Interdisciplinary Study of Two Novel Anticonvulsants in Alcoholism

• Sponsor: Boston Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00862563
• Collaborator: National Institute on Alcohol Abuse and Alcoholism (NIAAA) (NIH)
• Enrollment: 85
• Location: 1
• Arms: 4
• Duration (Months): 51
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Alcoholism; Alcohol Dependence; Alcohol Abuse	Drug: Topiramate; Drug: Zonisamide; Drug: Levetiracetam; Drug: Sugar Pill	Phase 2

Detailed Description

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 85 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Placebo-Controlled, Parallel Group Design Trial of; Levetiracetam, Zonisamide, Topiramate, and Placebo Control for the Treatment of Alcohol Dependent Subjects.
• Study Start Date: May 1, 2009
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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. [Weeks 10, 11, 12]

   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.

Secondary Outcome Measures

1. AB-Neurotoxicity Scale. [Week 12]

   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.

2. Mean Percent Days Heavy Drinking [Weeks 10, 11, 12]

   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.

3. Percent Days Drinking [Weeks 10, 11, 12]

   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.

4. Controlled Word Association Test (COWAT)- Letter Fluency [Baseline & Week 12]

   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.

5. COWAT-Category [Baseline, Week12]

   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.

6. Wechsler Memory Scales (WMS)-3d Ed Digit Span-Age Adjusted Total [Baseline, Week 12]

   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.

7. Wechsler Memory Scale-3rd Ed. Spatial Span [Baseline, Week 12]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

To be admitted into this study candidates must meet the following criteria:

1. DSM-IV-TR Diagnosis of Alcohol Dependence.

2. 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.

3. Male or Female 21- 65 years of age.

4. Able to provide informed consent and comprehend study procedures.

5. 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.

6. A score of >8 on the Alcohol Use Disorder Identification Test (AUDIT) during screening.

7. Must be suitable for outpatient management of alcoholism.

8. Express desire to stop drinking or reduce alcohol consumption.

9. Provide contact information for themselves or an alternate contact that the staff will call in case of missed appointment.

10. Women must be postmenopausal for at least one year, be surgically sterile, or be using an effective method of birth control.

11. 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:

1. Dependent on DSM IV-TR drugs or substances other than ethanol, nicotine, or caffeine.

2. 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.

3. Receiving inpatient treatment for alcohol dependence, other then alcohol detoxification, within 4 weeks prior to enrollment into this study.

4. Subjects with a score of 10 or greater on the Clinical Institute Withdrawal Assessment for Alcohol-Revised on first or second visits.

5. Being treated with acamprosate, disulfiram or naltrexone within two weeks prior to randomization:

6. 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

7. Subjects who are legally mandated to participate in an alcohol treatment program.

8. Use of any medication known to inhibit or induce cytochrome P450 3A4 enzymes.

9. Subjects who have attempted suicide or who have had suicidal ideation within 30 days of their first visit.

10. Subjects with renal disease or history of kidney stones.

11. Subjects with AST or ALT >3 times the upper limit of the normal range during screening.

12. History of significant neurological disorder.

13. Subjects who are pregnant (as assessed by serum HCG) or lactating.

14. 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.

15. Subjects with history of treatment with levetiracetam, topiramate or zonisamide.

16. Score of 25 or less on the Folstein Mini- Mental examination.

17. History of anticonvulsant-induced rash.

18. Taking drugs that contain "sulfa" moiety, such as sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid).

19. 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.

