Alcohol Use Disorder
Conditions
Brief summary
The purpose of this study is to determine whether the catechol-O-methyltransferase (COMT) inhibitor tolcapone, relative to placebo, reduces alcohol drinking and alcohol cue-elicited brain activation and increases brain activation associated with cognitive control as a function of a participant's genotype at a polymorphism in the COMT gene.
Interventions
DRUGTolcapone
DRUGPlacebo
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Medical University of South Carolina
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
1. Age 21-40 (to focus on an age group still on a trajectory of increasing alcohol consumption). 2. Meets Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria for current Alcohol Use Disorder. 3. Currently not engaged in, and does not want treatment for, alcohol-related problems. 4. Able to read and understand questionnaires and informed consent. 5. Lives within 50 miles of the study site. 6. Able to maintain abstinence from alcohol for two days (without the aid of detoxification medications), as determined by self report and breathalyzer measurements.
Exclusion criteria
1. Current DSM-5 diagnosis of any other substance use disorder except Nicotine Use Disorder. 2. Any psychoactive substance use (except marijuana and nicotine) within the last 30 days, as indicated by self-report and urine drug screen. For marijuana, no use within the last seven days by verbal report and negative (or decreasing) urine tetrahydrocannibinol (THC) levels. 3. Current DSM-5 Axis I diagnosis, including major depression, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, bipolar affective disorder, schizophrenia, dissociative disorders, eating disorders, or any other psychotic or organic mental disorder. 4. Current suicidal ideation or homicidal ideation. 5. Need for maintenance or acute treatment with any psychoactive medication, including antiepileptic medications. 6. Currently taking medication known to affect alcohol intake (e.g., disulfiram, naltrexone, acamprosate, topiramate). 7. History of severe alcohol withdrawal (e.g., seizure, delirium tremens), as evidenced by self-report and assessment with Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar). 8. Clinically significant medical problems such as cardiovascular, renal, gastrointestinal, or endocrine problems that would impair participation or limit medication ingestion. 9. Past alcohol-related medical illness, such as gastrointestinal bleeding, pancreatitis, or peptic ulcer. 10. Current or past hepatocellular disease, as indicated by verbal report or elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than the upper limit of the normal range at screening. 11. Females of childbearing potential who are pregnant (by urine human chorionic gonadotropin), nursing, or who are not using a reliable form of birth control. 12. Current charges pending for a violent crime (not including drinking while intoxicated). 13. Lack of a stable living situation. 14. Presence of ferrous metal in the body, as evidenced by metal screening and self-report. 15. Severe claustrophobia or morbid obesity that preclude placement in the MRI scanner. 16. History of head injury with \> 2 minutes of unconsciousness.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Standard Drinks Per Day Consumed During Natural (Usual Environment) Conditions | Days 1-6 of study medication ingestion | Number of standard alcoholic drinks per day that participants reported consuming, as assessed by the Timeline Follow-back method. |
| Total Number of Drinks Under Controlled Conditions (Bar Lab) | 2 hours during the alcohol challenge procedure | Total number of drinks, out of 8 possible, that participants chose to consume in the bar laboratory after receipt of a priming drink, targeted by sex and body weight to produce a breath alcohol concentration of 0.03 g/dL. Each of the drinks that participants chose to consume was targeted to produce a breath alcohol concentration of 0.015 g/dL. Participants were given a bar credit of $16 with which to purchase drinks, at the cost of $2/drink, and were told that any money they did not spend would be given to them the following day. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cognitive-control-associated Brain Activation (fMRI) | 7 days--change between baseline and scan on day 7 | Magnitude of change between baseline and day 7 scan in the BOLD signal in the right inferior frontal gyrus to spatial working memory |
| Alcohol Cue-elicited Brain Activation (fMRI) | 7 days--change between baseline and scan on day 7 | Magnitude of change between baseline and day 7 scan in the right inferior frontal gyrus blood oxygenation level dependent (BOLD) signal to alcohol cues, relative to neutral beverage cues (alcohol cue reactivity task described in Schacht et al., 2013, Neuropsychopharmacology) |
Countries
United States
Participant flow
Pre-assignment details
Participants were genotyped for the COMT rs4680 single nucleotide polymorphism and subsequently randomized, on the basis of their rs4680 genotype, to take tolcapone or placebo for eight days. Outcomes were the number of standard alcoholic drinks consumed during Days 1-6 (Natural Drinking Period), alcohol cue-elicited brain activation on Day 7 (Neuroimaging), and the number of drinks, out of 8 possible, that participants chose to self-administer in the lab on Day 8 (Bar Laboratory).
