Rapid Determination Of The Clinical Utility Of Perampanel For The Treatment Of Alcohol Dependence
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
The main goal of the proposed study is to determine whether the 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Perampanel 6mg 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. |
Drug: 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.
Other Names:
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| Placebo Comparator: Placebo Participants will have 3 test days each, 2 weeks apart, in a randomized order, following either pretreatment with placebo 7 days prior to each test day, and then observed dosing of placebo 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. |
Drug: Placebo
Placebo given in place of perampanel during the pre-treatment period and lab session days.
|
| Experimental: Perampanel 10 mg Participants will have 3 test days each, 2 weeks apart, in a randomized order, following either pretreatment with daily perampanel 2mg 7 days prior to each test day, and then observed dosing of high dose perampanel (10mg) 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. |
Drug: 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.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Biphasic Alcohol Effects Scale (BAES) [Day 8]
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.
- Biphasic Alcohol Effects Scale (BAES) [Day 24]
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.
- Biphasic Alcohol Effects Scale (BAES) [Day 40]
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.
- Drug Effects Questionaire (DEQ) [Day 8]
consists of four items that measure current alcohol effects: 'feel alcohol', 'feel high', 'like alcohol', and 'want more alcohol'.
- Drug Effects Questionaire (DEQ) [Day 24]
consists of four items that measure current alcohol effects: 'feel alcohol', 'feel high', 'like alcohol', and 'want more alcohol'.
- Drug Effects Questionaire (DEQ) [Day 40]
consists of four items that measure current alcohol effects: 'feel alcohol', 'feel high', 'like alcohol', and 'want more alcohol'.
Secondary Outcome Measures
- Visual Analog Scales of Mood States (VAS) [Day 8, 24, and 0]
A 5-item scale designed to assess subjective alcohol effects: high, anxious, drowsy, irritable, and nauseous. It has been used in previous studies by our group and has good sensitivity to drug effect.
- Alcohol Urge Questionnaire (AUQ) [Day 8, 24, and 40]
A valid eight-item Likert-type scale designed to assess acute alcohol craving
- Subjective High Assessment Scale (SHAS) [Day 8, 24, 40]
We will use the SHAS7, a reliable and valid 7-item scale assessing the amount (ranging from 0-36) of each experiential item (e.g., feeling "drunk" or "high") related to alcohol exposure
- Side Effect Questionnaire (SEQ) [Day 8, 24, 40]
This consists of a list of side effects associated with perampanel (e.g., fatigue, dizziness), rated from 0="none" to 4="severe".
- Profile of Mood States (POMS) 2 Short Versions [Day 8, 24, 40]
The 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
- Stop Signal Test (SST, also know as Go/No-Go) [Day 8, 24, 40]
SST is a commonly used test of response inhibition. This test consists of two parts. In the first part, the subject is introduced to the press pad, and told to press the left hand button when they see a left-pointing arrow or press the right hand button when they see a right-pointing arrow. There is one block of 16 trials for the subject to practice this. In the second part, the subject is told to continue pressing the buttons on the press pad when they see the arrows, as before, but, if they hear an auditory signal (a beep), they should withhold their response and not press the button.
- The Balloon Analogue Risk Task (BART) [Day 8, 24, and 40]
This is a valid and commonly used test of risk-taking, an aspect of impulsivity. This task is computerized, and subjects press a button to analogously pump air into a balloon on the screen. Subjects are told they can earn 1 cent for each pump of the balloon banked to a reward account before they cash out and stop pumping. The balloons break at various random intervals and if the balloon breaks, the subjects lose money out of the reward account. We will use a 10-balloon paradigm, a briefer but valid version of this task. They can earn a maximum of 7.5 dollars per administration, with 4 administrations per lab, for a total of up to $90 additional pay over the course of the study, though actual payouts will likely be substantially less.
Eligibility Criteria
Criteria
Inclusion Criteria:
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males and females
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between the ages of 21 and 55 years;
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NTSHDs as defined above, and must have had at least 5 SD in one day on at least some occasions in the past and been able to tolerate it without an adverse reaction
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generally medically and neurologically healthy on the basis of history, physical examination, EKG, screening laboratory results (CBC w/ differential, TSH, Free-T4, AST, ALT, GGT, BUN, creatinine, electrolytes, urinalysis, beta-HCG). Individuals with LFTs that are no more than 3 times above the normal levels will be included;
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women with a negative pregnancy test and not nursing, must be regularly using birth control
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negative breath alcohol at screening and on each test day;
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not taking any psychoactive medication or opioids (in past 30-days);
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are non-treatment seeking.
Exclusion Criteria:
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they need detoxification determined by a CIWA score of >8 or have had a history of alcohol detoxification in the past;
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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;
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meet criteria for 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)
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unwillingness to remain alcohol-free 12 hours prior to test days;
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Connecticut | Farmington | Connecticut | United States | 06030 |
| 2 | Yale New Haven Hospital Research Unit | New Haven | Connecticut | United States | 06510 |
| 3 | West Haven Veterans Affairs | West Haven | Connecticut | United States | 06515 |
| 4 | Albert Arias | Richmond | Virginia | United States | 23219 |
Sponsors and Collaborators
- Virginia Commonwealth University
- University of Connecticut
- Yale University
- National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Investigators
- Principal Investigator: Albert Arias, MD, Virginia CommonwealthUniversity
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- HM20014446
- 1407014397
- R21AA026681