20. Subjects with a sulfa allergy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Boston University School of Medicine	Boston	Massachusetts	United States	02118

Sponsors and Collaborators

• Boston Medical Center
• National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Investigators

• Principal Investigator: Domenic A Ciraulo, MD, Boston University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Dominic Ciraulo, Department Chair, Psychiatry, Boston Medical Center
• ClinicalTrials.gov Identifier: NCT00862563
• Other Study ID Numbers: NIAAA-CIR-AA015923; P60AA013759; 1R01AA015923
• First Posted: Mar 17, 2009
• Last Update Posted: Apr 28, 2015
• Last Verified: Apr 1, 2015

• Keywords provided by Dominic Ciraulo, Department Chair, Psychiatry, Boston Medical Center: Alcoholism; Alcohol Dependence; Alcohol Abuse; Substance Abuse; Alcoholic Intoxication
• Additional relevant MeSH terms: Alcoholism; Topiramate; Zonisamide; Levetiracetam

Study Results

Participant Flow

Arm/Group Title	Zonisamide	Levetiracetam	Topiramate	Sugar Pill
Arm/Group Description	zonisamide: 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.	Levetiracetam: 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.	Topiramate: 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.	Placebo: Matched placebo will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14.
Period Title: Overall Study
STARTED	19	21	21	24
COMPLETED	15	17	15	19
NOT COMPLETED	4	4	6	5

Baseline Characteristics

Arm/Group Title	Zonisamide	Levetiracetam	Topiramate	Sugar Pill	Total
Arm/Group Description	zonisamide: 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.	Levetiracetam: 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.	topiramate: 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.	Placebo: Matched placebo will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14.	Total of all reporting groups
Overall Participants	19	21	21	24	85
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	19 100%	21 100%	21 100%	24 100%	85 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	47.0 (10.0)	47.5 (10.5)	46.8 (10.5)	46.8 (7.3)	47.0 (9.4)
Sex: Female, Male (Count of Participants)
Female	8 42.1%	9 42.9%	9 42.9%	11 45.8%	37 43.5%
Male	11 57.9%	12 57.1%	12 57.1%	13 54.2%	48 56.5%
Region of Enrollment (participants) [Number]
United States	19 100%	21 100%	21 100%	24 100%	85 100%
Education (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	15.6 (2.5)	15.2 (2.4)	15.4 (1.9)	15.3 (2.7)	15.4 (2.4)
Alcohol Use Identification Test (AUDIT) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	22.1 (5.9)	23.1 (5.2)	24.6 (5.7)	23.7 (4.7)	23.4 (5.4)
Wechsler Abbreviated Scale of Intelligence (WAIS) (scale scores) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scale scores]	115.3 (8.9)	113.3 (11.6)	113.6 (12.6)	110.7 (14.0)	113.1 (12.0)

Outcome Measures

1. Primary Outcome

Title	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.
Description	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.
Time Frame	Weeks 10, 11, 12

Outcome Measure Data

Analysis Population Description

Alcohol dependent subjects. Number of participants analyzed are provided for the number of subjects for data that was available for the timeframe for the specific analyses, i.e. Weeks 10,11,12.

