Alcohol Abuse, Alcohol Dependence, Alcoholism
Conditions
Keywords
Alcoholism, Alcohol Dependence, Alcohol Abuse, Substance Abuse, Alcoholic Intoxication
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.
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).
Interventions
DRUGTopiramate
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.
DRUGZonisamide
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.
DRUGLevetiracetam
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.
DRUGSugar Pill
Matched placebo will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14.
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Boston Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
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. \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Zonisamide 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. | 19 |
| Levetiracetam 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. | 21 |
| Topiramate 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. | 21 |
| Sugar Pill Placebo: Matched placebo will be administered orally twice daily beginning on Day 1, Week 1 and continue through Day 7, Week 14. | 24 |
| Total | 85 |
Baseline characteristics
| Characteristic | Zonisamide | Levetiracetam | Topiramate | Sugar Pill | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 21 Participants | 21 Participants | 24 Participants | 85 Participants |
| Age, Continuous | 47.0 Years STANDARD_DEVIATION 10 | 47.5 Years STANDARD_DEVIATION 10.5 | 46.8 Years STANDARD_DEVIATION 10.5 | 46.8 Years STANDARD_DEVIATION 7.3 | 47.0 Years STANDARD_DEVIATION 9.4 |
| Alcohol Use Identification Test (AUDIT) | 22.1 units on a scale STANDARD_DEVIATION 5.9 | 23.1 units on a scale STANDARD_DEVIATION 5.2 | 24.6 units on a scale STANDARD_DEVIATION 5.7 | 23.7 units on a scale STANDARD_DEVIATION 4.7 | 23.4 units on a scale STANDARD_DEVIATION 5.4 |
| Education | 15.6 years STANDARD_DEVIATION 2.5 | 15.2 years STANDARD_DEVIATION 2.4 | 15.4 years STANDARD_DEVIATION 1.9 | 15.3 years STANDARD_DEVIATION 2.7 | 15.4 years STANDARD_DEVIATION 2.4 |
| Region of Enrollment United States | 19 participants | 21 participants | 21 participants | 24 participants | 85 participants |
| Sex: Female, Male Female | 8 Participants | 9 Participants | 9 Participants | 11 Participants | 37 Participants |
| Sex: Female, Male Male | 11 Participants | 12 Participants | 12 Participants | 13 Participants | 48 Participants |
| Wechsler Abbreviated Scale of Intelligence (WAIS) | 115.3 scale scores STANDARD_DEVIATION 8.9 | 113.3 scale scores STANDARD_DEVIATION 11.6 | 113.6 scale scores STANDARD_DEVIATION 12.6 | 110.7 scale scores STANDARD_DEVIATION 14 | 113.1 scale scores STANDARD_DEVIATION 12 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 19 | 11 / 21 | 13 / 21 | 11 / 24 |
| serious Total, serious adverse events | 1 / 19 | 0 / 21 | 0 / 21 | 0 / 24 |
Outcome results
Primary
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.
Time frame: Weeks 10, 11, 12
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zonisamide | 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. | Week 10 | 3.8 Standard Drinks per day | Standard Error 0.9 |
| Zonisamide | 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. | Week 12 | 2.5 Standard Drinks per day | Standard Error 0.7 |
| Zonisamide | 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. | Week 11 | 3.4 Standard Drinks per day | Standard Error 0.6 |
| Sugar Pill | 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. | Week 10 | 6.3 Standard Drinks per day | Standard Error 0.9 |
| Sugar Pill | 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. | Week 12 | 6.0 Standard Drinks per day | Standard Error 0.9 |
| Sugar Pill | 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. | Week 11 | 6.8 Standard Drinks per day | Standard Error 1.2 |
| Topiramate | 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. | Week 11 | 2.7 Standard Drinks per day | Standard Error 0.7 |
| Topiramate | 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. | Week 10 | 3.2 Standard Drinks per day | Standard Error 0.8 |
| Topiramate | 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. | Week 12 | 2.5 Standard Drinks per day | Standard Error 0.7 |
| Levetiracetam | 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. | Week 10 | 4.6 Standard Drinks per day | Standard Error 0.8 |
| Levetiracetam | 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. | Week 12 | 4.3 Standard Drinks per day | Standard Error 0.7 |
| Levetiracetam | 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. | Week 11 | 4.3 Standard Drinks per day | Standard Error 0.7 |
Comparison: 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.p-value: 0.06ANOVA
Comparison: 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.p-value: 0.008ANOVA
Comparison: 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.p-value: 0.07Mixed Models Analysis
Comparison: 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,p-value: 0.003ANOVA
Comparison: 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. .p-value: 0.0002ANOVA
Comparison: 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.p-value: 0.0007ANOVA
Comparison: 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.p-value: 0.15ANOVA
Comparison: 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.p-value: 0.014ANOVA
Comparison: 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.p-value: 0.1ANOVA
Secondary
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.
