants was substantially below this pre-specified target.

Results Point of Contact

• Title: Dr. David Gorelick
• Organization: University of Maryland School of Medicine

dgorelick@som.umaryland.edu

410-408-6806

Study Officials

• David A Gorelick, MD, PhD

  University of Maryland, Baltimore

  PRINCIPAL INVESTIGATOR

• Henry R Kranzler, MD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: treatment assignment and genotype classification known only to research pharmacist and study biostatistician who performed randomization.
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: 2 x 2 factorial design: treatment intervention (active, placebo) x genotype (responsive, non-responsive)

Study Record Dates

• First Submitted: January 23, 2015
• First Posted: February 3, 2015
• Study Start: August 1, 2015
• Primary Completion: March 31, 2020
• Study Completion: March 31, 2020
• Last Updated: January 14, 2022
• Results First Posted: January 14, 2022

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)