Arm/Group Title	Zonisamide	Sugar Pill	Topiramate	Levetiracetam
Arm/Group Description	zonisamide: 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.	Placebo: Matched placebo will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14.	Topiramate: 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.	Levetiracetam: 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.
Measure Participants	16	20	16	17
Week 10	3.8 (0.9)	6.3 (0.9)	3.2 (0.8)	4.6 (0.8)
Week 11	3.4 (0.6)	6.8 (1.2)	2.7 (0.7)	4.3 (0.7)
Week 12	2.5 (0.7)	6.0 (0.9)	2.5 (0.7)	4.3 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zonisamide, Sugar Pill
	Comments	Comparison of Week 10 means for mean drinks per day obtained for the placebo and zonisamide groups. Means used for the analysis are least means squares 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments	p<0.05 considered to be significant
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-2.1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.1
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Zonisamide, Sugar Pill
	Comments	Comparison of Week 11 means for mean drinks per day obtained for the placebo and zonisamide groups. Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	p< 0.05 was considered to be significant.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-3.0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.1
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Zonisamide, Sugar Pill
	Comments	Comparison of Week 12 mean for mean drinks per day obtained for the placebo and zonisamide groups. Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments	p< 0.05 was considered to be significant.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-2.1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.2
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Topiramate
	Comments	Comparison of Week 10 mean for mean drinks per day obtained for the placebo and topiramate groups. Means used for the analysis are least squares means 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,
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p<0.05 is considered as being significant.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means.
	Estimated Value	-3.4
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.1
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Topiramate
	Comments	Comparison of Week 11 means for mean drinks per day obtained for the placebo and topiramate groups. Means used for the analysis are least squares means 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. .
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-4.4
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.1
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Topiramate
	Comments	Comparison of Week 12 means for mean drinks per day obtained for the placebo and topiramate groups. Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-4.1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.2
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Levetiracetam
	Comments	Comparison of Week 10 means for mean drinks per day obtained for the placebo and levetiracetam groups. Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.15
	Comments	p<0.05 considered to be significant
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-1.64
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.1
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Levetiracetam
	Comments	Comparison of Week 11 means for mean drinks per day obtained for the placebo and levetiracetam groups. Means used for the analysis are least squares means 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 covariate values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments	p< 0.05 is considered to be significant.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-2.9
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.2
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Levetiracetam
	Comments	Comparison of Week 12 means for mean drinks per day obtained for the placebo and levetiracetam groups. Means used for the analysis are least squares means s 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1
	Comments	p< 0.05 is considered to be significant.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-2.0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.2
	Estimation Comments

2. Secondary Outcome

Title	AB-Neurotoxicity Scale.
Description	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.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Alcohol dependent subjects.

Arm/Group Title	Zonisamide	Levetiracetam	Topiramate	Sugar Pill
Arm/Group Description	zonisamide: 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.	Levetiracetam: 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.	topiramate: 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.	Placebo: Matched placebo will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14.
Measure Participants	15	17	15	19
Mean (Standard Error) [Scale Scores]	7.1 (2.2)	11.3 (2.7)	15.4 (3.3)	5.8 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Levetiracetam
	Comments	Comparison between mean values obtained for the topiramate and placebo groups for Week 12. Model generated least mean squares were used for this analysis.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments	p< 0.05 is considered to be significant.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean difference Week 12
	Estimated Value	8.9
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.6
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Zonisamide, Levetiracetam
	Comments	Comparison of means for the zonisamide and placebo group for Week 12. Mixed models generated means were used in this analysis.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.784
	Comments	p< 0.05 is considered to be significant.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference Week 12
	Estimated Value	0.98
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.6
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Levetiracetam
	Comments	Comparison of means for the levetiracetam and placebo groups for Week 12. Model generated least mean squares were used for this analysis.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.264
	Comments	p< 0.05 is considered to be significant.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean difference Week 12
	Estimated Value	3.65
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.3
	Estimation Comments

3. Secondary Outcome

Title	Mean Percent Days Heavy Drinking
Description	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.
Time Frame	Weeks 10, 11, 12

Outcome Measure Data

Analysis Population Description

Alcohol dependent subjects. Alcohol dependent subjects. Number of participants analyzed are provided for the number of subjects for data that was available for the time frame for the specific analyses, i.e. Weeks 10,11,12.