Time frame: Week 12
Population: Alcohol dependent subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zonisamide | AB-Neurotoxicity Scale. | 7.1 Scale Scores | Standard Error 2.2 |
| Sugar Pill | AB-Neurotoxicity Scale. | 11.3 Scale Scores | Standard Error 2.7 |
| Topiramate | AB-Neurotoxicity Scale. | 15.4 Scale Scores | Standard Error 3.3 |
| Levetiracetam | AB-Neurotoxicity Scale. | 5.8 Scale Scores | Standard Error 1.6 |
Comparison: Comparison between mean values obtained for the topiramate and placebo groups for Week 12. Model generated least mean squares were used for this analysis.p-value: 0.015ANOVA
Comparison: Comparison of means for the zonisamide and placebo group for Week 12. Mixed models generated means were used in this analysis.p-value: 0.784ANOVA
Comparison: Comparison of means for the levetiracetam and placebo groups for Week 12. Model generated least mean squares were used for this analysis.p-value: 0.264ANOVA
Secondary
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.
Time frame: Baseline & Week 12
Population: Alcohol Dependent Subjects. Number of participants analyzed represent the number for whom Week 12 data was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zonisamide | Controlled Word Association Test (COWAT)- Letter Fluency | Baseline | 46.5 Number of Words Produced | Standard Error 3.1 |
| Zonisamide | Controlled Word Association Test (COWAT)- Letter Fluency | Week 12 | 32.5 Number of Words Produced | Standard Error 2.2 |
| Sugar Pill | Controlled Word Association Test (COWAT)- Letter Fluency | Week 12 | 45.4 Number of Words Produced | Standard Error 2.7 |
| Sugar Pill | Controlled Word Association Test (COWAT)- Letter Fluency | Baseline | 46.2 Number of Words Produced | Standard Error 3 |
| Topiramate | Controlled Word Association Test (COWAT)- Letter Fluency | Baseline | 43.4 Number of Words Produced | Standard Error 3.8 |
| Topiramate | Controlled Word Association Test (COWAT)- Letter Fluency | Week 12 | 28.1 Number of Words Produced | Standard Error 2 |
| Levetiracetam | Controlled Word Association Test (COWAT)- Letter Fluency | Baseline | 47.4 Number of Words Produced | Standard Error 2.8 |
| Levetiracetam | Controlled Word Association Test (COWAT)- Letter Fluency | Week 12 | 50.5 Number of Words Produced | Standard Error 2.4 |
Comparison: 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.p-value: <0.0001Mixed Models Analysis
Comparison: 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.p-value: <0.0001Mixed Models Analysis
Comparison: 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.p-value: 0.3Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week12
Population: Alcohol Dependent Subjects. Number of participants analyzed represent the number for whom Week 12 data was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zonisamide | COWAT-Category | Baseline | 22.6 Number of Words Produced | Standard Error 1.1 |
| Zonisamide | COWAT-Category | Week 12 | 17.4 Number of Words Produced | Standard Error 0.7 |
| Sugar Pill | COWAT-Category | Week 12 | 21.2 Number of Words Produced | Standard Error 1 |
| Sugar Pill | COWAT-Category | Baseline | 20.9 Number of Words Produced | Standard Error 0.9 |
| Topiramate | COWAT-Category | Baseline | 21.9 Number of Words Produced | Standard Error 1.3 |
| Topiramate | COWAT-Category | Week 12 | 17.0 Number of Words Produced | Standard Error 1.2 |
| Levetiracetam | COWAT-Category | Baseline | 21.6 Number of Words Produced | Standard Error 1.2 |
| Levetiracetam | COWAT-Category | Week 12 | 20.8 Number of Words Produced | Standard Error 0.7 |
Comparison: 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.p-value: 0.003Mixed Models Analysis
Comparison: 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 interactionp-value: 0.01Mixed Models Analysis
Comparison: 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 interactionp-value: 0.36Mixed Models Analysis
Secondary
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.
