Carisbamate as a Potential Treatment for Alcohol Dependence

Study Overview
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Brief Summary
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The purpose of this study is to determine the effects of treatment with carisbamate compared to treatment with placebo, on alcohol-induced stimulant and subjective effects in non-treatment seeking alcohol-dependent human volunteers.

Detailed Description
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This within-subjects placebo-controlled experimental protocol will assess the effects of carisbamate (600mg qd) on the positive subjective effects of alcohol in non-treatment-seeking alcohol-dependent volunteers. Participants will receive study drug (carisbamate or placebo) from days 2- 4. On day 4, study drug will be followed by alcohol (0.8g/kg; 16% by volume) and a placebo beverage (1% by volume as a mask), both separated by 2 hours. Physiologic, subjective effects and BAL will be obtained after the alcohol challenges. Participants will be discharged on day 4 and asked to return a week later to repeat the study under the alternate study drug condition (active carisbamate vs. placebo).

Official Title
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Carisbamate as a Potential Treatment for Alcohol Dependence

Conditions
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Alcohol Dependence, Alcohol Abuse, Substance Abuse

Intervention / Treatment
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* Drug: Carisbamate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be an English-speaking volunteer who is not seeking treatment at the time of the study Be between 18-55 years of age Meet DSM-IV TR criteria for alcohol abuse; participants may or may not meet criteria for nicotine dependence. Nicotine dependence is allowed but not required because most alcohol users smoke cigarettes. Have a self-reported history of using alcohol. Have vital signs as follows: resting pulse must be < 90 bpm and the blood pressure must be < 150 mmHg systolic and < 90 mmHg diastolic. Have hematology and chemistry laboratory tests that are within normal (+/- 10%) limits with the following exceptions: liver function tests (total bilirubin, ALT, AST, and alkaline phosphatase) < 3 x the upper limit of normal, and b) kidney function tests (creatinine and BUN) within normal limits Have a baseline EKG that demonstrates clinically normal sinus rhythm, clinically normal conduction, and no clinically significant arrhythmias Have a medical history and brief physical examination demonstrating no clinically significant contraindications for study participation, in the judgment of the admitting physician and the principal investigator. Exclusion Criteria: Meet DSM IV TR criteria for dependence on drugs other than alcohol or nicotine. Have any history or evidence suggestive of seizure disorder or brain injury Have any previous medically adverse reaction to alcohol, including loss of consciousness, chest pain, or epileptic seizure Have neurological or psychiatric disorders, such as: psychosis, bipolar illness or major depression as assessed by SCID organic brain disease or dementia assessed by clinical interview history of any psychiatric disorder which would require ongoing treatment or which would make study compliance difficult history of suicide attempts within the past year and/or current suicidal ideation/plan Have evidence of clinically significant heart disease or hypertension, as determined by the PI Have evidence of untreated or unstable medical illness including: neuroendocrine, autoimmune, renal, hepatic, or active infectious disease Have symptomatic HIV or are taking antiretroviral medication Be pregnant or nursing. Other females must either be unable to conceive (i.e., surgically sterilized, sterile, or post-menopausal) or be using a reliable form of contraception (e.g., abstinence, birth control pills, intrauterine device, condoms, or spermicide). All females must provide negative pregnancy urine tests before study entry, upon hospital admission, and at the end of study participation Have any other illness, condition, or use of psychotropic medications, which in the opinion of the PI and/or the admitting physician would preclude safe and/or successful completion of the study. Currently seeking help for alcohol dependence. Subjects with or prone to clinically significant alcohol withdrawal. More than thirty days of abstinence from alcohol in the ninety days prior to enrollment. A history of major alcohol-related medical complications requiring hospitalization (i.e. pancreatitis). Contraindication(s) to take the study medication such as renal or hepatic impairment, nephrolithiasis, congenital metabolic disorders or history of seizures. Moderate-to-severe renal impairment defined as creatinine clearance less than 30 mL/min. Use of inhibitors/substrates for renal cationic transporters, or medications contraindicated with ethanol. A history of violence or aggression, assessed as part of the clinical interview at screening visit.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants will receive placebo from days 2- 4. | Drug: Placebo<br>* Placebo treatment only<br>* Other names: Sugar Pill;|