Arm/Group Title	Zonisamide	Sugar Pill	Topiramate	Levetiracetam
Arm/Group Description	Zonisamide: 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.	Placebo: Matched placebo will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14.	Topiramate: 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.	Levetiracetam: 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.
Measure Participants	16	20	16	17
Week 10	38.4 (10.7)	65.7 (6.5)	32.1 (8.5)	49.6 (9.4)
Week 11	36.6 (8.5)	61.7 (8.1)	29.5 (7.1)	47.9 (9.3)
Week 12	34.3 (11.0)	60.9 (8.0)	21.0 (8.1)	44.5 (8.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zonisamide, Sugar Pill
	Comments	Comparison of Week 10 means for mean percent heavy drinking days obtained for the placebo and zonisamide groups Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments	p< 0.05 is considered to be significant.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-24.4
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.7
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Zonisamide, Sugar Pill
	Comments	Comparison of Week 11 means for mean percent heavy drinking days obtained for the placebo and zonisamide groups Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.036
	Comments	p<0.05 is considered to be significant
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-20.9
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.8
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Zonisamide, Sugar Pill
	Comments	Comparison of Week 12 means for mean percent heavy drinking days obtained for the placebo and zonisamide groups Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.24
	Comments	p< 0.05 is considered to be significant
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-22.8
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.9
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Topiramate
	Comments	Comparison of Week 10 means for mean percent heavy drinking days obtained for the placebo and topiramate groups Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments	p<0.05 is considered to be significant.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-33.0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.0
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Topiramate
	Comments	Comparison of Week 11 means for mean percent heavy drinking days obtained for the placebo and topiramate groups Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments	p< 0.05 is considered to be significant
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-29.7
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.2
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Topiramate
	Comments	Comparison of Week 12 means for mean percent heavy drinking days obtained for the placebo and topiramate groups Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p<0.05 is considered to be significant.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-37.7
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.3
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Levetiracetam
	Comments	Comparison of Week 10 means for mean percent heavy drinking days obtained for the placebo and levetiracetam groups Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments	p< 0.05 is considered to be significant
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-20.7
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.0
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Levetiracetam
	Comments	Comparison of Week 11 means for mean percent heavy drinking days obtained for the placebo and levetiracetam groups Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments	p< 0.05 is considered to be significant
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-23.3
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.2
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Levetiracetam
	Comments	Comparison of Week 12 means for mean percent heavy drinking days obtained for the placebo and levetiracetam groups Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments	p<0.05 is considered to be significant
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-24.8
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.3
	Estimation Comments

4. Secondary Outcome

Title	Percent Days Drinking
Description	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.
Time Frame	Weeks 10, 11, 12

Outcome Measure Data

Analysis Population Description

Alcohol dependent subjects. Alcohol dependent subjects. Number of participants analyzed are provided for the number of subjects for data that was available for the timeframe for the specific analyses, i.e. Weeks 10,11,12.

Arm/Group Title	Zonisamide	Levetiracetam	Topiramate	Sugar Pill
Arm/Group Description	Encapsulated zonisamide with a target maintenance doses of 400 mg/day administered as 4 capsules per day. zonisamide: 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.	Encapsulated levetiracetam with a target maintenance doses of 2000 mg/day administered as 4 capsules per day . Levetiracetam: 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.	Encapsulated topiramate with a target maintenance doses of 300 mg/day administered as 4 capsules per day . topiramate: 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.	Encapsulated sugar pill with a target maintenance dose administered as 4 capsules per day. Placebo: Matched placebo will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14.
Measure Participants	15	17	15	19
Week 10	61.6 (9.5)	72.2 (8.3)	51.8 (10.1)	83.6 (5.2)
Week 11	62.1 (9.3)	68.9 (8.6)	43.8 (9.6)	87.2 (5.1)
Week 12	61.3 (9.9)	73.1 (7.6)	51.4 (11.0)	78.2 (6.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zonisamide, Levetiracetam
	Comments	Comparison of Week 10 means for mean percent drinking days obtained for the placebo and zonisamide groups Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	p<0.05 is considered to be significant
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-22.5
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.8
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Zonisamide, Levetiracetam
	Comments	Comparison of Week 11 means for mean percent drinking days obtained for the placebo and zonisamide groups Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-24.1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.9
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Zonisamide, Levetiracetam
	Comments	Comparison of Week 12 means for mean percent drinking days obtained for the placebo and zonisamide groups Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.044
	Comments	p< 0.05 is considered to be significant.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least square means
	Estimated Value	-16.3
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.0
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Levetiracetam
	Comments	Comparison of Week 10 means for mean percent drinking days obtained for the placebo and topiramate. Means used for the analysis are least squares means from a two-way repeated measures mixed models analysis, with Week (time) as the the within subject factor and treatment as the between group factors. Baseline values were used as covariates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p< 0.05 is considered to be significant
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-38.1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.0
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Levetiracetam
	Comments	Comparison of Week 11 means for mean percent drinking days obtained for the placebo and topiramate. Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p<0.05 is considered to be significant.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-47.6
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.1
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Levetiracetam
	Comments	Week 12.Comparison of Week 12 means for mean percent drinking days obtained for the placebo and topiramate. Means used for the analysis are least squares means 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments	p<0.05 is considered to be significant.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-34.0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.2
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Levetiracetam
	Comments	Comparison of Week 10 means for mean percent drinking days obtained for the placebo and levetiracetam groups. Means used for the analysis are least squares means from a two-way repeated measures mixed models analysis. Baseline values were used as covariates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments	p<0.05 is considered to be significant
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-19.3
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 8.0
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Levetiracetam
	Comments	Comparison of Week 11 means for mean percent drinking days obtained for the placebo and levetiracetam groups. Means used for the analysis are least squares means from a two-way repeated measures mixed models analysis. Baseline values were used as covariates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	p<0.05 is considered to be significant.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-31.2
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.1
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Levetiracetam
	Comments	.Comparison of Week 12 means for mean percent drinking days obtained for the placebo and levetiracetam groups. Means used for the analysis are least squares means from a two-way repeated measures mixed models analysis.Baseline values were used as covariates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments	p< 0.05 is considered to be significant
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference between least squares means
	Estimated Value	-18.5
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.2
	Estimation Comments

