Effectiveness of Zonisamide in Alcohol Dependent Veterans

Effectiveness of Zonisamide in the Treatment of Alcohol Dependent Veterans

This is a randomized, placebo-controlled, double-blind, 16 week trial of the medication zonisamide for the treatment of heavy drinking alcoholic Veterans.

Study Overview

• Status: Terminated
• Conditions: Alcohol Use Disorder
• Intervention / Treatment: Drug: Placebo; Drug: Zonisamide

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 Veterans 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 Veteran sample, the investigators will include Veterans with co-morbid mood and anxiety disorders.

The investigators also plan to explore the interaction between genotype and medication on drinking outcomes.

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • VA Connecticut Healthcare System West Haven Campus, West Haven, CT

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Female/male veterans 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 alcohol dependence diagnosis by the Diagnostic and Statistical Manual IV Text Revision (DSM-IV-TR) 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., aspartate aminotransferase (AST) and alanine aminotransferase (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 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 zonisamide 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, posttraumatic stress 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 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)	Drug: Placebo; Placebo
Experimental: 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.	Drug: Zonisamide; Titration of dose to 500mg oral, daily, over 8 weeks, then 7 weeks of treatment at that dose; Other Names: Zonegran

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	over 8 weeks (weeks 9-16)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Subjects With No Heavy Drinking Days (PSNHDD)	Percentage of Subjects with No Heavy Drinking Days (PSNHDD) The PSNHDD can be derived from each subject's timeline follow back (TLFB) data.	Baseline
Gamma Glutamyl Transferase (GGT)	Difference between groups on change in levels of Gamma glutamyl transferase (GGT) over time from baseline to endpoint, which will include several interim data points. This will analyzed with a mixed models longitudinal analysis (repeated measures). Normal range for GGT levels are 10 U/L - 65 U/L - above 65 U/L above 65 U/L is considered a high GGT level	Baseline, Week 4, 8 and 16
Number of Heavy Drinking Days Per Week	The difference in the number of heavy drinking days per week compared between groups (zonisamide and placebo) during the time spent on the target dose of the medication. Performed using a mixed models longitudinal analysis (repeated measures).	over 16 weeks (weeks 1-16)
Alcohol Urge Questionnaire Score (AUQ)	This is the change in AUQ scores (urge to drink) measured weekly compared between groups using repeated measures. The AUQ is a 8 item participant rated questionnaire. Participants indicate how much they agree or disagree with the statements by selecting one number, 1 strongly disagree through 7 strongly agree. Participants can scores between 8 (lowest) - 56 (highest), the higher the score the more urge to drink.	over 16 weeks (weeks 1-16)
Change in Quality of Life	Change in quality of life scores measured by the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). The Q-LES-Q is a 16 item participant rated questionnaire. Participants indicate how they are feeling over the 16 item from Very poor (1), Poor (2), Fair (3), Good (4), and Very Good (5). Participants can scores between 14 (lowest) - 70 (highest) the higher the score more satisfied with quality of life.	Over 16 weeks (Baseline and 16 weeks)
Level of Alcohol-related Problems (SIP)	Change in level of alcohol-related problems measured by the Short Index of Problems (SIP). The SIP is a 15 item participant rated questionnaire. Participants rate the number of events that drinkers sometimes experience. Participants indicate how often each of the items has happened. They are scored by selecting one number, 0 Never; 1 Once or a few times; 2 Once or twice a week; 3 Daily or almost daily. Participants can scores between 0 (lowest) - 45 (highest) - the higher score the more drinking problems.	over 16 weeks (Baseline and Week 16)

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Albert J Arias, MD, VA Connecticut Healthcare System West Haven Campus, West Haven, CT

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2015
• Primary Completion (Actual): October 1, 2018
• Study Completion (Actual): October 1, 2018

Study Registration Dates

• First Submitted: February 14, 2015
• First Submitted That Met QC Criteria: February 14, 2015
• First Posted (Estimate): February 23, 2015

Study Record Updates

• Last Update Posted (Actual): December 7, 2020
• Last Update Submitted That Met QC Criteria: December 2, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Alcohol Dependence; Alcoholism; Alcohol Use Disorder; Zonisamide; Anticonvulsants; Drinking Behaviors; Alcoholic Intoxication
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Alcohol Drinking; Alcoholism; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Anticonvulsants; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Zonisamide
• Other Study ID Numbers: CLNA-003-14S; ICX001012A (Other Identifier: VA Connecticut Healthcare System)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes