Alcohol Use Disorder
Conditions
Keywords
Alcohol Use Disorder, Alcoholism, Alcohol Dependence, Zonisamide, Alcohol Intoxication, Drinking Behaviors, Anticonvulsants
Brief summary
This is a randomized, placebo-controlled, double-blind, 16 week trial of the medication zonisamide for the treatment of heavy drinking alcoholic civilians.
Detailed description
This is a 16-week randomized, double blind, placebo-controlled trial designed to determine the effectiveness of zonisamide treatment for reducing heavy drinking and overall drinking in 160 treatment-seeking, regularly heavy drinking, alcohol-dependent civilians who want to quit drinking or reduce consumption to non-hazardous levels. The investigators will use state-of-the-art methodology and outcome assessments, including medical management (MM) therapy (a minimal behavioral intervention aimed at reinforcing treatment goals and adherence to medication), which is simple and easily implemented in primary care settings. The use of MM in the study will increase the generalizability of results, allowing a more accurate assessment of zonisamide's effectiveness than if a more intensive behavioral intervention were to be used. To demonstrate zonisamide's effectiveness in a representative civilian sample, the investigators will include civilians with co-morbid mood and anxiety disorders.
Interventions
DRUGZonisamide
Titration of dose to 500mg oral, daily, over 8 weeks, then 7 weeks of treatment at that dose
DRUGPlacebo
Placebo
Sponsors
University of Connecticut
Yale University
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
VA Connecticut Healthcare System
Virginia Commonwealth University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Female/male aged 21-70 years * Regular heavy drinkers as defined by averaging 2 heavy drinking days per week over 90 days baseline pre-treatment timeline follow-back (TLFB), and current DSM-IV-TR alcohol dependence that recognize a need to reduce or stop drinking (Note: heavy drinking days will be defined as follows; for men greater than or equal to 5 drinks in a day and for women greater than or equal to 4 drinks in a day) * Women of child-bearing potential (i.e., no hysterectomy, bilateral oophorectomy, or tubal ligation or \<2 years postmenopausal), must be non-lactating, practicing a reliable method of birth control, and have a negative serum pregnancy test prior to initiation of treatment; * Willingness to provide signed, informed consent to participate in the study
Exclusion criteria
* A current, clinically significant physical disease or abnormality (i.e., neurologic, renal, rheumatologic, gastrointestinal, hematologic, pulmonary, endocrine, cardiovascular, hepatic, or autoimmune disease that, in the context of the study would represent a risk to the subject, or significant laboratory abnormalities such as hepatic aminotransferase levels (i.e., AST and ALT) greater than 300% of the upper limit of normal or direct bilirubin levels \>150% of the upper limit of normal) on the basis of medical history, physical examination, or routine laboratory evaluation. Other specific exclusionary disorders include; * History of clinically significant renal calculi or renal failure; a significant indication of renal compromise will be defined by an elevation of serum creatinine above the investigators' laboratory's limit of normal, or a known history of renal failure or chronic renal disease, or any current or chronic disease that could reasonably be expected to result in renal failure * History of hypersensitivity to ZNS or any sulfonamide, Stevens-Johnson Syndrome, penicillin allergy, or history of any severe drug allergic reaction; History of systemic autoimmune disease such as lupus erythematosis, fibromyalgia, or rheumatoid arthritis; * Current blood dyscrasia or a history of such, with the exception of a past history of iron deficiency anemia * History of seizure disorder * Use of any of a number of medications that might prominently influence drinking patterns or cause risk of harm or injury (e.g., topiramate, disulfiram, naltrexone, acetazolamide, stimulants such as amphetamine, or tramadol; Schizophrenia, bipolar disorder, PTSD, or substantial suicide or violence risk (i.e., can't be managed safely in the outpatient setting) on the basis of history or psychiatric examination; j) currently dependent on opioids or benzodiazepines or other sedatives * Considered by the investigators to be clinically inappropriate for study participation or have participated in another pharmacotherapy study in the past thirty days * Subjects with prominent signs of physical dependence, and/or medical comorbidities such that study physicians feel they should consider immediate detoxification, and referred for medical detoxification in a normal treatment setting