Time frame: Weeks 10, 11, 12
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zonisamide | Mean Percent Days Heavy Drinking | Week 10 | 38.4 Percentage of Days/Week | Standard Error 10.7 |
| Zonisamide | Mean Percent Days Heavy Drinking | Week 12 | 34.3 Percentage of Days/Week | Standard Error 11 |
| Zonisamide | Mean Percent Days Heavy Drinking | Week 11 | 36.6 Percentage of Days/Week | Standard Error 8.5 |
| Sugar Pill | Mean Percent Days Heavy Drinking | Week 10 | 65.7 Percentage of Days/Week | Standard Error 6.5 |
| Sugar Pill | Mean Percent Days Heavy Drinking | Week 12 | 60.9 Percentage of Days/Week | Standard Error 8 |
| Sugar Pill | Mean Percent Days Heavy Drinking | Week 11 | 61.7 Percentage of Days/Week | Standard Error 8.1 |
| Topiramate | Mean Percent Days Heavy Drinking | Week 11 | 29.5 Percentage of Days/Week | Standard Error 7.1 |
| Topiramate | Mean Percent Days Heavy Drinking | Week 10 | 32.1 Percentage of Days/Week | Standard Error 8.5 |
| Topiramate | Mean Percent Days Heavy Drinking | Week 12 | 21.0 Percentage of Days/Week | Standard Error 8.1 |
| Levetiracetam | Mean Percent Days Heavy Drinking | Week 10 | 49.6 Percentage of Days/Week | Standard Error 9.4 |
| Levetiracetam | Mean Percent Days Heavy Drinking | Week 12 | 44.5 Percentage of Days/Week | Standard Error 8.7 |
| Levetiracetam | Mean Percent Days Heavy Drinking | Week 11 | 47.9 Percentage of Days/Week | Standard Error 9.3 |
Comparison: 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.p-value: 0.013ANOVA
Comparison: 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.p-value: 0.036ANOVA
Comparison: 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.p-value: 0.24ANOVA
Comparison: 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.p-value: 0.0004ANOVA
Comparison: 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.p-value: 0.0015ANOVA
Comparison: 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.p-value: <0.0001ANOVA
Comparison: 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.p-value: 0.04ANOVA
Comparison: 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.p-value: 0.025ANOVA
Comparison: 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.p-value: 0.018ANOVA
Secondary
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.
Time frame: Weeks 10, 11, 12
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zonisamide | Percent Days Drinking | Week 10 | 61.6 Percentage of Days/ Week | Standard Error 9.5 |
| Zonisamide | Percent Days Drinking | Week 12 | 61.3 Percentage of Days/ Week | Standard Error 9.9 |
| Zonisamide | Percent Days Drinking | Week 11 | 62.1 Percentage of Days/ Week | Standard Error 9.3 |
| Sugar Pill | Percent Days Drinking | Week 10 | 72.2 Percentage of Days/ Week | Standard Error 8.3 |
| Sugar Pill | Percent Days Drinking | Week 12 | 73.1 Percentage of Days/ Week | Standard Error 7.6 |
| Sugar Pill | Percent Days Drinking | Week 11 | 68.9 Percentage of Days/ Week | Standard Error 8.6 |
| Topiramate | Percent Days Drinking | Week 12 | 51.4 Percentage of Days/ Week | Standard Error 11 |
| Topiramate | Percent Days Drinking | Week 11 | 43.8 Percentage of Days/ Week | Standard Error 9.6 |
| Topiramate | Percent Days Drinking | Week 10 | 51.8 Percentage of Days/ Week | Standard Error 10.1 |
| Levetiracetam | Percent Days Drinking | Week 12 | 78.2 Percentage of Days/ Week | Standard Error 6.2 |
| Levetiracetam | Percent Days Drinking | Week 10 | 83.6 Percentage of Days/ Week | Standard Error 5.2 |
| Levetiracetam | Percent Days Drinking | Week 11 | 87.2 Percentage of Days/ Week | Standard Error 5.1 |
Comparison: 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.p-value: 0.005ANOVA
Comparison: 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.p-value: 0.003ANOVA
Comparison: 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.p-value: 0.044ANOVA
Comparison: 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.p-value: <0.0001ANOVA
Comparison: 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.p-value: <0.0001ANOVA
Comparison: 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.p-value: 0.0004ANOVA
Comparison: 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.p-value: 0.017ANOVA
Comparison: 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.p-value: 0.0002ANOVA
Comparison: .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.p-value: 0.026ANOVA
Secondary
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.