| Active Comparator: Carisbamate<br>Participants will receive carisbamate 600mg qd from days 2- 4. | Drug: Carisbamate<br>* 600mg Orally on days 2-4<br>* Other names: YKP 509;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Biphasic Alcohol Effects Scale (BAES) Scores | The Biphasic Alcohol Effects Scale (BAES) is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. The BAES consists of 14 items that are rated on a eleven-point scale. The Sedation and Stimulation subscales are calculated by summing the following items (for the 14-point scale): Stimulation: = BAES3 + BAES4 + BAES5 + BAES11 + BAES12 + BAES13 +BAES14/ Sedation: = BAES1 + BAES2 + BAES6 + BAES7 + BAES8 + BAES9 + BAES10. Individuals are instructed to rate the extent to which drinking alcohol has produced these feelings in you at the present time from 0 (not at all) to 10 (extremely). Higher scores on the Sedative Subscale represent extreme sedation (0 not at all sedated - 70 extremely sedated). Higher scores on the Stimulant Subscale represent extreme stimulation (0 not at all stimulated - 70 extremely stimulated). Scale scores are calculated as the sum of respective stimulant and sedative effects items. | 15, 30 and 60 minutes after consumption of placebo (1% alcohol by volume) and alcohol (0.8g/kg; 16% by volume) beverages, stimulant ratings | 
| Mean Alcohol Urge Questionnaire (AUQ) Scores | The Alcohol Urge Questionnaire (AUQ) consists of eight statements about the respondent's feelings and thoughts about drinking as they are completing the questionnaire (i.e., right now). Drinking refers to various types of alcohol, including beer, wine and liquor. The respondent is asked to respond to each statement about alcohol craving via a 7-item Likert scale ranging from 0-strongly disagree to 6- strongly agree. Item scores were averaged and the total score also ranges from 0-6. | 15, 30 and 60 minutes after consumption of placebo (1% alcohol by volume) and alcohol (0.8g/kg; 16% by volume) beverages. | 
| Mean Positive and Negative Affect Schedule (PANAS) Scores | The Positive and Negative Affect Schedule (PANAS) is a self-report questionnaire that consists of two 10-item scales to measure both positive and negative affect. Each item is rated on a 5-point scale of 1 (not at all) to 5 (very much). Range between 10 and 50 points. Higher positive affect scores indicated a better outcome, while lower negative affect scores indicated a better outcome. | 15, 30 and 60 minutes after consumption of placebo (1% alcohol by volume) and alcohol (0.8g/kg; 16% by volume) beverages. | 
| MEAN DRUG EFFECTS QUESTIONNAIRE (DEQ) SCORES | Self-reported subjective drug effects questionnaire evaluated whether a respondent was currently affected by doses of alcohol. Participants completed VAS at regular intervals after ingesting active alcohol (0.8g/kg; 16% by volume) or placebo (1% by volume as a mask). The questionnaire assessed the extent to which subjects experience four subjective states: Feel Drug, Feel High, and Want More. The Feel Drug, Feel High, Like Drug, Dislike Drug, and Want More subscales are reported.Each item is rated on a 100-point scale of 1 (not at all) to 100 (extremely). 100 represents the highest score for that subjective state, and the higher the score, the worse the outcome. | 15, 30 and 60 minutes after consumption of placebo (1% alcohol by volume) and alcohol (0.8g/kg; 16% by volume) beverages. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Physiologic Effects of Carisbamate: Mean Systolic and Diastolic Blood Pressure | systolic and diastolic blood pressure will be monitored after consuming carisbamate and alcohol | 15, 30 and 60 minutes after alcohol (0.8 mg/kg;16% by volume) consumption | 
| Physiologic Effects of Carisbamate: Mean Heart Rate | pulse will be monitored after consuming carisbamate and alcohol | 15, 30 and 60 minutes after alcohol (0.8 mg/kg;16% by volume) consumption |