5. Secondary Outcome

Title	Controlled Word Association Test (COWAT)- Letter Fluency
Description	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.
Time Frame	Baseline & Week 12

Outcome Measure Data

Analysis Population Description

Alcohol Dependent Subjects. Number of participants analyzed represent the number for whom Week 12 data was available.

Arm/Group Title	Zonisamide	Levetiracetam	Topiramate	Sugar Pill
Arm/Group Description	Encapsulated zonisamide with a target maintenance doses of 400 mg/day administered as 4 capsules per day. zonisamide: 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.	Encapsulated levetiracetam with a target maintenance doses of 2000 mg/day administered as 4 capsules per day . Levetiracetam: 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.	Encapsulated topiramate with a target maintenance doses of 300 mg/day administered as 4 capsules per day . topiramate: 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.	Encapsulated sugar pill with a target maintenance dose administered as 4 capsules per day. Placebo: Matched placebo will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14.
Measure Participants	13	17	15	17
Baseline	46.5 (3.1)	46.2 (3.0)	43.4 (3.8)	47.4 (2.8)
Week 12	32.5 (2.2)	45.4 (2.7)	28.1 (2.0)	50.5 (2.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zonisamide, Levetiracetam
	Comments	Data were analyzed using two-way repeated measures mixed models analysis. It was hypothesized that COWAT-Letter Fluency scores would change towards a downward direction for the zonisamide as compared to the placebo group resulting in significant treatment x time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p< 0.01 is considered to be significant.
	Method	Mixed Models Analysis
	Comments	p value is for the group x time interaction term.'

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Levetiracetam
	Comments	Data were analyzed using two-way repeated measures mixed models analysis. It was hypothesized that COWAT-Letter Fluency scores would change towards a downward direction for the topiramate as compared to the placebo group resulting in a significant treatment x time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p<0.01 is considered to be significant
	Method	Mixed Models Analysis
	Comments	p value is for group x time interaction term for the comparison of data for the topiramate and placebo group.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Levetiracetam
	Comments	Data were analyzed using two-way repeated measures mixed models analysis. It was hypothesized that COWAT-Letter Fluency scores would change towards a downward direction for the levetiracetam as compared to the placebo group resulting in a significant treatment x time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.30
	Comments	p<0.01 is considered to be significant.
	Method	Mixed Models Analysis
	Comments	p value is for interaction effect for the comparison of data for the levetiracetam and placebo groups.

