Matching Genotypes and Serotonergic Medications for Alcoholism

February 18, 2012 updated by: George Kenna, Brown University
Sertraline, a serotonin-specific reuptake inhibitor (SSRI) that increases basal serotonin levels, was shown to reduce alcohol consumption in lower risk/severity and later onset (LOA) but not higher risk/severity earlier onset alcoholic individuals (EOA). By contrast, ondansetron, a 5-HT3 receptor reduced alcohol consumption in EOAs but not LOAs. To explain this contrast in clinical efficacy, one approach suggests that differential serotonergic response is based on a functional polymorphism of the 5-HTTLPR promoter region of the serotonin re-uptake transporter (SERT). These alleles have typically been classified as biallelic genotypes: LL, SS and SL. The LL variant is postulated to be associated with EOA and the SS/SL variants associated with LOA. To test this hypothesis the investigators therefore propose to match and mismatch serotonergic treatments to genetic polymorphic variants [in 132 non-treatment seeking alcohol dependent volunteers] in a double-blind placebo controlled 2 x 2 design human laboratory study. The investigators propose to randomize non-treatment-seeking alcohol dependent persons based on their 5'-HTTLPR variant genotype (LL or SS/SL) into one of two counterbalanced arms: participants in the first arm (LL) will first receive one drug (either 200mg/day of sertraline or ondansetron 0.5mg/day) for three weeks followed by an alcohol self-administration experiment (ASAE), [with a 1 week down-titration period if sertraline received first, during the first week of the "placebo period"] then receive placebo for two more weeks (this will be a single-blind portion to use as a comparison group and to wash out the pharmacodynamic effects of the first drug) followed by a second ASAE. Participants will then receive the second drug for three weeks followed by a third ASAE [all will receive medication for an additional 1 week period and those receiving sertraline last will be down-titrated]. Participants in the second arm (SS/SL) will receive the same medications in the same balanced design. Individuals in both arms will receive weekly medication management to enhance medication adherence. The long-term objective of this research is to prospectively examine serotonergic treatment matching for alcohol dependence based on genotyping. Of equal importance, the investigators also recognize the strong contribution of additional genetic and environmental influences on alcohol consumption.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Medications and genetics have been identified as research priorities by NIAAA. The present application proposes to test two genetic-drug matching hypotheses to better understand heterogeneity among alcoholics. Previous basic science, treatment and genetic research suggests that active drinkers with the LL genetic variant of the serotonin transporter 5'-HTTLPR (a hypothesized genetic risk factor for early onset alcoholism) will respond better to ondansetron than sertraline or placebo. Conversely, active drinkers with the SS or SL genetic variant of the serotonin transporter 5'-HTTLPR (a hypothesized genetic risk factor for late onset alcoholism) will respond better to sertraline than ondansetron or placebo. The objective of this research is to match and mismatch serotonergic treatments to genetic polymorphic variants in a double-blind placebo controlled 2 x 2 design laboratory study where the 2 arms will be counterbalanced. The specific aims are to investigate: (1) whether LL-carriers receiving ondansetron results in a significant reduction in alcohol consumption during an alcohol self-administration experiment (ASAE) and during the period of treatment; (2) whether SL and SS-carriers receiving sertraline will result in a significant reduction in alcohol consumption during an ASAE and during the period of treatment; (3) examine mechanism of action for craving and subjective effects during the ASAE sessions: (4) whether there is a reduction in alcohol consumption during the ASAEs in the presence of the LG, and LA 5-HTTLPR variants and when LL participants receive ondansetron or when LL participants receive sertraline; (5) if the primary aims are moderated by the presence of the C (-1019) G polymorphism of the 5-HT1A gene promoter. We propose to randomize 132 non-treatment-seeking alcohol dependent participants based on their 5'-HTTLPR variant genotype (LL or SS/SL) into one of two counterbalanced arms: e.g. subjects in the first arm will first receive one drug (either 200mg/day of sertraline or ondansetron 0.5mg/day) for three weeks followed by an ASAE, then receive placebo for three weeks (this will be a single-blind portion to use as a comparison group and to wash out the pharmacodynamic effects of the first drug) followed by a second ASAE. Finally, participants will receive the second drug for three weeks followed by a third ASAE. Volunteers in the second arm will receive the same medications in a counter-balanced fashion. There will be a 1-week down titration after the first and third segments for all subjects. The long-term objective of this proposed research is to examine serotonergic treatment matching for alcohol dependence based on genotyping, and begin to investigate patient variation when matched prospectively with one serotonergic treatment or the other.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
79

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Rhode Island
      • Providence, Rhode Island, United States, 02912
        • Center for Alcohol and Addiction Studies

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

21 years to 65 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Must be between 21 and 65 years old (inclusive).
  2. Participants may be male or female and must be in good health as confirmed by medical history, baseline physical examination, ECG, laboratory tests, urinalysis and vital signs.