Participants by arm
| Arm | Count |
|---|---|
| Placebo/rs4680 Val/Val Placebo three times per day for eight days
Individuals with the rs4680 val/val genotype | 16 |
| Tolcapone/rs4680 Val/Val Tolcapone 100 mg three times per day for three days Tolcapone 200 mg three times per day for five days
Individuals with the rs4680 val/val genotype | 12 |
| Placebo/rs4680 Val/Met Placebo three times per day for eight days
Individuals with the rs4680 val/met genotype | 17 |
| Tolcapone/rs4680 Val/Met Tolcapone 100 mg three times per day for three days Tolcapone 200 mg three times per day for five days
Individuals with the rs4680 val/met genotype | 16 |
| Placebo/rs4680 Met/Met Placebo three times per day for eight days
Individuals with the rs4680 met/met genotype | 15 |
| Tolcapone/rs4680 Met/Met Tolcapone 100 mg three times per day for three days Tolcapone 200 mg three times per day for five days
Individuals with the rs4680 met/met genotype | 14 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Bar Laboratory | Adverse Event | 1 | 0 | 2 | 0 | 1 | 0 |
| Bar Laboratory | Procedure not done due to COVID-19 pandemic | 0 | 5 | 5 | 3 | 5 | 1 |
| Bar Laboratory | Protocol Violation | 0 | 0 | 0 | 1 | 0 | 0 |
| Natural Drinking Period | Adverse Event | 1 | 0 | 0 | 1 | 0 | 0 |
| Natural Drinking Period | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 |
| Neuroimaging | Motion artifacts in imaging data | 1 | 0 | 1 | 0 | 1 | 0 |
| Neuroimaging | Not scanned | 0 | 0 | 1 | 0 | 0 | 2 |
| Neuroimaging | Protocol Violation | 2 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo/rs4680 Met/Met | Tolcapone/rs4680 Met/Met | Total | Tolcapone/rs4680 Val/Met | Placebo/rs4680 Val/Met | Tolcapone/rs4680 Val/Val | Placebo/rs4680 Val/Val |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 26.3 years STANDARD_DEVIATION 5.2 | 25.3 years STANDARD_DEVIATION 5.7 | 26.5 years STANDARD_DEVIATION 5.1 | 26.3 years STANDARD_DEVIATION 5 | 25.7 years STANDARD_DEVIATION 4.7 | 29.3 years STANDARD_DEVIATION 4.7 | 26.9 years STANDARD_DEVIATION 5.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 4 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 7 Participants | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 12 Participants | 79 Participants | 14 Participants | 15 Participants | 11 Participants | 12 Participants |
| Region of Enrollment United States | 15 participants | 14 participants | 90 participants | 16 participants | 17 participants | 12 participants | 16 participants |
| Sex: Female, Male Female | 6 Participants | 9 Participants | 37 Participants | 6 Participants | 5 Participants | 6 Participants | 5 Participants |
| Sex: Female, Male Male | 9 Participants | 5 Participants | 53 Participants | 10 Participants | 12 Participants | 6 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 12 | 0 / 17 | 0 / 16 | 0 / 15 | 0 / 14 |
| other Total, other adverse events | 1 / 16 | 0 / 12 | 0 / 17 | 1 / 16 | 0 / 15 | 0 / 14 |
| serious Total, serious adverse events | 0 / 16 | 0 / 12 | 0 / 17 | 0 / 16 | 0 / 15 | 0 / 14 |
Outcome results
Primary
Total Number of Drinks Under Controlled Conditions (Bar Lab)
Total number of drinks, out of 8 possible, that participants chose to consume in the bar laboratory after receipt of a priming drink, targeted by sex and body weight to produce a breath alcohol concentration of 0.03 g/dL. Each of the drinks that participants chose to consume was targeted to produce a breath alcohol concentration of 0.015 g/dL. Participants were given a bar credit of $16 with which to purchase drinks, at the cost of $2/drink, and were told that any money they did not spend would be given to them the following day.
Time frame: 2 hours during the alcohol challenge procedure
Population: Due to the COVID-19 pandemic and the need for social distancing, a protocol amendment was required to remove the bar lab procedure. Thus, this outcome was assessed for only the first 63 participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo/rs4680 Val/Val | Total Number of Drinks Under Controlled Conditions (Bar Lab) | 5.353 Drinks | Standard Error 0.721 |
| Tolcapone/rs4680 Val/Val | Total Number of Drinks Under Controlled Conditions (Bar Lab) | 3.256 Drinks | Standard Error 0.955 |
| Placebo/rs4680 Val/Met | Total Number of Drinks Under Controlled Conditions (Bar Lab) | 5.01 Drinks | Standard Error 0.812 |
| Tolcapone/rs4680 Val/Met | Total Number of Drinks Under Controlled Conditions (Bar Lab) | 4.964 Drinks | Standard Error 0.752 |
| Placebo/rs4680 Met/Met | Total Number of Drinks Under Controlled Conditions (Bar Lab) | 1.68 Drinks | Standard Error 0.935 |
| Tolcapone/rs4680 Met/Met | Total Number of Drinks Under Controlled Conditions (Bar Lab) | 4.732 Drinks | Standard Error 0.704 |
Comparison: Analysis was an ANCOVA testing the interaction between rs4680 genotype and medication groupp-value: 0.014ANCOVA
Primary
Total Number of Standard Drinks Per Day Consumed During Natural (Usual Environment) Conditions
Number of standard alcoholic drinks per day that participants reported consuming, as assessed by the Timeline Follow-back method.
