Interdisciplinary Study of Two Novel Anticonvulsants in Alcoholism

Study Overview
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Brief Summary
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This is a double-blind, placebo-controlled, parallel group design study with 4 treatment groups; levetiracetam, zonisamide, topiramate, and placebo control. Subjects will receive study medications for 14 weeks. Potential subjects will be initially screened for interest in study participation and alcohol consumption level to determine basic eligibility by telephone, or in person. Individuals who meet telephone screening criteria will be scheduled for a clinic appointment to obtain informed consent and conduct screening assessments. Subjects who report average drinks per day that are within the guidelines for safe levels of alcohol consumption (i.e. 2 drinks/ day males; 1 drink/day females-HHS standard) in the two weeks prior to screening will be excluded. Subjects meeting screening criteria will be scheduled for a second randomization visit. During this visit baseline assessments will be obtained. Eligible subjects will then be randomized to a treatment group and will be provided with the first week's study medications. The goal is to directly compare the efficacy and tolerability of two novel anticonvulsants, zonisamide and levetiracetam, with placebo, and using topiramate, which has extensive evidence supporting its efficacy in alcoholism, as a positive control group. We believe that this will be the first direct comparison of these agents in alcoholism, and the results will provide information on the efficacy and safety of the medications.

Detailed Description
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This is a double-blind, placebo-controlled, parallel group design study with 4 treatment groups; levetiracetam, zonisamide, topiramate, and placebo control. This study evaluated the effects of zonisamide (400 mg per day) on alcohol consumption and its neurotoxic effects in subjects with AUDS. A double-blind placebo-controlled clinical trial was conducted using two comparator anticonvulsant drugs, topiramate (300 mg daily) and levetiracetam (2000 mg/day), which does not impair cognition. Topiramate was used as an active control in this study. Study medications were administered for 14 weeks, including a 2-week taper period. Target maintenance doses of study medications were administered to subjects during study weeks 8-12. Dosage reductions were made if needed to allow subjects to tolerate their study medication. During the medication taper phase of the study (Weeks 13-14) the Principal Investigator is allowed flexibility in the titration schedule in instances when the subject is experiencing events consistent with withdrawal, for example anxiety. Neurotoxicity of study drugs was assessed using neuropsychological tests and the AB-Neurotoxicity scale. An adaptive randomization procedures with sex and heavy drinking history being factors in the assignment of subjects to the treatment groups. will be done using sex and very heavy drinking. Very heavy drinking is defined as male subjects consuming more then 10 standard drinks per day and female subjects consuming more then 8 standard drinks per day for more then 40 percent of the days in the screening TLFB. Medication adherence was facilitated using Brief Behavioral Compliance Enhancement Treatment. It is a brief, standardized therapy that emphasizes medication adherence as being crucial to the improvement of drinking behavior. Subject assessments included, but were not limited to the following: 1) TLFB, 2) Adverse Events (AEs) assessment ,3) A-B Neurotoxicity Scale (weeks 1,4,8,12,15),and 4) Neuropsychological battery Assessments- including the Controlled Word Association Test (COWAT) and Digit and Spatial Span portions of the Wechsler Memory Scale- 3rd (weeks 1,12).

Official Title
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A Double-Blind, Placebo-Controlled, Parallel Group Design Trial of; Levetiracetam, Zonisamide, Topiramate, and Placebo Control for the Treatment of Alcohol Dependent Subjects.

Conditions
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Alcoholism, Alcohol Dependence, Alcohol Abuse

Intervention / Treatment
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* Drug: Topiramate
* Drug: Zonisamide
* Drug: Levetiracetam
* Drug: Sugar Pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be admitted into this study candidates must meet the following criteria: DSM-IV-TR Diagnosis of Alcohol Dependence. A minimal level of an average of 28 standard drinks per week for women or 35 drinks per week for men over a baseline 28 day consecutive period prior to the screening session during the 90 day time line follow-back. Male or Female 21- 65 years of age. Able to provide informed consent and comprehend study procedures. Negative urine toxicological screen for opioids, cocaine, amphetamines, methamphetamine, and benzodiazepines. The test may be repeated for opioids or benzodiazepines shown to be medically prescribed for an acute disorder. The urine test may also be repeated if the Investigator deems necessary. A score of >8 on the Alcohol Use Disorder Identification Test (AUDIT) during screening. Must be suitable for outpatient management of alcoholism. Express desire to stop drinking or reduce alcohol consumption. Provide contact information for themselves or an alternate contact that the staff will call in case of missed appointment. Women must be postmenopausal for at least one year, be surgically sterile, or be using an effective method of birth control. Must be able to take oral medications, adhere to the regimen and be willing to return for follow up visits. Exclusion Criteria: Subjects meeting the following criteria will be excluded from the study: Dependent on DSM IV-TR drugs or substances other than ethanol, nicotine, or caffeine. DSM IV-TR diagnosis of any current Axis I diagnosis other than alcohol dependence, nicotine dependence, or caffeine dependence that in the opinion of the study physicians might require intervention with either pharmacological or non-pharmacological therapy that will interfere with the course of the study. Receiving inpatient treatment for alcohol dependence, other then alcohol detoxification, within 4 weeks prior to enrollment into this study. Subjects with a score of 10 or greater on the Clinical Institute Withdrawal Assessment for Alcohol-Revised on first or second visits. Being treated with acamprosate, disulfiram or naltrexone within two weeks prior to randomization: Currently being treated with any of the following medications: a) antipsychotic agents. b) antimanic or anticonvulsant agents. c) sedative- hypnotics. d) chronic opioid treatment. e) psychomotor stimulants- amphetamine derivatives, methylphenidate Subjects who are legally mandated to participate in an alcohol treatment program. Use of any medication known to inhibit or induce cytochrome P450 3A4 enzymes. Subjects who have attempted suicide or who have had suicidal ideation within 30 days of their first visit. Subjects with renal disease or history of kidney stones. Subjects with AST or ALT >3 times the upper limit of the normal range during screening. History of significant neurological disorder. Subjects who are pregnant (as assessed by serum HCG) or lactating. Subjects known to have clinically significant medical conditions that in the opinion of the study physician would preclude administration of the study medications or limit participation in the clinical trial. Subjects with history of treatment with levetiracetam, topiramate or zonisamide. Score of 25 or less on the Folstein Mini- Mental examination. History of anticonvulsant-induced rash. Taking drugs that contain sulfa moiety, such as sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). During the 2 weeks prior to screening subjects who report average drinks per day that are within the guidelines for safe levels of alcohol consumption (i.e. 2 drinks/ day males; 1 drink/day females-HHS standard) will be excluded. Subjects with a sulfa allergy. -