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Drinks Per Week | over 8 weeks (weeks 9-16) | Difference between groups in the number of total standard drinks per week over 8 weeks (weeks 9-16, the weeks on the target dose) performed using a mixed models longitudinal analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gamma Glutamyl Transferase (GGT) Levels | over 16 weeks (weeks 1-16) | Difference between groups on levels of GGT over time from baseline to endpoint, which will includes two interim data points for a total of four time points. This will analyzed with a mixed models longitudinal analysis (repeated measures). Levels are in Units per Liter. |
| Number of Heavy Drinking Days Per Week | over the last 8 weeks (weeks 9-16) | The difference in the number of heavy drinking days per week compared between groups (zonisamide and placebo) for the last 8 weeks of treatment (during the time spent on the target dose of the medication). Performed using a mixed models longitudinal analysis (repeated measures). |
| Percentage of Subjects With No Heavy Drinking Days | over the last 8 weeks (weeks 9-16) | percentage of subjects with no heavy drinking days (PSNHDD) The PSNHDD can be derived from each subject's Timeline Followback (TLFB) data. |
| Change in Quality of Life | over 16 weeks (weeks 1-16) and at 2 week and 3 month follow up | Change in quality of life scores measured by the Q-LES-Q. ' Min: 16 Max: 80 Higher Scores = Higher Life Enjoyment |
| Level of Alcohol-related Problems | over 16 weeks (weeks 1-16) and at 2 week and 3 month follow up | level of alcohol-related problems measured by the Short Index of Problems (SIP), total score Min score: 0 Max Score: 45 Higher score= more problems |
| Change in Alcohol Urge Questionnaire Score (AUQ) | over 16 weeks (weeks 1-16) and at 2 week and 3 month follow up | This is the change in AUQ scores (urge to drink) measured weekly compared between groups using repeated measures Min value: 8 Max value: 42 higher score = worse craving |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Zonisamide Subjects will receive zonisamide titrated to a target dose of 500mg orally, daily, double-blind (Titration of dose to 500mg oral, daily, over 8 weeks, then 7 weeks of treatment at that dose). Subjects may increase their dose to 600mg daily during the target treatment period if it is thought to be beneficial.
Zonisamide: Titration of dose to 500mg oral, daily, over 8 weeks, then 7 weeks of treatment at that dose | 77 |
| Placebo Patients will receive placebo pills that are made to match the zonisamide medication (via over-encapsulation, double-blind, subjects will receive same number of capsules as the active medication group)
Placebo: Placebo | 79 |
| Total | 156 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 28 | 17 |
Baseline characteristics
| Characteristic | Zonisamide | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 51.2 years STANDARD_DEVIATION 11.6 | 51.5 years STANDARD_DEVIATION 10.5 | 51.9 years STANDARD_DEVIATION 9.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 11 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 70 Participants | 145 Participants | 75 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 24 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 63 Participants | 129 Participants | 66 Participants |
| Region of Enrollment United States | 77 participants | 156 participants | 79 participants |
| Sex: Female, Male Female | 31 Participants | 58 Participants | 27 Participants |
| Sex: Female, Male Male | 46 Participants | 98 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 77 | 1 / 79 |
| other Total, other adverse events | 73 / 77 | 76 / 79 |
| serious Total, serious adverse events | 2 / 77 | 2 / 79 |
Outcome results
Primary
Number of Drinks Per Week
Difference between groups in the number of total standard drinks per week over 8 weeks (weeks 9-16, the weeks on the target dose) performed using a mixed models longitudinal analysis.