6. Secondary Outcome

Title	COWAT-Category
Description	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.
Time Frame	Baseline, Week12

Outcome Measure Data

Analysis Population Description

Alcohol Dependent Subjects. Number of participants analyzed represent the number for whom Week 12 data was available.

Arm/Group Title	Zonisamide	Levetiracetam	Topiramate	Sugar Pill
Arm/Group Description	zonisamide: 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.	Levetiracetam: 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.	topiramate: 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.	Placebo: Matched placebo will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14.
Measure Participants	13	17	15	17
Baseline	22.6 (1.1)	20.9 (0.9)	21.9 (1.3)	21.6 (1.2)
Week 12	17.4 (0.7)	21.2 (1.0)	17.0 (1.2)	20.8 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zonisamide, Levetiracetam
	Comments	Data were analyzed using two-way repeated measures mixed models analysis. It was hypothesized that COWAT-Category scores would change towards a downward direction for the zonisamide as compared to the placebo group resulting in significant treatment x time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p<0.01 is considered to be significant.
	Method	Mixed Models Analysis
	Comments	p value is for the group x time interaction effect for the paired comparison of COWAT-category data for the zonisamide and placebo groups.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Levetiracetam
	Comments	Data were analyzed using two-way repeated measures mixed models analysis. It was hypothesized that COWAT-Category scores would change towards a downward direction for the topiramate as compared to the placebo group resulting in significant treatment x time interaction
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments	p< 0.01 is considered to be significant.
	Method	Mixed Models Analysis
	Comments	The p value shown is for the group x time interaction effect for the comparison of data from the topiramate and the placebo groups.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Levetiracetam
	Comments	Data were analyzed using two-way repeated measures mixed models analysis. It was hypothesized that COWAT-Category scores would change towards a downward direction for the levetiracetam as compared to the placebo group resulting in significant treatment x time interaction
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.36
	Comments	p<0.01 is considered to be significant.
	Method	Mixed Models Analysis
	Comments	The p value is for the group x time interaction effect for the comparison of the levetiracetam and placebo groups.

7. Secondary Outcome

Title	Wechsler Memory Scales (WMS)-3d Ed Digit Span-Age Adjusted Total
Description	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.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Alcohol Dependent Subjects. Number of participants analyzed represent the number for whom Week 12 data was available.

Arm/Group Title	Zonisamide	Levetiracetam	Topiramate	Sugar Pill
Arm/Group Description	Encapsulated zonisamide with a target maintenance doses of 400 mg/day administered as 4 capsules per day. zonisamide: 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.	Encapsulated levetiracetam with a target maintenance doses of 2000 mg/day administered as 4 capsules per day . Levetiracetam: 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.	Encapsulated topiramate with a target maintenance doses of 300 mg/day administered as 4 capsules per day . topiramate: 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.	Encapsulated sugar pill with a target maintenance dose administered as 4 capsules per day. Placebo: Matched placebo will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14.
Measure Participants	13	17	15	17
Baseline	11.8 (0.8)	11.9 (0.7)	12.1 (0.6)	12.6 (0.7)
Week 12	10.0 (0.9)	12.2 (0.8)	7.7 (0.6)	13.0 (0.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zonisamide
	Comments	Data were analyzed using two-way repeated measures mixed models analysis. It was hypothesized that Digit span scores would change towards a downward direction for the zonisamide as compared to the placebo group resulting in significant treatment x time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments	p<0.01 is considered to be significant
	Method	Mixed Models Analysis
	Comments	p value is for the group x time interaction effect

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Levetiracetam
	Comments	Data were analyzed using two-way repeated measures mixed models analysis. It was hypothesized that age adjusted Digit Span scores would change towards a downward direction for the topiramate as compared to the placebo group resulting in significant treatment x time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p<0.01 is considered to be significant.
	Method	Mixed Models Analysis
	Comments	p value shown is for the group X time interaction effect.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Levetiracetam
	Comments	Data were analyzed using two-way repeated measures mixed models analysis. It was hypothesized that Digit span scores would change towards a downward direction for the levetiracetam as compared to the placebo group resulting in significant treatment x time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.95
	Comments	p<0.01 is considered to be significant.
	Method	Mixed Models Analysis
	Comments	p value shown is for the group x time interaction effect.