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zonisamide<br>Encapsulated zonisamide with a target maintenance doses of 400 mg/day administered as 4 capsules per day. | Drug: Zonisamide<br>* Zonisamide will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14. Subjects will be dose titrated as tolerated to a target doses of 2000 400 mg of zonisamide.<br>* Other names: zonegran;|
| Experimental: Levetiracetam<br>Encapsulated levetiracetam with a target maintenance doses of 2000 mg/day administered as 4 capsules per day . | Drug: Levetiracetam<br>* Levetiracetam will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14. Subjects will be dose titrated as tolerated to a target doses of 2000 mg levetiracetam capsules.<br>* Other names: Keppra;|
| Active Comparator: Topiramate<br>Encapsulated topiramate with a target maintenance doses of 300 mg/day administered as 4 capsules per day . | Drug: Topiramate<br>* Topiramate will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14. Subjects will be dose titrated as tolerated to a target doses 300 mg topiramate.<br>* Other names: Topamax;|
| Placebo Comparator: Sugar Pill<br>Encapsulated sugar pill with a target maintenance dose administered as 4 capsules per day. | Drug: Sugar Pill<br>* Matched placebo will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Primary Efficacy Measure is the Mean Number of Drinks Consumed Per Day Over the Period From Treatment Weeks 10 Through 12 When All Study Medications Should be at Their Maximum Steady Levels Based on Their Known Pharmacokinetic Properties. | Mean standard drinks consumed per day for each treatment week, weeks 10 thru 12. Actual mean values obtained are shown. Analyses are based on model generated least squares means for a two -way repeated measures mixed models analysis for data obtained for weeks 1 through 12, with baseline values used as covariates. Week (time) was used as the within subject factor and treatment group was the between group factor. | Weeks 10, 11, 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AB-Neurotoxicity Scale. | Total Scores AB-Neurotoxicity Scale Week 12. This scale provides subject ratings of anticonvulsant neurotoxic effects. Scores may range 0 to 72, with possibility of an additional 30 points being for complaints not listed in the list of complaints provides. Total scores, therefore, may be as high as 102, with higher scores indicating greater severity of problems. Actual mean scores are shown. Means for the analysis are least means squares values obtained from a two-way repeated measures mixed models analysis, with Week (time) as the the within subject factor and treatment as the between group factor. Baseline values were used as covariates. | Week 12 | 
| Mean Percent Days Heavy Drinking | Mean weekly values for each treatment group for percent days heavy drinking. Heavy drinking was defined as 4 or more drinks per day for women and 5 or more drinks per day for men. | Weeks 10, 11, 12 | 
| Percent Days Drinking | Mean percent days drinking for Weeks 10, 11, 12. A drinking day is considered to be a day in which 1 or more drinks have been consumed. Means are model generated least means squares values obtained from a two-way repeated measures analysis from data obtained from Weeks 1 through 12, with Week as the within subject factor and treatment group as the between group factor. | Weeks 10, 11, 12 | 
| Controlled Word Association Test (COWAT)- Letter Fluency | Number of words generated that start with a set of 3 letters. The COWAT provides a measure of verbal fluency. Actual means for COWAT results are shown. | Baseline & Week 12 | 
| COWAT-Category | Number of words produced by subjects over 60 seconds for a semantic category (Animals). The COAWAT-Category sub-test provides a measure of verbal fluency. Mean value shown are actual means for the number of words produced. | Baseline, Week12 | 
| Wechsler Memory Scales (WMS)-3d Ed Digit Span-Age Adjusted Total | WMS Digit Span is a measure of working memory. Subjects respond by repeating lists of number sequences presented by the test administrator. Age adjusted scores are presented below. Scores may range between 1 and 19, with lower scores indicating poorer performance on the task. | Baseline, Week 12 | 
| Wechsler Memory Scale-3rd Ed. Spatial Span | WMS Spatial Span test measures working memory for a spatial sequence of numbers. This assesses visual working memory. Age adjusted scaled scores are presented. Score may range between 1 and 19, with lower scores indicating greater impairment in performance. | Baseline, Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alcoholism, Alcohol Dependence, Alcohol Abuse, Substance Abuse, Alcoholic Intoxication