Alcoholism
Conditions
Keywords
Alcoholism, Heavy Drinking, Perampanel
Brief summary
The purpose of this study is to determine whether perampanel alters the response to alcohol for heavy drinkers. It is hypothesized that perampanel will reduce the rewarding and reinforcing properties of alcohol in the laboratory setting.
Detailed description
The main goal of the proposed study is to determine whether the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor (AMPA-R) antagonist perampanel alters the response to ethanol (i.e., the rewarding and reinforcing effects) using a validated laboratory paradigm of intravenous (IV) ethanol infusion. Fifty non-treatment seeking heavy drinkers (NTSHDs), N=50, and twenty-five social drinkers (N=25) will undergo three test days each: once after receiving a placebo medication, once after receiving moderate dose perampanel, and once after receiving a higher dose of perampanel. This experiment is the first step in a series of expedient studies that will rapidly determine perampanel's potential as a treatment for alcohol dependence. If findings show perampanel reduces the rewarding and reinforcing properties of alcohol in the laboratory setting (in humans), it would provide a strong rationale for clinical treatment trials with this medication. This approach is innovative because it tests a highly novel AMPA-R antagonist for the treatment of alcoholism, and uses a state-of-the-art computer assisted IV alcohol pump infusion system (called CAIS) to reduce variability in blood alcohol concentrations, thus improving the data quality.
Interventions
DRUGPerampanel
Perampanel is a noncompetitive (allosteric) antagonist of the AMPA-R that is well-absorbed (100% bioavailability), has good blood-brain-barrier penetration, and rapidly reaches peak plasma concentrations (1 hour). To date, there have been no clinical trials of AMPA-R antagonists (e.g., perampanel) for the treatment of alcoholism.
DRUGPlacebo
Placebo given in place of perampanel during the pre-treatment period and lab session days.
Sponsors
University of Connecticut
Yale University
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Virginia Commonwealth University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* males and females * between the ages of 21 and 55 years; * Nontreatment-seeking Heavy Drinkers (NTSHDs)as defined above, and must have had at least 5 Standard Drinks (SD) in one day on at least some occasions in the past and been able to tolerate it without an adverse reaction * generally medically and neurologically healthy on the basis of history, physical examination, Electrocardiogram, screening laboratory results (Complete Blood Count w/ differential, Thyroid Stimulating Hormone, Free-T4, Aspartate Transferase, Alanine Transferase, Gamma-Glutamyl Transferase, Blood Urea Nitrogen, creatinine, electrolytes, urinalysis, beta-Human Chorionic Gonadotropin). Individuals with Liver Function Tests (LFT) that are no more than 3 times above the normal levels will be included; * women with a negative pregnancy test and not nursing, must be regularly using birth control * negative breath alcohol at screening and on each test day; * not taking any psychoactive medication or opioids (in past 30-days); * are non-treatment seeking.
Exclusion criteria
* they need detoxification determined by a Clinical Institute Withdrawal Assessment (CIWA) score of \>8 or have had a history of alcohol detoxification in the past; * have been in treatment for an alcohol problem within the last 6 months, or if the severity of their alcohol problem based on the research physician's assessment warrants definitive treatment; * meet criteria for Diagnostic Statistical Manual (DSM) -IV psychiatric and substance use disorder diagnosis (other than alcohol abuse/dependence, cannabis abuse/dependence and nicotine dependence; those diagnoses will be allowed; participants can be either smokers up to 1 pack per day or non-smokers) based on history and psychiatric evaluation that includes a structured diagnostic interview (Structured Clinical Interview for DSM-IV Axis I Disorders: SCID) * unwillingness to remain alcohol-free 12 hours prior to test days; * have a significant ongoing serious medical condition such as Diabetes Mellitus, liver disease (see above LFT guideline), renal disease (as evidenced by serum creatinine above our laboratory's reference limit of 1.7 mg/dL, or have a history of adverse reaction to IV placement/blood draw
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Biphasic Alcohol Effects Scale (BAES): Stimulant Subscale | 98 minutes | A 14-item scale with 7 items designed to assess stimulant effects from alcohol intoxication and 7 items developed to measure the sedative effects of alcohol. This scale was selected as a primary outcome measure because it is sensitive to the effect of alcohol. This outcome item reports the Stimulant Subscale results analyzed with mixed models. Each item can be scored a minimum of zero (0) or up to 10 with the 10 representing feeling more or the most intoxicated in that item's description (e.g., excited). The minimum score is 0 and the maximum score is 70. For the time frame, the values at different time points were combined (averaged) into a single value that represents the effect during the time interval of interest (12 to 110 minutes). |
