Zonisamide Treatment of Alcohol Use Disorder: an Evaluation of Efficacy and Mechanism of Action (Z-Comp)

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

Study Overview

• Status: Completed
• 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 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.

• Study Type: Interventional
• Enrollment (Actual): 156
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • UConn Health
    • New Haven, Connecticut, United States, 06520
      • Yale University
    • West Haven, Connecticut, United States, 06515
      • West Haven Veterans Affairs
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

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 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

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
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 7 weeks, then 9 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: Brand name: Zonegran
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; Other Names: Brand name: 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	percentage of subjects with no heavy drinking days (PSNHDD) The PSNHDD can be derived from each subject's Timeline Followback (TLFB) data.	over the last 8 weeks (weeks 9-16)
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.	over 16 weeks (weeks 1-16)
Number of Heavy Drinking Days Per Week	The difference in the number of heavy drinking days per week compared between groups (zonisamide and placebo) 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).	over the last 8 weeks (weeks 9-16)
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	over 16 weeks (weeks 1-16) and at 2 week and 3 month follow up
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	over 16 weeks (weeks 1-16) and at 2 week and 3 month follow up
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	over 16 weeks (weeks 1-16) and at 2 week and 3 month follow up

Collaborators and Investigators

• Sponsor: Virginia Commonwealth University
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA); Yale University; VA Connecticut Healthcare System; University of Connecticut
• Investigators: Principal Investigator: Albert Arias, MD, Virginia Commonwealth University

Study record dates

Study Major Dates

• Study Start: October 1, 2016
• Primary Completion (Actual): April 22, 2021
• Study Completion (Actual): April 22, 2021

Study Registration Dates

• First Submitted: September 9, 2016
• First Submitted That Met QC Criteria: September 9, 2016
• First Posted (Estimate): September 14, 2016

Study Record Updates

• Last Update Posted (Actual): October 13, 2022
• Last Update Submitted That Met QC Criteria: October 10, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Alcohol Dependence; Alcoholism; Alcohol Use Disorder; Zonisamide; Anticonvulsants; Alcohol Intoxication; Drinking Behaviors
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Pathologic Processes; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Alcohol Drinking; Alcoholism; Disease; 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: HM20014185; 1605017700 (Other Identifier: Yale University); 7R01AA024466-04 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

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