Time frame: over 8 weeks (weeks 9-16)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zonisamide | Number of Drinks Per Week | 19.7 Number of drinks per week | Standard Error 2.2 |
| Placebo | Number of Drinks Per Week | 23.7 Number of drinks per week | Standard Error 1.98 |
p-value: 0.013Mixed Models Analysis
Secondary
Change in Alcohol Urge Questionnaire Score (AUQ)
This is the change in AUQ scores (urge to drink) measured weekly compared between groups using repeated measures Min value: 8 Max value: 42 higher score = worse craving
Time frame: over 16 weeks (weeks 1-16) and at 2 week and 3 month follow up
Population: Due to protocol changes over the course of the study, data for some outcomes was not collected for all participants. Results are reported for all participants for whom data is available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zonisamide | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 5 (Week 5) | 13.84 score on a scale | Standard Deviation 1.09 |
| Zonisamide | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 8 (Week 11) | 13.6 score on a scale | Standard Deviation 1.2 |
| Zonisamide | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 4 (Week 3) | 15.2 score on a scale | Standard Deviation 1.12 |
| Zonisamide | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 9 (Week 13) | 13.6 score on a scale | Standard Deviation 1.2 |
| Zonisamide | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 6 (Week 7) | 12.8 score on a scale | Standard Deviation 0.96 |
| Zonisamide | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 10 (Week 16) | 13.36 score on a scale | Standard Deviation 1.2 |
| Zonisamide | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 3 (Week 1) | 14.4 score on a scale | Standard Deviation 0.96 |
| Zonisamide | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 11 (2 Week follow up) | 14.56 score on a scale | Standard Deviation 0.17 |
| Zonisamide | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 7 (Week 9) | 14.08 score on a scale | Standard Deviation 1.2 |
| Zonisamide | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 12 (3 Month follow up) | 14.16 score on a scale | Standard Deviation 1.28 |
| Zonisamide | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 2 (Baseline) | 16.2 score on a scale | Standard Deviation 1.04 |
| Placebo | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 12 (3 Month follow up) | 13.68 score on a scale | Standard Deviation 0.96 |
| Placebo | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 2 (Baseline) | 16.06 score on a scale | Standard Deviation 1.04 |
| Placebo | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 3 (Week 1) | 17.12 score on a scale | Standard Deviation 1.2 |
| Placebo | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 4 (Week 3) | 15.28 score on a scale | Standard Deviation 0.96 |
| Placebo | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 5 (Week 5) | 14.4 score on a scale | Standard Deviation 1 |
| Placebo | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 6 (Week 7) | 14.72 score on a scale | Standard Deviation 1.04 |
| Placebo | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 7 (Week 9) | 16.24 score on a scale | Standard Deviation 1.12 |
| Placebo | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 8 (Week 11) | 14.56 score on a scale | Standard Deviation 1.12 |
| Placebo | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 9 (Week 13) | 14.4 score on a scale | Standard Deviation 0.96 |
| Placebo | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 10 (Week 16) | 13.36 score on a scale | Standard Deviation 0.96 |
| Placebo | Change in Alcohol Urge Questionnaire Score (AUQ) | Visit 11 (2 Week follow up) | 14.32 score on a scale | Standard Deviation 1.04 |
p-value: 0.889ANOVA
Secondary
Change in Quality of Life
Change in quality of life scores measured by the Q-LES-Q. ' Min: 16 Max: 80 Higher Scores = Higher Life Enjoyment
Time frame: over 16 weeks (weeks 1-16) and at 2 week and 3 month follow up
Population: Due to protocol changes over the course of the study, data for some outcomes was not collected for all participants. Results are reported for all participants for whom data is available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zonisamide | Change in Quality of Life | Visit 2 (Baseline) | 60 score on a scale | Standard Error 13.6 |
| Zonisamide | Change in Quality of Life | Visit 10 (Week 16) | 61.6 score on a scale | Standard Error 1.6 |
| Zonisamide | Change in Quality of Life | Visit 11 (2 Week Follow up) | 68 score on a scale | Standard Error 2.96 |
| Zonisamide | Change in Quality of Life | Visit 12 (3 Month Follow up) | 65.12 score on a scale | Standard Error 12.96 |
| Placebo | Change in Quality of Life | Visit 12 (3 Month Follow up) | 64.64 score on a scale | Standard Error 13.76 |
| Placebo | Change in Quality of Life | Visit 2 (Baseline) | 59.84 score on a scale | Standard Error 12.48 |
| Placebo | Change in Quality of Life | Visit 11 (2 Week Follow up) | 60.48 score on a scale | Standard Error 2.72 |
| Placebo | Change in Quality of Life | Visit 10 (Week 16) | 63.2 score on a scale | Standard Error 13.44 |
p-value: 0.482ANOVA
Secondary
Gamma Glutamyl Transferase (GGT) Levels
Difference between groups on levels of GGT over time from baseline to endpoint, which will includes two interim data points for a total of four time points. This will analyzed with a mixed models longitudinal analysis (repeated measures). Levels are in Units per Liter.
