Clinical Trial of Topiramate for Cocaine Addiction

Study Overview
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Brief Summary
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This is an outpatient clinical trial of topiramate for addressing cocaine dependence and reduction of cocaine associated behaviors in opiate dependent drug users maintained on methadone treatment. The study aims to answer whether topiramate is safe and acceptable to methadone patients reduces cocaine use helps with collateral problems such as alcohol abuse, tobacco dependence, anxiety, PTSD and/or pain symptoms. The study will also evaluate topiramate effect on neuro-cognitive performance.

Detailed Description
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This is an outpatient clinical trial of topiramate treatment for cocaine dependence and reduction of cocaine-associated HIV risk behavior. Topiramate is of high current interest in this regard, having been identified my National Institute on Drud Abuse (NIDA) leadership as among only a small number of tested candidates providing a positive signal and warranting further clinical investigation (Vocci, 2005). Topiramate is a marketed antiepileptic that enhances the GABAergic system and antagonizes the glutamatergic system, both new targets in the search for anti-cocaine treatments. A published pilot trial has supported topiramate's efficacy, and it is especially intriguing as potentially beneficial against other disorders prevalent among drug users, such as mood, anxiety, panic disorders, PTSD, pain and cognitive dysfunction, that may contribute to drug use. Design/Methods: This is phase II, double-blind randomized (stratified) 4 group, 2x2 design, evaluating topiramate versus placebo under each of two levels of cocaine-abstinence motivation -- cocaine-abstinence-contingent versus non-contingent voucher incentives. Conduct will be in a methadone maintenance context to ensure adequate retention and adherence, with participants dually dependent on opioids and cocaine. The target topiramate stabilization dose is 300 mg/day (150 mg b.i.d.), with one dose per day being observed at the clinic. The voucher-incentive manipulation provides valuable information about the role of motivation in modulating medication effects; it also provides a positive control condition to document the sensitivity of the study methods for detecting therapeutic benefit. Enrollment will be 300 patients ( 240 completers, 60/group). Participation will be up to 33 weeks - Baseline/Placebo-Run-in (5 weeks), Randomized Medication Treatment (20 weeks, induction, stable dosing, taper), Randomized Voucher Treatment (12 weeks, embedded in Medication period), and Therapeutic Disposition (up to 8 weeks). Data analysis focuses on the 8-week period of stable dosing and concurrent vouchers. The primary outcome variable is days abstinent from cocaine, as determined by a combination of self-report and objective confirmation by quantitative urinalysis toxicology of cocaine metabolite levels and application of the Preston rule for determining abstinence. Secondary outcome variables are measures of adverse behaviors and symptoms commonly co-occurring in cocaine abusers (alcohol abuse, tobacco use, depression, anxiety, PTSD, pain, neuro-cognitive and psychomotor performance dysfunction) that may contribute to drug use and/or detrimental effects. Significance: This randomized controlled clinical trial will provide valuable information about the actions and therapeutic effectiveness of the promising candidate anti-cocaine pharmacotherapy topiramate, and about the conditions, correlates, and modulators of any observed effectiveness. It will also provide valuable methodological information contributing to the continuing evolution of clinical trial methods for evaluating potential drug abuse treatment medications.

Official Title
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Clinical Trial of Topiramate for Cocaine Addiction

Conditions
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Cocaine Dependence

Intervention / Treatment
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* Drug: topiramate
* Behavioral: Contingency Reinforcement
* Drug: placebo + NonCR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 - 55 years old active opioid and cocaine dependence seeking treatment for cocaine and opioid dependence eligible for methadone maintenance per state and federal regulations able and willing to provide a urine sample thrice a week willing to answer questionnaires on a weekly basis willing to provide breath samples for presence of alcohol thrice weekly fluent in the English language Exclusion Criteria: allergy to sulfonamide drugs diabetes, respiratory insufficiency, renal tubular acidosis, renal insufficiency, heart failure, liver insufficiency, chronic diarrhea, other chronic diseases predisposing to a risk of acidosis history of nephrolithiasis HIV positive individuals who meet AIDS criteria by CDC criteria or are taking antiretroviral medications serious psychiatric illness (psychosis, dementia) glaucoma or family history of glaucoma prostate hyperplasia, shy bladder, irritable bladder, difficulty providing urine samples on demand female participants: being pregnant, lactating, or unwilling to use an effective method of contraception use of antiepileptic agents benzodiazepine dependence latex allergy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 topiramate + CR<br>topiramate and contingency reinforcement for urine sample confirming cocaine abstinence | Drug: topiramate<br>* topiramate powder 0mg - 150 mg with lactate in blind capsules. Two capsules dispensed daily. One capsule ingested under supervision at the methadone window. One capsule to be ingested at home at bedtime. Participant is expected to return the empty blister pack on the following day. capsules are administered from week 4 through 25 of the trial<br>* Other names: CAS 97240-79-4;Behavioral: Contingency Reinforcement<br>* monetary reward for self-reported cocaine abstinence confirmed by urine toxicology results<br>* Other names: contingency management;|
| Experimental: 2 topiramate + NonCR<br>Topiramate and random reinforcement irrespective of cocaine use | Drug: topiramate<br>* topiramate powder 0mg - 150 mg with lactate in blind capsules. Two capsules dispensed daily. One capsule ingested under supervision at the methadone window. One capsule to be ingested at home at bedtime. Participant is expected to return the empty blister pack on the following day. capsules are administered from week 4 through 25 of the trial<br>* Other names: CAS 97240-79-4;|
| Placebo Comparator: 4 Placebo + NonCR<br> | Drug: placebo + NonCR<br>* participant receives placebo capsules and monetary reinforcers by chance, irrespective of cocaine use or abstinence<br>|
| Active Comparator: 3 Placebo + CR<br>Placebo and contingency reinforcement for urine sample confirming cocaine abstinence | Behavioral: Contingency Reinforcement<br>* monetary reward for self-reported cocaine abstinence confirmed by urine toxicology results<br>* Other names: contingency management;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Cocaine Positive Urine Samples Per Treatment Condition | Percentage of cocaine positive urine samples as measured by Preston new use rule (50% reduction in cocaine metabolites from previous urine) | Urine samples collected 3 times weekly from week 1 through 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Voucher Earnings | Voucher earnings used as a measurement of contigency management (CM) or operate conditioning. Volunteers were rewarded vouchers of escalating monetary value for cocaine abstinence, as indicated by a cocaine negative urine sample. The first cocaine negative urine earned a $2.50 voucher, and the value increased by $1.50 for each subsequent cocaine negative sample. Volunteers were awarded a bonus of $10.00 for every three consecutive cocaine negative urine samples. Urine samples were collected 3 times per week, and vouchers were attainable between Weeks 8 and 20. Contingency management as a measurement of operant conditioning in which positive reinforcement is applied (in this case vouchers of monetary value) and cocaine abstinence | 12 weeks (Weeks 8-20) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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addiction, drug dependence, stimulant