Effect of Zonisamide on Cocaine Reinforcement, Craving, and Relapse

Study Overview
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Brief Summary
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This is a residential pilot trial to evaluate the pharmacodynamic interaction between zonisamide and cocaine, with the goal of evaluating zonisamide's potential for the treatment of cocaine dependence.

Detailed Description
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This is a residential pilot trial to evaluate the effect of zonisamide (ZNS) on cocaine reinforcement, craving and relapse. Cocaine addiction remains a major social and medical problem that imposes a significant burden on our society, as more than a half million cocaine dependent individuals are seeking treatment every year. Medications that act to antagonize the glutamate system and/or increase the GABA-system are new targets in the search towards effective cocaine treatment. ZNS is part of a new line of antiepileptic agents that act both as glutamate antagonists and to enhance the Gamma-AminoButyric acid (GABA) system. Topiramate, a similar agent, showed a positive signal in a pilot trial for cocaine dependence. ZNS has the advantages of a longer half-life requiring only once a day dosing and, being better tolerated, it requires a shorter induction phase and can be administered at higher doses. We hypothesize that ZNS in moderate to high doses will attenuate the central effect of cocaine and improve the neural perturbations resulting from cocaine use, thus decreasing cocaine craving. Healthy, adult cocaine dependent volunteers will be enrolled on our residential unit for 44 days for this double-blind within subject study. The pharmacodynamic interactions between ZNS and cocaine will be measured in cocaine self-administration procedure offering alternative reinforcers with monetary values. Cocaine reinforcing effect will be evaluated over a range of doses, and subjective and objective outcomes on mood and behavior will be collected. In addition, the effect of ZNS on ad-lib smoking will be studied on the days when no other procedure interferes with smoking behaviors. Neurocognitive and psychomotor effects of ZNS treatment will also be studied with an extensive test battery on the day of the week when no cocaine is administered. This study will explore the potential therapeutic effect of ZNS for the treatment of cocaine dependence while providing necessary safety assessments required for possible future outpatient clinical trials.

Official Title
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Effect of Zonisamide on Cocaine Reinforcement, Craving, and Relapse

Conditions
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Cocaine Dependence

Intervention / Treatment
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* Drug: Zonisamide
* Drug: Placebo
* Drug: Cocaine Hydrochloride
* Behavioral: Neurocognitive and Performance Battery
* Behavioral: Smoking Assessments