| Biphasic Alcohol Effects Scale (BAES)- Sedative Subscale | 98 minutes | A 14-item scale with 7 items designed to assess stimulant effects from alcohol intoxication and 7 items developed to measure the sedative effects of alcohol. This scale was selected as a primary outcome measure because it is sensitive to the effect of alcohol. This entry item show the results for the sedative subscale evaluated in mixed models. Each item can be scored a minimum of zero (0) or up to 10 with the 10 representing feeling more or the most intoxicated in that item's description (e.g., sedated). The minimum score is 0 and the maximum score is 70. For the time frame, the values at different time points were combined (averaged) into a single value that represents the effect during the time interval of interest (12 to 110 minutes). |
| Drug Effects Questionaire (DEQ) | 98 min | consists of four items that measure current alcohol effects: 'feel alcohol', 'feel high', 'like alcohol', and 'want more alcohol'. For the time frame, the values at different time points were combined (averaged) into a single value that represents the effect during the time interval of interest (12 to 110 minutes). There are five items on the scale with scores of 0 to 100, and the total score is used by averaging all five items, thus, the minimum total score on the scale is 0 and the maximum is 100. The lowest score 0 represents not at all or not experiencing any drug effects from alcohol, and 100 represents extremely experiencing alcohol effects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Alcohol Urge Questionnaire (AUQ) | 98 min | A valid eight-item Likert-type scale designed to assess acute alcohol craving. Each item is scored on a 1 to 7 scale (Strongly Disagree = 1 and Strongly Agree = 7). Items 2 and 7 are reverse scored. A total score is computed by averaging the item scores. Higher scores reflect greater craving. The minimum score is 7, and the maximum is 49. For the time frame, the values at different time points were combined (averaged) into a single value that represents the effect during the time interval of interest (12 to 110 minutes). |
| Side Effect Questionnaire (SEQ) | 98 minutes | This consists of a list of side effects associated with perampanel (e.g., fatigue, dizziness), rated from 0=none to 4=severe. The mean for each subject across all items is included in each group/arm mean. The lowest score on the scale would be 0 and the maximum 4, as the mean across items is taken and not a sum. For the time frame, the values at different time points were combined (averaged) into a single value that represents the effect during the time interval of interest (12 to 110 minutes). |
| Profile of Mood States (POMS) 2 Short Version Total Score | 98 minutes | The Profile of Mood States (POMS) 2 short version contains a subset of 35 items from the full-length versions. This subset comprises those five items on full version POMS scale that exhibited good item-total correlations and best predicted their respective scale scores, this is a TOTAL score Representing total mood disturbance. For the time frame, the values at different time points were combined (averaged) into a single value that represents the effect during the time interval of interest (12 to 110 minutes). The minimum is 0 and the maximum is 100 with higher numbers indicating greater mood disturbance. |
Countries
United States
Participant flow
Pre-assignment details
random assignment. Crossover
Participants by arm
| Arm | Count |
|---|---|
| Combined Group Crossover Study - Placebo/6mg/10mg Crossover design with all participants completing three conditions. Participants will have 3 test days each, 2 weeks apart, in a randomized order, following either pretreatment with daily perampanel 2mg days prior to each test day, and then observed dosing moderate 6mg dose perampanel in the lab 1 hour before a one-time alcohol infusion . Each lab session occurs exactly a week after starting the medication for that round. The wash out period between lab test session phases will be 7-10 days. Subjects will receive 2 days of 2mg perampanel after each lab to taper down (included in the washout period). The next appointment will be brief at the start of the next phase, at which point the next week of low dose perampanel or placebo will be started. With the washout period and the 7 day taper of the next phase, the actual lab sessions will occur 14-17 days apart. All test days will involve administration of alcohol with the same 3 target doses (target BrAc=20mg%, 60mg%, and 100mg%) in a step-wise fashion.