8. Secondary Outcome

Title	Wechsler Memory Scale-3rd Ed. Spatial Span
Description	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.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Alcohol Dependent Subjects. Number of participants analyzed represent the number for whom Week 12 data was available.

Arm/Group Title	Zonisamide	Levetiracetam	Topiramate	Sugar Pill
Arm/Group Description	Encapsulated zonisamide with a target maintenance doses of 400 mg/day administered as 4 capsules per day. zonisamide: 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.	Encapsulated levetiracetam with a target maintenance doses of 2000 mg/day administered as 4 capsules per day . Levetiracetam: 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.	Encapsulated topiramate with a target maintenance doses of 300 mg/day administered as 4 capsules per day . Topiramate: 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.	Encapsulated sugar pill with a target maintenance dose administered as 4 capsules per day. Placebo: Matched placebo will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14.
Measure Participants	13	17	15	17
Baseline	10.8 (0.7)	10.5 (0.6)	12.0 (0.6)	10.8 (0.8)
Week 12	7.9 (0.9)	10.9 (0.5)	8.4 (0.7)	10.4 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zonisamide, Levetiracetam
	Comments	Data were analyzed using two-way repeated measures mixed models analysis. It was hypothesized that Spatial Span scores would change towards a downward direction for the zonisamide as compared to the placebo group resulting in significant treatment x time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.038
	Comments	p<0.01 is considered to be significant.
	Method	Mixed Models Analysis
	Comments	p value shown is for the group x time effect.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Levetiracetam
	Comments	Data were analyzed using two-way repeated measures mixed models analysis. It was hypothesized that Digit span scores would change towards a downward direction for the topiramate as compared to the placebo group resulting in significant treatment x time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0025
	Comments	p<0.01 is considered to be significant.
	Method	Mixed Models Analysis
	Comments	p value shown is for the group x time interaction effect.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill, Levetiracetam
	Comments	Data were analyzed using two-way repeated measures mixed models analysis. It was hypothesized that Digit span scores would change towards a downward direction for the levetiracetam as compared to the placebo group resulting in significant treatment x time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3
	Comments	p<0.01 is considered to be significant
	Method	Mixed Models Analysis
	Comments	p value shown is for the group x time interaction effect.