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age at least 21 years old, not older than 45 years. Evidence of cocaine dependence. Not seeking treatment for cocaine abuse. Able and willing to be restricted to our unit for 6-7 weeks. Able to answer frequent questionnaires reliably and consistently. Smoker. Exclusion Criteria: Allergy to Sulfonamide drugs (e.g. topiramate, zonisamide, sulfamethoxazole/trimethoprim). Diabetes, respiratory insufficiency, renal tubular acidosis or renal insufficiency, heart failure, liver insufficiency, chronic diarrhea, other chronic diseases predisposing to acidosis. Renal insufficiency defined as serum creatine > 1.30 mg/DL for males or > 1.03 mg/DL for females. History of nephrolithiasis, unexplained hematuria on screening urinalysis. History of head injury (with loss of consciousness longer than a few minutes). History of seizure, or use of antiepileptic medications. HIV positive individuals who meet AIDS by Centers for Disease Control (CDC) criteria or are on antiretroviral medications. BMI < 19 or BMI > 34. Total cholesterol > 240mg%. Serous psychiatric illness with psychosis, dementia. Glaucoma, family history of glaucoma, one-sided blindness. For female participants: being pregnant, lactating or not using an effective method of contraception. Physical dependence on any drug other than cocaine, nicotine, or caffeine.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zonisamide<br>Participants administered blind capsules containing either placebo or zonisamide. | Drug: Zonisamide<br>* Eight capsules administered daily in split doses at 22:00 and 09:00.<br>* Other names: CAS 68291-97-4,;Drug: Cocaine Hydrochloride<br>* Cocaine Challenge Sessions: Human laboratory sessions with administration of moderate doses of cocaine by the intravenous route under controlled conditions and cardiovascular monitoring.<br>* Other names: C17H21NO4;Behavioral: Neurocognitive and Performance Battery<br>* Participants will complete tests to assess their abilities and performances on a number of tasks given by a computer or other type of equipment.<br>Behavioral: Smoking Assessments<br>* Participants answer questions about smoking and smoking behaviors are monitored.<br>|
| Placebo Comparator: Placebo<br>Participants administered only placebo capsules containing lactose. | Drug: Placebo<br>* capsules administered in split doses at 22:00 and 09:00.<br>Drug: Cocaine Hydrochloride<br>* Cocaine Challenge Sessions: Human laboratory sessions with administration of moderate doses of cocaine by the intravenous route under controlled conditions and cardiovascular monitoring.<br>* Other names: C17H21NO4;Behavioral: Neurocognitive and Performance Battery<br>* Participants will complete tests to assess their abilities and performances on a number of tasks given by a computer or other type of equipment.<br>Behavioral: Smoking Assessments<br>* Participants answer questions about smoking and smoking behaviors are monitored.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Visual Analog Questionnaire (VAQ) Score | VAQ measures the change in effect after dose administration. Participants rate 6 items (Any Drug Effect, Rush, Good Effects, Bad Effects, Liking, & Desire for Cocaine) by pointing an arrow along a 100-point line anchored at either end with none (0) & extremely (100). Each participant's score is equal to the sum of all 6 ratings, & the mean of all participant's scores is reported across each condition. The VAQ is only administered to subjects in the zonisamide (Zon) condition (n=8). Repeated within-subject measures ANOVA performed to observe the main effects of Zon dose (0, 300, & 600mg) & cocaine dose (1, 20, & 40mg), & their interaction. All 8 subjects who received Zon completed both 300mg & 600mg doses. Assessments obtained on Week 1 (0mg Zon), Week 3 (300mg Zon), & Week 5 (600mg Zon), in which all 3 cocaine were co-administered at these times. Cocaine not administered (only Zon) during Weeks 2 & 4, thus no measures taken at these times | Weeks 1-5; mean of weeks 1, 3 and 5 reported | 
| Behavioral Choice Measures | In each condition of cocaine-zonisamide dose, participants were asked to choose whether they would rather have a repeated cocaine dose (same dose as most recent administration) or cash of varying monetary value. The mean number of cocaine choices across each drug condition are reported. This measure only included participants in the zonisamide (Zon) condition (n=8), with each arm representing variation in co-administration of cocaine-Zon. Repeated within-subject measures ANOVA performed to observe the main effects of zonisamide dose (0, 300, and 600mg) and cocaine dose (1, 20, and 40mg), and their interaction. Only participants who received the active zonisamide medication (n=8) were included in this portion of the analysis. During self-administration sessions are every 15 min over 1hr45min period. Assessment on Weeks 1 (0mg Zon), 3 (300mg Zon), 5 (600mg Zon), in which varying cocaine doses co-administered. Cocaine not administered (only Zon) during Weeks 2 & 4 | Weeks 1-5, mean of weeks 1, 3 and 5 reported | 
| Cocaine Craving | Cocaine craving measured by Cocaine Selectivity Severity Assessment (CSSA). The CSSA is a reliable and valid tool to measure cocaine withdrawal severity within a 24 hr period, and has been shown to predict treatment response in a treatment setting. Participants are asked to rate 18-items on a Likert scale 0-7, with composite scores ranging 0-126 and higher numbers indicative of more severe withdrawal. Mean scores on CSSA across 39-day time period are reported. | Day 1-39 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drug Value Questionnaire | Street Value of Sampled Dose. After co-administration of cocaine-zonisamide, participants were asked to hypothetically estimate the value of the drug they received, if they were to purchase it on the street. The mean value (dollars) across all drug conditions is reported here. Repeated within-subject measures ANOVA performed to observe the main effects of zonisamide dose (0, 300, and 600mg) and cocaine dose (0, 20, and 40mg), and their interaction. Only participants who received the active zonisamide medication (n=8) were included in this portion of the analysis. Additionally, all 8 subjects who received zonisamide completed both 300mg and 600mg doses. Within-subject repeated interval during self-administration sessions. Cocaine not administered (only Zon) during Weeks 2 & 4, thus no measures taken at these times | Weeks 1-5; mean of weeks 1, 3 and 5 reported | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cocaine, addiction, drug dependence, anticonvulsant, zonisamide, drug self-administration, nicotine withdrawal, neurocognition