  3. Female participants must be:

    Postmenopausal for at least one year, surgically sterile, or Practicing an effective method of birth control before entry and throughout the study; have a negative urine pregnancy test at baseline screening and prior to the alcohol challenge sessions.

  4. Participants must understand that this is not a treatment study.
  5. A diagnosis of Alcohol dependence using Module E of the structured clinical interview for the DSM-IV (SCID). Alcohol dependent as defined by an AUDIT score ≥ 12 and men must consume ≥ 35 and women ≥ 28 standardized alcoholic beverages a week.
  6. Participants must be willing to take oral medication, adhere to the medication regimen and be willing to return for weekly visits and the alcohol challenge sessions.
  7. Participants must be able to read and comprehend written instructions and comprehend and complete all scale and inventories required by the protocol.
  8. Participants must have signed an informed consent indicating they understand the purpose of and procedures required for the study and willingness to participate.

Exclusion Criteria:

  1. Pregnancy or breast feeding women.
  2. Positive urine drug screen at baseline for any illegal substance other than marijuana.
  3. Participants will be excluded if they have: (a) clinically significant medical abnormalities (i.e. ECG, hematological assessment, bilirubin > 150% of the upper limit of normal or ALT or AST elevations >300% the upper limit of normal, biochemistry including urinalysis, electrolytes,). (Persons with medical conditions that are adequately controlled by their primary care physician will not be excluded.)
  4. Current use of psychotropic medications that cannot be discontinued
  5. Medical contraindications for use of sertraline or ondansetron
  6. Taking drugs that interfere with the metabolism of either drug that cannot be stopped per study physician.
  7. Allergic to sertraline or ondansetron
  8. Must have a breath alcohol concentration (BrAC) = 0.000 at the beginning of the alcohol challenge sessions.
  9. Creatinine clearance ≤ 60 dl/min.
  10. Individuals with a reasonable expectation of being institutionalized during the course of the trial or pending legal charges.
  11. Participants who have significant alcohol withdrawal symptoms (clinical institute withdrawal assessment for alcohol revised (CIWA-Ar) >10.
  12. lifetime depression or a history of suicide
  13. history of seizures (e.g. epilepsy) or migraine headaches -

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: DIAGNOSTIC
  • Allocation: RANDOMIZED
  • Interventional Model: SINGLE_GROUP
  • Masking: TRIPLE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
EXPERIMENTAL: Ondansetron, Placebo, Sertraline
LL-carriers receiving ondansetron compared to either placebo or sertraline, will result in a significant reduction in alcohol consumption.
Drug: Ondansetron and Sertraline
capsule 0.25mg twice a day for 21 days and capsule 100mg twice a day
EXPERIMENTAL: Sertraline, Placebo, Ondansetron
SL and SS-carriers receiving sertraline compared to either placebo or ondansetron, will result in a significant reduction in alcohol consumption.
Drug: Ondansetron and Sertraline
capsule 0.25mg twice a day for 21 days and capsule 100mg twice a day

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Number of drinks/day consumed
Time Frame: 13 weeks
To evaluate the efficacy of ondansetron for reducing drinking in participants who carry the LL variant of the serotonin transporter gene (5-HTTLPR): We hypothesize that LL-carriers receiving ondansetron compared to either placebo or sertraline, will result in a significant reduction in alcohol consumption.
13 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Number of Drinks/Day consumed.
Time Frame: 13 weeks
To evaluate the efficacy of sertraline for reducing drinking in participants who carry either the SL or SS variants of the 5-HTTLPR: We hypothesize that SL and SS-carriers receiving sertraline compared to either placebo or ondansetron, will result in a significant reduction in alcohol consumption.
13 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Brown University

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 1, 2008

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 1, 2012

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 1, 2012

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 27, 2010

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 28, 2010

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 29, 2010

Study Record Updates

Last Update Posted (ESTIMATE)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
February 22, 2012

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 18, 2012

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • AA016079-01A1

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