Adverse Events

Time Frame	Adverse event data was collected for a period of 17 weeks for each subject and for a total of throughout the entire study.
Arm/Group Title	Zonisamide		Levetiracetam		Topiramate		Sugar Pill
Arm/Group Description	zonisamide: 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.		Levetiracetam: 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.		topiramate: 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.		Placebo: Matched placebo will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14.
All Cause Mortality
	Zonisamide		Levetiracetam		Topiramate		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Zonisamide		Levetiracetam		Topiramate		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)		0/21 (0%)		0/21 (0%)		0/24 (0%)
Psychiatric disorders
Suicide Attempt	1/19 (5.3%)	1	0/21 (0%)	1	0/21 (0%)	1	0/24 (0%)	1
Other (Not Including Serious) Adverse Events
	Zonisamide		Levetiracetam		Topiramate		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/19 (78.9%)		11/21 (52.4%)		13/21 (61.9%)		11/24 (45.8%)
Gastrointestinal disorders
Constipation	1/19 (5.3%)	1	0/21 (0%)	0	1/21 (4.8%)	1	0/24 (0%)	0
Diarrhea	2/19 (10.5%)	2	2/21 (9.5%)	2	0/21 (0%)	0	2/24 (8.3%)	2
GI Distress	1/19 (5.3%)	1	0/21 (0%)	0	0/21 (0%)	0	0/24 (0%)	0
Nausea	0/19 (0%)	0	1/21 (4.8%)	1	2/21 (9.5%)	2	2/24 (8.3%)	2
General disorders
Altered Taste	2/19 (10.5%)	2	0/21 (0%)	0	0/21 (0%)	0	0/24 (0%)	0
Infections and infestations
Sinus Infection	1/19 (5.3%)	1	0/21 (0%)	0	0/21 (0%)	0	0/24 (0%)	0
Nervous system disorders
Confusion	0/19 (0%)	0	0/21 (0%)	0	2/21 (9.5%)	2	0/24 (0%)	0
Decreased Libido	1/19 (5.3%)	1	0/21 (0%)	0	1/21 (4.8%)	1	1/24 (4.2%)	1
Fatigue	3/19 (15.8%)	3	5/21 (23.8%)	5	2/21 (9.5%)	2	3/24 (12.5%)	3
Headache	3/19 (15.8%)	3	6/21 (28.6%)	6	4/21 (19%)	4	2/24 (8.3%)	2
Impaired Concentration	1/19 (5.3%)	1	0/21 (0%)	0	1/21 (4.8%)	1	1/24 (4.2%)	1
Impaired Memory	1/19 (5.3%)	1	0/21 (0%)	0	3/21 (14.3%)	3	1/24 (4.2%)	1
Irritability	2/19 (10.5%)	2	2/21 (9.5%)	2	4/21 (19%)	4	0/24 (0%)	0
Lightheaded	1/19 (5.3%)	1	0/21 (0%)	0	0/21 (0%)	0	0/24 (0%)	0
Loss of Appetite	2/19 (10.5%)	2	0/21 (0%)	0	1/21 (4.8%)	1	0/24 (0%)	0
Paraesthesia	0/19 (0%)	0	0/21 (0%)	0	4/21 (19%)	4	2/24 (8.3%)	2
Sedation	1/19 (5.3%)	1	1/21 (4.8%)	1	0/21 (0%)	0	0/24 (0%)	0
Slowed Thinking	1/19 (5.3%)	1	0/21 (0%)	0	0/21 (0%)	0	0/24 (0%)	0
Weight Loss	1/19 (5.3%)	1	0/21 (0%)	0	2/21 (9.5%)	2	0/24 (0%)	0
Word Finding	1/19 (5.3%)	1	0/21 (0%)	0	1/21 (4.8%)	1	0/24 (0%)	0
Psychiatric disorders
Anxiety	3/19 (15.8%)	3	2/21 (9.5%)	2	3/21 (14.3%)	3	2/24 (8.3%)	2
Depression	0/19 (0%)	0	1/21 (4.8%)	1	3/21 (14.3%)	3	0/24 (0%)	0
Dissociation	1/19 (5.3%)	1	0/21 (0%)	0	0/21 (0%)	0	0/24 (0%)	0
Disoriented	0/19 (0%)	0	0/21 (0%)	0	2/21 (9.5%)	2	0/24 (0%)	0
Insomnia	2/19 (10.5%)	2	1/21 (4.8%)	1	0/21 (0%)	0	0/24 (0%)	0
Reproductive system and breast disorders
Erectile Dsyfunction	0/19 (0%)	0	0/21 (0%)	0	3/21 (14.3%)	3	0/24 (0%)	0
Skin and subcutaneous tissue disorders
Prurtitus	1/19 (5.3%)	1	0/21 (0%)	0	2/21 (9.5%)	2	0/24 (0%)	0
Rash	2/19 (10.5%)	2	0/21 (0%)	0	0/21 (0%)	0	0/24 (0%)	0

Limitations/Caveats

Early termination lead to a small number of subjects in each group being analyzed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.