Perampanel: Perampanel is a noncompetitive (allosteric) antagonist of the AMPA-R that is well-absorbed (100% bioavailability), has good blood-brain-barrier penetration, and rapidly reaches peak plasma concentrations (1 hour). To date, there have been no clinical trials of AMPA-R antagonists (e.g., perampanel) for the treatment of alcoholism. | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 | 4 | 0 | 2 |
Baseline characteristics
| Characteristic | Combined Group Crossover Study - Placebo/6mg/10mg |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants |
| Age, Continuous | 28.1 years STANDARD_DEVIATION 8.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 22 | 0 / 22 |
| other Total, other adverse events | 4 / 22 | 1 / 22 | 4 / 22 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 | 0 / 22 |
Outcome results
Primary
Biphasic Alcohol Effects Scale (BAES)- Sedative Subscale
A 14-item scale with 7 items designed to assess stimulant effects from alcohol intoxication and 7 items developed to measure the sedative effects of alcohol. This scale was selected as a primary outcome measure because it is sensitive to the effect of alcohol. This entry item show the results for the sedative subscale evaluated in mixed models. Each item can be scored a minimum of zero (0) or up to 10 with the 10 representing feeling more or the most intoxicated in that item's description (e.g., sedated). The minimum score is 0 and the maximum score is 70. For the time frame, the values at different time points were combined (averaged) into a single value that represents the effect during the time interval of interest (12 to 110 minutes).
Time frame: 98 minutes
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Medication Dose | Biphasic Alcohol Effects Scale (BAES)- Sedative Subscale | 4.624 score on a scale | Standard Deviation 1.784 |
| Perampanel 6mg Dose | Biphasic Alcohol Effects Scale (BAES)- Sedative Subscale | 7.159 score on a scale | Standard Deviation 1.649 |
| Perampanel 10mg Dose | Biphasic Alcohol Effects Scale (BAES)- Sedative Subscale | 10.263 score on a scale | Standard Deviation 1.797 |
Comparison: mixed models, medication was a within-subjects factorp-value: 0.071Mixed Models Analysis
Primary
Biphasic Alcohol Effects Scale (BAES): Stimulant Subscale
A 14-item scale with 7 items designed to assess stimulant effects from alcohol intoxication and 7 items developed to measure the sedative effects of alcohol. This scale was selected as a primary outcome measure because it is sensitive to the effect of alcohol. This outcome item reports the Stimulant Subscale results analyzed with mixed models. Each item can be scored a minimum of zero (0) or up to 10 with the 10 representing feeling more or the most intoxicated in that item's description (e.g., excited). The minimum score is 0 and the maximum score is 70. For the time frame, the values at different time points were combined (averaged) into a single value that represents the effect during the time interval of interest (12 to 110 minutes).
Time frame: 98 minutes
Population: Non-treatment Seeking Heavy Drinkers of whom all participated in three separate lab days, each following a different dose of perampanel or placebo.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Medication Dose | Biphasic Alcohol Effects Scale (BAES): Stimulant Subscale | 13.756 score on a scale | Standard Error 2.747 |
| Perampanel 6mg Dose | Biphasic Alcohol Effects Scale (BAES): Stimulant Subscale | 14.053 score on a scale | Standard Error 2.658 |
| Perampanel 10mg Dose | Biphasic Alcohol Effects Scale (BAES): Stimulant Subscale | 13.026 score on a scale | Standard Error 2.816 |
Comparison: Medication dose was a within-subjects factor (crossover design)p-value: 0.867Mixed Models Analysis
Primary
Drug Effects Questionaire (DEQ)
consists of four items that measure current alcohol effects: 'feel alcohol', 'feel high', 'like alcohol', and 'want more alcohol'. For the time frame, the values at different time points were combined (averaged) into a single value that represents the effect during the time interval of interest (12 to 110 minutes). There are five items on the scale with scores of 0 to 100, and the total score is used by averaging all five items, thus, the minimum total score on the scale is 0 and the maximum is 100. The lowest score 0 represents not at all or not experiencing any drug effects from alcohol, and 100 represents extremely experiencing alcohol effects.
