Alcohol Drinking
Conditions
Keywords
Randomized Trial, Medication for Heavy Drinking, Topiramate Treatment
Brief summary
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
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.
Interventions
DRUGtopiramate
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)
DRUGplacebo
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)
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Center for Research Resources (NCRR)
UConn Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Heavy Drinking Days Per Week by Medication Group | 12 weeks (from initiation to end of treatment) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Mean Abstinent Days Per Week by Medication Group | 12 weeks | — |
| Gamma-glutamyl Transferase (GGT) at Midpoint | 6 weeks (from initiation to 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. |
| Gamma-glutamyl Transferase (GGT) at End of Treatment | 12 weeks (from initiation to 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. |
| Severity of Alcohol-related Problems at End of Treatment | 12 weeks (from intiation to 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. |
Countries
United States
Participant flow
Recruitment details
The study was initiated at the University of Connecticut Health Center in March 2008 and was transferred to the University of Pennsylvania in December 2010. The last study visit was completed on 11/20/2013. We enrolled a total of 200 subjects, randomizing 138 to study medication. We recruited participants using flyers, newspaper and radio ads.
Participants by arm
| Arm | Count |
|---|---|
| Total Topiramate Group topiramate (up to 200 mg orally)
topiramate: 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) | 67 |
| Total Placebo Group placebo
placebo: 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) | 71 |
| Total | 138 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse effect | 6 | 2 |
| Overall Study | Lack of Efficacy | 1 | 4 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | relapse | 1 | 0 |
| Overall Study | Time constraints | 3 | 1 |
Baseline characteristics
| Characteristic | Total Placebo Group | Total | Total Topiramate Group |
|---|---|---|---|
| Age, Continuous | 52.8 years STANDARD_DEVIATION 7.4 | 51.07 years STANDARD_DEVIATION 8.3 | 49.3 years STANDARD_DEVIATION 9 |
| Annual Income $120,000 or more | 28 participants | 56 participants | 28 participants |
| Annual Income $40,000-$79,999 | 15 participants | 29 participants | 14 participants |
| Annual Income $80,000 -$119,000 | 19 participants | 37 participants | 18 participants |
| Annual Income Less than $40,000 | 9 participants | 15 participants | 6 participants |
| Annual Income Missing | 0 participants | 1 participants | 1 participants |
| Beck Depression Inventory score | 6.8 units on a scale STANDARD_DEVIATION 5.3 | 6.48 units on a scale STANDARD_DEVIATION 5.07 | 6.1 units on a scale STANDARD_DEVIATION 4.8 |
| Education | 15.3 years STANDARD_DEVIATION 2.5 | 15.5 years STANDARD_DEVIATION 2.5 | 15.8 years STANDARD_DEVIATION 2.5 |
| Genotype AA | 8 Participants | 23 Participants | 15 Participants |
| Genotype AC | 32 Participants | 61 Participants | 29 Participants |
| Genotype CC | 31 Participants | 54 Participants | 23 Participants |
| Lifetime major depression (M.D.) Lifetime episode Major Depression | 22 # of participants | 40 # of participants | 18 # of participants |
| Lifetime major depression (M.D.) No lifetime Major Depression episode | 49 # of participants | 98 # of participants | 49 # of participants |
| Location of enrollment University Of Connecticut | 37 participants | 76 participants | 39 participants |
| Location of enrollment University of Pennsylvania | 34 participants | 62 participants | 28 participants |
| Marital Status Married | 45 Number of participants | 84 Number of participants | 39 Number of participants |
| Marital Status Not married | 26 Number of participants | 54 Number of participants | 28 Number of participants |
| Mean Daily Alcohol Consumption | 5.207 Number of SD Drinks per day STANDARD_DEVIATION 1.735 | 5.314 Number of SD Drinks per day STANDARD_DEVIATION 1.875 | 5.426 Number of SD Drinks per day STANDARD_DEVIATION 2.019 |
| Proportion Heavy drinking Days preceding screening visit | .66 Proportion Heavy drinking days STANDARD_DEVIATION 0.27 | .66 Proportion Heavy drinking days STANDARD_DEVIATION 0.27 | .67 Proportion Heavy drinking days STANDARD_DEVIATION 0.27 |
| Proportion of abstinent days | 0.12 Proportion of abstinent days STANDARD_DEVIATION 0.15 | 0.12 Proportion of abstinent days STANDARD_DEVIATION 0.15 | 0.13 Proportion of abstinent days STANDARD_DEVIATION 0.16 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 14 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 66 Participants | 122 Participants | 56 Participants |
| Sex: Female, Male Female | 30 Participants | 52 Participants | 22 Participants |
| Sex: Female, Male Male | 41 Participants | 86 Participants | 45 Participants |
| Short Index of Problems | 15.5 units on a scale STANDARD_DEVIATION 6.7 | 15.20 units on a scale STANDARD_DEVIATION 7.6 | 14.9 units on a scale STANDARD_DEVIATION 8.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 36 / 67 | 16 / 71 |
| serious Total, serious adverse events | 0 / 67 | 0 / 71 |
Outcome results
Primary
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.
Time frame: 12 weeks (from initiation to end of treatment)
Population: Intention to treat (ITT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Med | Mean Heavy Drinking Days Per Week by Medication Group | 1.82 Number of heavy drinking days | Standard Error 0.082 |
| Placebo Group | Mean Heavy Drinking Days Per Week by Medication Group | 2.94 Number of heavy drinking days | Standard Error 0.091 |
p-value: 0.001Mixed Models Analysis
Secondary
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.
