Alcohol Dependence, Nicotine Dependence
Conditions
Keywords
alcohol, alcoholism, nicotine, cigarette
Brief summary
This research study aims to test whether topiramate (a drug that is being used for seizure) will help individuals who have problems with both alcohol and nicotine. The investigators believe that individuals taking topiramate will be more successful at abstaining from both alcohol and nicotine than individuals taking placebo.
Detailed description
We propose a novel pharmacological strategy for treating alcohol and nicotine dependence concomitantly. The reinforcing effects of both alcohol and nicotine are mediated through the cortico-mesolimbic dopamine (CMDA) system, and the concomitant use of both drugs enhances their pharmacological effects. We propose a better approach to control dopamine (DA) effects by contemporaneous indirect modulation of DA release and its functional expression. Both DA release from its cell bodies in the ventral tegmental area and the expression of its reinforcing effects through the cortico-mesolimbic system are modulated by gamma-aminobutyric acid (GABA) efferents under the tonic control of glutamate-mediated excitatory amino acid pathways. Thus, it is reasonable to hypothesize that a medication that facilitates cortico-mesolimbic GABAergic function and inhibits glutamate action should diminish both nicotine's and alcohol's reinforcing effects by inhibiting the release of midbrain DA and its functional expression through pathways projecting from the nucleus accumbens to the cortex. The promise of this novel approach is exemplified by our recent proof-of-concept demonstration that topiramate compared with placebo significantly improved smoking abstinence rates and decreased serum cotinine levels among alcohol dependent smokers. An important clinical effect of topiramate in alcohol-dependent individuals appears to be that its anti-withdrawal effects promote the gradual tapering of drinking. Hence, due to this unique anti-withdrawal effect of topiramate, we propose to adopt the same methodology for treating alcohol-dependent individuals, as is common practice with smokers, of setting a target quit date (TQD) after which relapse to either drug can be measured. We propose an 18-week, double-blind clinical trial with follow-up visits at 1 month and 3 months, in which alcohol-dependent smokers will receive brief behavioral compliance enhancement treatment (BBCET) plus a smoking self-help manual as their psychosocial treatment, and will be randomized to receive placebo,high-dose topiramate (up to 250 mg/day), or low-dose topiramate (up to 125 mg/day) to prevent relapse to heavy drinking and smoking. Each of the 3 treatment arms shall contain 98 individuals, with a total N of 294. The TQD will occur at the beginning of the 6th week of treatment. Our primary objective is to determine whether both low- and high-dose topiramate will be more efficacious than placebo at reducing the percentage of heavy drinking days and increasing the continuous abstinence rate for smoking determined by a combination of self-report and carbon monoxide (CO) monitoring after the TQD and in the last 4 weeks of treatment. We also will be able to determine whether a lower dose of topiramate is as efficacious as the higher dose and, therefore, is associated with a lower adverse profile. Our secondary objectives are to test whether topiramate will be more efficacious than placebo at improving quality of life and reducing craving after the TQD and in the last 4 weeks of treatment and whether this improvement will be sustained in the follow-up phase.