Time frame: 98 min
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Medication Dose | Drug Effects Questionaire (DEQ) | 42.538 score on a scale | Standard Error 3.379 |
| Perampanel 6mg Dose | Drug Effects Questionaire (DEQ) | 40.619 score on a scale | Standard Error 3.269 |
| Perampanel 10mg Dose | Drug Effects Questionaire (DEQ) | 43.267 score on a scale | Standard Error 3.442 |
Comparison: mixed modelsp-value: 0.667Mixed Models Analysis
Secondary
Alcohol Urge Questionnaire (AUQ)
A valid eight-item Likert-type scale designed to assess acute alcohol craving. Each item is scored on a 1 to 7 scale (Strongly Disagree = 1 and Strongly Agree = 7). Items 2 and 7 are reverse scored. A total score is computed by averaging the item scores. Higher scores reflect greater craving. The minimum score is 7, and the maximum is 49. For the time frame, the values at different time points were combined (averaged) into a single value that represents the effect during the time interval of interest (12 to 110 minutes).
Time frame: 98 min
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Medication Dose | Alcohol Urge Questionnaire (AUQ) | 16.481 score on a scale | Standard Error 1.266 |
| Perampanel 6mg Dose | Alcohol Urge Questionnaire (AUQ) | 17.314 score on a scale | Standard Error 1.177 |
| Perampanel 10mg Dose | Alcohol Urge Questionnaire (AUQ) | 18.723 score on a scale | Standard Error 1.289 |
p-value: 0.285Mixed Models Analysis
Secondary
Profile of Mood States (POMS) 2 Short Version Total Score
The Profile of Mood States (POMS) 2 short version contains a subset of 35 items from the full-length versions. This subset comprises those five items on full version POMS scale that exhibited good item-total correlations and best predicted their respective scale scores, this is a TOTAL score Representing total mood disturbance. For the time frame, the values at different time points were combined (averaged) into a single value that represents the effect during the time interval of interest (12 to 110 minutes). The minimum is 0 and the maximum is 100 with higher numbers indicating greater mood disturbance.
Time frame: 98 minutes
Population: Nontreatment-seeking Heavy Drinkers (NTSHDs)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Medication Dose | Profile of Mood States (POMS) 2 Short Version Total Score | 20.25 score on a scale | Standard Error 1.49 |
| Perampanel 6mg Dose | Profile of Mood States (POMS) 2 Short Version Total Score | 21.75 score on a scale | Standard Error 1.335 |
| Perampanel 10mg Dose | Profile of Mood States (POMS) 2 Short Version Total Score | 20.619 score on a scale | Standard Error 1.533 |
Comparison: We report the main effect of dose on the outcome measurep-value: 0.691Mixed Models Analysis
Secondary
Side Effect Questionnaire (SEQ)
This consists of a list of side effects associated with perampanel (e.g., fatigue, dizziness), rated from 0=none to 4=severe. The mean for each subject across all items is included in each group/arm mean. The lowest score on the scale would be 0 and the maximum 4, as the mean across items is taken and not a sum. For the time frame, the values at different time points were combined (averaged) into a single value that represents the effect during the time interval of interest (12 to 110 minutes).
Time frame: 98 minutes
Population: Non-Treatment Seeking Heavy Drinkers
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Medication Dose | Side Effect Questionnaire (SEQ) | 0.895 score on a scale | Standard Error 0.294 |
| Perampanel 6mg Dose | Side Effect Questionnaire (SEQ) | .992 score on a scale | Standard Error 0.261 |
| Perampanel 10mg Dose | Side Effect Questionnaire (SEQ) | 1.13 score on a scale | Standard Error 0.28 |
Comparison: Mixed Modelsp-value: 0.843Mixed Models Analysis