Time frame: Baseline, Week 12
Population: Alcohol Dependent Subjects. Number of participants analyzed represent the number for whom Week 12 data was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zonisamide | Wechsler Memory Scale-3rd Ed. Spatial Span | Baseline | 10.8 units on a scale | Standard Error 0.7 |
| Zonisamide | Wechsler Memory Scale-3rd Ed. Spatial Span | Week 12 | 7.9 units on a scale | Standard Error 0.9 |
| Sugar Pill | Wechsler Memory Scale-3rd Ed. Spatial Span | Week 12 | 10.9 units on a scale | Standard Error 0.5 |
| Sugar Pill | Wechsler Memory Scale-3rd Ed. Spatial Span | Baseline | 10.5 units on a scale | Standard Error 0.6 |
| Topiramate | Wechsler Memory Scale-3rd Ed. Spatial Span | Baseline | 12.0 units on a scale | Standard Error 0.6 |
| Topiramate | Wechsler Memory Scale-3rd Ed. Spatial Span | Week 12 | 8.4 units on a scale | Standard Error 0.7 |
| Levetiracetam | Wechsler Memory Scale-3rd Ed. Spatial Span | Baseline | 10.8 units on a scale | Standard Error 0.8 |
| Levetiracetam | Wechsler Memory Scale-3rd Ed. Spatial Span | Week 12 | 10.4 units on a scale | Standard Error 0.8 |
Comparison: 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.p-value: 0.038Mixed Models Analysis
Comparison: 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.p-value: 0.0025Mixed Models Analysis
Comparison: 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.p-value: 0.3Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 12
Population: Alcohol Dependent Subjects. Number of participants analyzed represent the number for whom Week 12 data was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zonisamide | Wechsler Memory Scales (WMS)-3d Ed Digit Span-Age Adjusted Total | Baseline | 11.8 units on a scale | Standard Error 0.8 |
| Zonisamide | Wechsler Memory Scales (WMS)-3d Ed Digit Span-Age Adjusted Total | Week 12 | 10.0 units on a scale | Standard Error 0.9 |
| Sugar Pill | Wechsler Memory Scales (WMS)-3d Ed Digit Span-Age Adjusted Total | Week 12 | 12.2 units on a scale | Standard Error 0.8 |
| Sugar Pill | Wechsler Memory Scales (WMS)-3d Ed Digit Span-Age Adjusted Total | Baseline | 11.9 units on a scale | Standard Error 0.7 |
| Topiramate | Wechsler Memory Scales (WMS)-3d Ed Digit Span-Age Adjusted Total | Baseline | 12.1 units on a scale | Standard Error 0.6 |
| Topiramate | Wechsler Memory Scales (WMS)-3d Ed Digit Span-Age Adjusted Total | Week 12 | 7.7 units on a scale | Standard Error 0.6 |
| Levetiracetam | Wechsler Memory Scales (WMS)-3d Ed Digit Span-Age Adjusted Total | Baseline | 12.6 units on a scale | Standard Error 0.7 |
| Levetiracetam | Wechsler Memory Scales (WMS)-3d Ed Digit Span-Age Adjusted Total | Week 12 | 13.0 units on a scale | Standard Error 0.9 |
Comparison: 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.p-value: 0.07Mixed Models Analysis
Comparison: 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.p-value: <0.0001Mixed Models Analysis
Comparison: 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.p-value: 0.95Mixed Models Analysis