Time frame: Days 1-6 of study medication ingestion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo/rs4680 Val/Val | Total Number of Standard Drinks Per Day Consumed During Natural (Usual Environment) Conditions | 6.018 standard drinks per day | Standard Error 0.586 |
| Tolcapone/rs4680 Val/Val | Total Number of Standard Drinks Per Day Consumed During Natural (Usual Environment) Conditions | 3.534 standard drinks per day | Standard Error 0.668 |
| Placebo/rs4680 Val/Met | Total Number of Standard Drinks Per Day Consumed During Natural (Usual Environment) Conditions | 3.998 standard drinks per day | Standard Error 0.538 |
| Tolcapone/rs4680 Val/Met | Total Number of Standard Drinks Per Day Consumed During Natural (Usual Environment) Conditions | 5.012 standard drinks per day | Standard Error 0.567 |
| Placebo/rs4680 Met/Met | Total Number of Standard Drinks Per Day Consumed During Natural (Usual Environment) Conditions | 5.271 standard drinks per day | Standard Error 0.596 |
| Tolcapone/rs4680 Met/Met | Total Number of Standard Drinks Per Day Consumed During Natural (Usual Environment) Conditions | 5.949 standard drinks per day | Standard Error 0.602 |
Comparison: Analysis was an ANCOVA testing the interaction between rs4680 genotype and medication group.p-value: 0.013ANCOVA
Other Pre-specified
Alcohol Cue-elicited Brain Activation (fMRI)
Magnitude of change between baseline and day 7 scan in the right inferior frontal gyrus blood oxygenation level dependent (BOLD) signal to alcohol cues, relative to neutral beverage cues (alcohol cue reactivity task described in Schacht et al., 2013, Neuropsychopharmacology)
Time frame: 7 days--change between baseline and scan on day 7
Population: Participants who completed both fMRI scans and had usable scan data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo/rs4680 Val/Val | Alcohol Cue-elicited Brain Activation (fMRI) | 0.09 Arbitrary units (Day 7 minus Baseline) | Standard Error 0.07 |
| Tolcapone/rs4680 Val/Val | Alcohol Cue-elicited Brain Activation (fMRI) | -0.045 Arbitrary units (Day 7 minus Baseline) | Standard Error 0.07 |
| Placebo/rs4680 Val/Met | Alcohol Cue-elicited Brain Activation (fMRI) | 0.066 Arbitrary units (Day 7 minus Baseline) | Standard Error 0.063 |
| Tolcapone/rs4680 Val/Met | Alcohol Cue-elicited Brain Activation (fMRI) | -0.164 Arbitrary units (Day 7 minus Baseline) | Standard Error 0.063 |
| Placebo/rs4680 Met/Met | Alcohol Cue-elicited Brain Activation (fMRI) | 0.138 Arbitrary units (Day 7 minus Baseline) | Standard Error 0.07 |
| Tolcapone/rs4680 Met/Met | Alcohol Cue-elicited Brain Activation (fMRI) | .006 Arbitrary units (Day 7 minus Baseline) | Standard Error 0.07 |
p-value: 0.83Mixed Models Analysis
p-value: 0.026Mixed Models Analysis
Other Pre-specified
Cognitive-control-associated Brain Activation (fMRI)
Magnitude of change between baseline and day 7 scan in the BOLD signal in the right inferior frontal gyrus to spatial working memory
Time frame: 7 days--change between baseline and scan on day 7
Population: Participants who completed both fMRI scans and had usable data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo/rs4680 Val/Val | Cognitive-control-associated Brain Activation (fMRI) | -0.196 Arbitrary units (Day 7 minus Baseline) | Standard Error 0.086 |
| Tolcapone/rs4680 Val/Val | Cognitive-control-associated Brain Activation (fMRI) | -0.063 Arbitrary units (Day 7 minus Baseline) | Standard Error 0.082 |
| Placebo/rs4680 Val/Met | Cognitive-control-associated Brain Activation (fMRI) | -0.178 Arbitrary units (Day 7 minus Baseline) | Standard Error 0.074 |
| Tolcapone/rs4680 Val/Met | Cognitive-control-associated Brain Activation (fMRI) | 0.076 Arbitrary units (Day 7 minus Baseline) | Standard Error 0.076 |
| Placebo/rs4680 Met/Met | Cognitive-control-associated Brain Activation (fMRI) | -0.017 Arbitrary units (Day 7 minus Baseline) | Standard Error 0.082 |
| Tolcapone/rs4680 Met/Met | Cognitive-control-associated Brain Activation (fMRI) | -0.224 Arbitrary units (Day 7 minus Baseline) | Standard Error 0.086 |
p-value: 0.062Mixed Models Analysis