Time frame: 12 weeks (from initiation to end of treatment)
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Med | Gamma-glutamyl Transferase (GGT) at End of Treatment | 36.3 IU/L | Standard Deviation 40.2 |
| Placebo Group | Gamma-glutamyl Transferase (GGT) at End of Treatment | 47.9 IU/L | Standard Deviation 52.1 |
p-value: 0.01Mixed Models Analysis
Secondary
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.
Time frame: 6 weeks (from initiation to midpoint)
Population: Subjects were measured at midpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Med | Gamma-glutamyl Transferase (GGT) at Midpoint | 37.6 IU/L | Standard Deviation 36.7 |
| Placebo Group | Gamma-glutamyl Transferase (GGT) at Midpoint | 50.1 IU/L | Standard Deviation 64.8 |
p-value: 0.06Mixed Models Analysis
Secondary
Mean Abstinent Days Per Week by Medication Group
Time frame: 12 weeks
Population: Intention to treat (ITT).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Med | Mean Abstinent Days Per Week by Medication Group | 2.00 Mean abstinent days per week | Standard Error 0.085 |
| Placebo Group | Mean Abstinent Days Per Week by Medication Group | 1.36 Mean abstinent days per week | Standard Error 0.065 |
p-value: 0.01Mixed Models Analysis
Secondary
Mean Abstinent Days Per Week by Medication Group and rs2832407 Genotype
Time frame: 12 weeks
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Med | Mean Abstinent Days Per Week by Medication Group and rs2832407 Genotype | 2.41 Mean Abstinent Days Per Week | Standard Error 0.148 |
| Placebo Group | Mean Abstinent Days Per Week by Medication Group and rs2832407 Genotype | 1.02 Mean Abstinent Days Per Week | Standard Error 0.09 |
| 3 Month Post Treatment Topiramate Group | Mean Abstinent Days Per Week by Medication Group and rs2832407 Genotype | 1.51 Mean Abstinent Days Per Week | Standard Error 0.119 |
| 3 Month Post Treatment Placebo Group | Mean Abstinent Days Per Week by Medication Group and rs2832407 Genotype | 1.44 Mean Abstinent Days Per Week | Standard Error 0.095 |
| 6 Month Post Treatment Topiramate Group | Mean Abstinent Days Per Week by Medication Group and rs2832407 Genotype | 2.26 Mean Abstinent Days Per Week | Standard Error 0.186 |
| 6 Month Post Treatment Placebo Group | Mean Abstinent Days Per Week by Medication Group and rs2832407 Genotype | 2.49 Mean Abstinent Days Per Week | Standard Error 0.227 |
p-value: 0.04Mixed Models Analysis
Secondary
Mean Daily Alcohol Consumption
Time frame: 12 weeks (from initiation to end of treatment); 3- and 6-months post-treatment
Population: Intention to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Med | Mean Daily Alcohol Consumption | 2.9859 Standard Drinks per day | Standard Deviation 2.01983 |
| Placebo Group | Mean Daily Alcohol Consumption | 3.5523 Standard Drinks per day | Standard Deviation 1.59254 |
| 3 Month Post Treatment Topiramate Group | Mean Daily Alcohol Consumption | 2.6129 Standard Drinks per day | Standard Deviation 1.84037 |
| 3 Month Post Treatment Placebo Group | Mean Daily Alcohol Consumption | 2.7560 Standard Drinks per day | Standard Deviation 1.92299 |
| 6 Month Post Treatment Topiramate Group | Mean Daily Alcohol Consumption | 2.6448 Standard Drinks per day | Standard Deviation 2.00703 |
| 6 Month Post Treatment Placebo Group | Mean Daily Alcohol Consumption | 2.8377 Standard Drinks per day | Standard Deviation 1.9623 |
Secondary
Mean Heavy Drinking Days Per Week by Medication Group and rs2832407 Genotype
Time frame: 12 weeks
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Med | Mean Heavy Drinking Days Per Week by Medication Group and rs2832407 Genotype | 1.28 Mean Heavy Drinking Days Per Week | Standard Error 0.131 |
| Placebo Group | Mean Heavy Drinking Days Per Week by Medication Group and rs2832407 Genotype | 3.49 Mean Heavy Drinking Days Per Week | Standard Error 0.141 |
| 3 Month Post Treatment Topiramate Group | Mean Heavy Drinking Days Per Week by Medication Group and rs2832407 Genotype | 2.30 Mean Heavy Drinking Days Per Week | Standard Error 0.13 |
| 3 Month Post Treatment Placebo Group | Mean Heavy Drinking Days Per Week by Medication Group and rs2832407 Genotype | 2.72 Mean Heavy Drinking Days Per Week | Standard Error 0.129 |
| 6 Month Post Treatment Topiramate Group | Mean Heavy Drinking Days Per Week by Medication Group and rs2832407 Genotype | 1.8 Mean Heavy Drinking Days Per Week | Standard Error 0.163 |
| 6 Month Post Treatment Placebo Group | Mean Heavy Drinking Days Per Week by Medication Group and rs2832407 Genotype | 1.54 Mean Heavy Drinking Days Per Week | Standard Error 0.211 |
p-value: 0.004Mixed Models Analysis
Secondary
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.
Time frame: 12 weeks (from intiation to end of treatment)
Population: Subject were measured at Baseline and Endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Med | Severity of Alcohol-related Problems at End of Treatment | 7.0 units on a scale | Standard Deviation 7.2 |
| Placebo Group | Severity of Alcohol-related Problems at End of Treatment | 11.1 units on a scale | Standard Deviation 7.5 |
p-value: 0.001Mixed Models Analysis