Time frame: over 16 weeks (weeks 1-16)
Population: Due to protocol changes over the course of the study, data for some outcomes was not collected for all participants or collected at slightly different timepoints. Results are reported for all participants for whom data is available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zonisamide | Gamma Glutamyl Transferase (GGT) Levels | Visit 5 (Week 5) | 52.33 International Units per Liter (UI/L) | Standard Error 23.7 |
| Zonisamide | Gamma Glutamyl Transferase (GGT) Levels | Visit 9 (Week 13) | 16.0 International Units per Liter (UI/L) | Standard Error 0 |
| Zonisamide | Gamma Glutamyl Transferase (GGT) Levels | Visit 7 (Week 9) | 59.49 International Units per Liter (UI/L) | Standard Error 10.05 |
| Zonisamide | Gamma Glutamyl Transferase (GGT) Levels | Visit 10 (Week 16) | 54.48 International Units per Liter (UI/L) | Standard Error 7.83 |
| Zonisamide | Gamma Glutamyl Transferase (GGT) Levels | Baseline Visit | 78.35 International Units per Liter (UI/L) | Standard Error 12.1 |
| Placebo | Gamma Glutamyl Transferase (GGT) Levels | Visit 10 (Week 16) | 56.65 International Units per Liter (UI/L) | Standard Error 10.23 |
| Placebo | Gamma Glutamyl Transferase (GGT) Levels | Baseline Visit | 71.88 International Units per Liter (UI/L) | Standard Error 11.12 |
| Placebo | Gamma Glutamyl Transferase (GGT) Levels | Visit 5 (Week 5) | 64.4 International Units per Liter (UI/L) | Standard Error 29.35 |
| Placebo | Gamma Glutamyl Transferase (GGT) Levels | Visit 7 (Week 9) | 70.24 International Units per Liter (UI/L) | Standard Error 24.43 |
| Placebo | Gamma Glutamyl Transferase (GGT) Levels | Visit 9 (Week 13) | 25.75 International Units per Liter (UI/L) | Standard Error 5.75 |
p-value: 0.054ANOVA
Secondary
Level of Alcohol-related Problems
level of alcohol-related problems measured by the Short Index of Problems (SIP), total score Min score: 0 Max Score: 45 Higher score= more problems
Time frame: over 16 weeks (weeks 1-16) and at 2 week and 3 month follow up
Population: Due to protocol changes over the course of the study, data for some outcomes was not collected for all participants. Results are reported for all participants for whom data is available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zonisamide | Level of Alcohol-related Problems | Visit 10 (Week 16) | 8.32 score on a scale | Standard Error 1.23 |
| Zonisamide | Level of Alcohol-related Problems | Visit 12 (3 Month follow up) | 6.92 score on a scale | Standard Error 1.08 |
| Zonisamide | Level of Alcohol-related Problems | Visit 2 (Baseline) | 14.94 score on a scale | Standard Error 1.13 |
| Placebo | Level of Alcohol-related Problems | Visit 10 (Week 16) | 11.6 score on a scale | Standard Error 1.03 |
| Placebo | Level of Alcohol-related Problems | Visit 2 (Baseline) | 16.4 score on a scale | Standard Error 0.94 |
| Placebo | Level of Alcohol-related Problems | Visit 12 (3 Month follow up) | 9.69 score on a scale | Standard Error 1.18 |
p-value: 0.04ANOVA
Secondary
Number of Heavy Drinking Days Per Week
The difference in the number of heavy drinking days per week compared between groups (zonisamide and placebo) for the last 8 weeks of treatment (during the time spent on the target dose of the medication). Performed using a mixed models longitudinal analysis (repeated measures).
Time frame: over the last 8 weeks (weeks 9-16)
Population: Due to protocol changes over the course of the study, data for some outcomes was not collected for all participants. Results are reported for all participants for whom data is available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zonisamide | Number of Heavy Drinking Days Per Week | 2.7 Number of heavy drinking days/week | Standard Error 0.34 |
| Placebo | Number of Heavy Drinking Days Per Week | 3.3 Number of heavy drinking days/week | Standard Error 0.3 |
p-value: 0.035Mixed Models Analysis
Secondary
Percentage of Subjects With No Heavy Drinking Days
percentage of subjects with no heavy drinking days (PSNHDD) The PSNHDD can be derived from each subject's Timeline Followback (TLFB) data.
Time frame: over the last 8 weeks (weeks 9-16)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zonisamide | Percentage of Subjects With No Heavy Drinking Days | 8.97 Percentage of participants |
| Placebo | Percentage of Subjects With No Heavy Drinking Days | 5.13 Percentage of participants |
p-value: 0.148Chi-squared