Topiramate Treatment of Problem Drinkers

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of topiramate in reducing drinking and heavy drinking frequency in problem drinkers. We hypothesize that at a dosage of up to 200mg/day, topiramate will be well tolerated in this patient population and that, compared to placebo treatment, topiramate will result in a greater reduction in the frequency of both drinking days and heavy drinking days.

Detailed Description
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It is estimated that 30% of the general population are problem drinkers (NIAAA 2007). Despite its high prevalence, problem drinkers are understudied, particularly with respect to medications that may help them to reduce their drinking to safe levels. The study will extend to this patient population findings from a trial of topiramate, which showed the drug to be well tolerated and efficacious in moderately-severe alcohol-dependent patients (Johnson et al. 2003). This is a 13-week, double-blind, placebo-controlled study of topiramate (12 weeks during which the dosage of study medication is gradually increased up to 200 mg orally and then maintained, and 1 week of medication taper) and medical management counseling to reduce drinking among problem drinkers (i.e., heavy drinkers without evidence of physical dependence on alcohol) who want to reduce their drinking. Participants attend weekly study visits for the first 5 weeks and then bi-weekly visits for the last 8 weeks of the study, and are randomly assigned to receive topiramate or placebo on a daily basis. In addition to study visits, participants report daily moods, drinking, and medication usage through an Interactive Voice Response (IVR) system they call each night. In-person follow-up evaluations are conducted at 3 and 6 months post-treatment to provide a measure of the durability of treatment effects. This study also aims to examine the relation between genotype and the response to topiramate treatment. An additional aim is to conduct a substudy to examine neural cells generated from skin fibroblast cells obtained from study participants via a skin biopsy (participation in the substudy is completely optional). Initially, we will examine variables key to reliably generating neurons from the cells and characterize these neurons using a variety of laboratory measures. A longer term goal is to compare gene expression in individuals who show a robust reduction in drinking following treatment with topiramate with those who show no beneficial treatment effects. A second additional aim is to explore whether the therapeutic and adverse effects of topiramate are similar in patients on a stable regimen of an antidepressant to those not receiving such therapy. Although exploratory, given the absence of data that directly address this issue, we will stratify subjects by the presence or absence of current antidepressant therapy. Careful evaluation of the study's hypotheses will provide important information on the efficacy and mechanism of effects of topiramate as a treatment for problem drinkers.

Official Title
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Topiramate Treatment of Problem Drinkers

Conditions
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Alcohol Drinking

Intervention / Treatment
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* Drug: topiramate
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 18 to 65 years, inclusive; have an average weekly ethanol consumption of >=24 standard drinks for men, or >=18 standard drinks for women; be able to read English at the 8th grade or higher level and show no evidence of significant cognitive impairment; be willing to nominate an individual who will know the patient's whereabouts in order to facilitate follow up during the study; if a woman of child-bearing potential (i.e., who has not had a hysterectomy, bilateral oophorectomy, tubal ligation or who are less than two 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; if applicable, individuals being treated with a single antidepressant that has been stable in dosage for a minimum of four weeks; and be willing to provide signed, informed consent to participate in the study (including a willingness to reduce drinking to non-hazardous levels). Exclusion Criteria: a current, clinically significant physical disease or abnormality on the basis of medical history, physical examination, or routine laboratory evaluation, including direct bilirubin elevations of >110% or transaminase elevations >300% normal (We will not exclude patients with hypertension, diabetes mellitus, asthma or other common medical conditions, as long as these are adequately controlled and the patient has an ongoing relationship with a primary-care practitioner); a history of nephrolithiasis; a history of glaucoma; a serious psychiatric illness (i.e., schizophrenia, bipolar disorder, severe or psychotic major depression, panic disorder, borderline or antisocial personality disorder, organic mood or mental disorders, eating disorder, or substantial suicide or violence risk) on the basis of history or psychiatric examination; a current Diagnostic & Statistical Manual of Mental Disorders 4th ed (DSM-IV) diagnosis of drug dependence (other than nicotine dependence); a current Diagnostic and Statistical Manual of Mental Disorders 4th ed (DSM-IV) diagnosis of alcohol dependence that is clinically moderate or severe; a history of hypersensitivity to topiramate; currently taking any tricyclic antidepressant (e.g., Adapin (doxepin), Anafranil (clomipramine), Elavil (amitryptyline), Pamelor (nortryptyline), Tofranil (imipramine), Sinequan (doxepin); or are considered by the investigators to be an unsuitable candidate for receipt of an investigational drug.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Total Topiramate Group<br>topiramate capsules beginning at 25 mg/day with gradual increase to a maximum of 200 mg orally) | Drug: topiramate<br>* up to 200mg/day orally (over 12 weeks during which the dosage is gradually increased up to 200 mg orally and then maintained, and 1 week of medication taper)<br>* Other names: Topamax;|
| Placebo Comparator: Total Placebo Group<br>inactive placebo matched in appearance with topiramate capsules | Drug: placebo<br>* placebo (12 weeks during which the dosage of study medication is gradually increased up to 200 mg orally and then maintained, and 1 week of medication taper)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Heavy Drinking Days Per Week by Medication Group | Change in the number of heavy drinking days during treatment phase of study. Drinking data were aggregated to the weekly level. The number of days per week of heavy drinking (i.e., four or more drinks in a day for women and five or more drinks in a day for men) and of abstinence were the primary outcomes. | 12 weeks (from initiation to end of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Abstinent Days Per Week by Medication Group |  | 12 weeks | 
| Mean Daily Alcohol Consumption |  | 12 weeks (from initiation to end of treatment); 3- and 6-months post-treatment | 
| Mean Heavy Drinking Days Per Week by Medication Group and rs2832407 Genotype |  | 12 weeks | 
| Mean Abstinent Days Per Week by Medication Group and rs2832407 Genotype |  | 12 weeks | 
| Severity of Alcohol-related Problems at End of Treatment | The Short Inventory of Problems (SIP). The SIP, a 15-item instrument, yields a total score that ranges from 0 to 45, higher score indicating higher levels of drinking problems. The SIP was derived from the Drinker Inventory of Consequences (DrInC), which was developed for use in Project MATCH (Miller and Tonigan 1995). We (Feinn et al. 2003) have found that, like the DrInC, the SIP measures a single factor of alcohol-related problems. Given that it is substantially shorter than the DrInC, we will use the SIP as a measure of alcohol-related consequences. | 12 weeks (from intiation to end of treatment) | 
| Gamma-glutamyl Transferase (GGT) at Midpoint | Gamma-glutamyl transferase (GGT) is a liver enzyme biochemical measure used to detect liver health and function and alcohol consumption. GGT is a very sensitive measure than can change very quickly compared to other biochemical markers. | 6 weeks (from initiation to midpoint) | 
| Gamma-glutamyl Transferase (GGT) at End of Treatment | Gamma-glutamyl transferase (GGT) is a liver enzyme biochemical measure used to detect liver health and function and alcohol consumption. GGT is a very sensitive measure than can change very quickly compared to other biochemical markers. | 12 weeks (from initiation to end of treatment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized Trial, Medication for Heavy Drinking, Topiramate Treatment