Interventions
DRUGLow-Dose Topiramate
Low-dose topiramate (up to 125 mg/day) with brief behavioral enhancement therapy
DRUGPlacebo
Placebo with brief behavioral enhancement therapy
DRUGHigh-Dose Topiramate
High-dose topiramate (up to 250 mg/day) with brief behavioral enhancement therapy
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
M.D. Anderson Cancer Center
University of California, San Diego
University of Virginia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males and females who have given written informed consent * Subjects must be above the age of 18 * Good physical health * Diagnostic and Statistical Manual (DSM)-IV diagnosis of mild to severe alcohol use disorder * Smoking ≥ 5 cigarettes/day * Currently drinking at least 8 standard drink units (SDUs) per week for women and at least 15 SDUs per week in the 30 days prior to randomization * Subjects must provide evidence of stable residence * The pregnancy test for females of child-bearing potential at screen and prior to randomization must be negative. Additionally, women of child-bearing potential must be using an acceptable form of contraception. * Literate in English and able to read, understand, and complete the rating scales and questionnaires accurately, follow instructions, and make use of the behavioral treatments * Willing to participate in a treatment program for alcohol and nicotine dependence
Exclusion criteria
Please contact site for additional information
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Continuous Smoking Abstinence in the Last 4 Weeks of Treatment Continuous Smoking Abstinence in the Last 4 Weeks of Treatment | Week 15 - 18 of the 18-week medication treatment | No smoking in the last 4 weeks of the 18-week treatment with an expired carbon monoxide level of \<10 ppm as the biochemical verification. We used the intent-to-treat assumption, where missing smoking data were considered as smoking. |
| Percentage of Heavy Drinking Days (PHDD) in the Last 4 Weeks of Treatment | Week 15 - 18 of the 18-week medication treatment | A heavy drinking day is defined as \>= 5 standard drinking units for men and \>= 4 standard drinking units for women. We calculated the PHDD used the intent-to-treat assumption, where missing drinking data were considered as heavy drinking. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Life in the Last 4 Weeks of Treatment | Week 15 - 18 of the 18-week medication treatment | We used the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) to measure quality of life in the last 4 weeks of treatment. Scoring involves summing the individual item scores on a 5-point scale, with higher scores indicating greater life satisfaction and enjoyment (better outcome). We report here a percent score of subscales contained within the Q-LES-Q, with higher scores indicating a better outcome. The subscales within the questionnaire have different numbers of items, resulting in different ranges of raw scores, so using a percent score, which used the following formula: (raw\_score - scale\_min\_possible\_score) / (scale\_max\_possible\_score - scale\_min\_possible\_score), helped normalize such differences, improving interpretation using the same range (i.e., 0 - 100) between subscales. |
| Craving for Alcohol and Cigarettes in the Last 4 Weeks of Treatment | Week 15 - 18 of the 18-week medication treatment | We used the Visual Analog Scales (VAS) to assess the craving levels for alcohol and cigarettes, respectively. VAS uses a 100 millimeter line, where 0 mm = no craving (minimum value) and 100 mm = strongest craving ever (maximum value). Participants are asked to make a mark on the line that best represents their current level of craving. Research staff then measure the distance in millimeters from the No Craving anchor (0 mm) to the participant's mark, which is their score. A higher score is equal to higher craving (worse outcome). Mean scores of the last 4 weeks of treatment are reported. |
Countries
United States
Participant flow
Recruitment details
Participants were 236 adults who met the DSM-5 criteria for Alcohol Use Disorder and Tobacco Use Disorder and recruited from three metropolitan areas in the U.S., including San Diego, California, Houston, Texas, and Charlottesville, Virginia. A Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) diagnosis of mild to severe alcohol use disorder was required and participants must have smoked an average of 5 or more cigarettes/day in the 30 days prior to randomization.
Pre-assignment details
Of 646 individuals who screened, 410 were excluded or uninterested. A total of 236 participants were enrolled and randomized into one of three study arms. Randomization was achieved using a block randomization procedure in which treatment groups were stratified to achieve a balance on age of onset for alcoholism (less than 26 years old or 26 years and older), gender, and drinks per drinking day (DDD) (\< 8 DDD or ≥ 8 DDD) and the number of cigarettes smoked (\<20 or \>20 cigarettes/day).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo with brief behavioral enhancement therapy | 84 |
| Low-Dose Topiramate Low-dose Topiramate (up to 125 mg/day) with brief behavioral enhancement therapy | 75 |
| High-Dose Topiramate High-dose Topiramate (up to 250 mg/day) with brief behavioral enhancement therapy | 77 |
| Total | 236 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 32 | 36 | 29 |
| Overall Study | Non-compliance | 1 | 1 | 1 |
| Overall Study | Physician Decision | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 14 | 3 | 6 |
Baseline characteristics
| Characteristic | Placebo | Total | High-Dose Topiramate | Low-Dose Topiramate |
|---|---|---|---|---|
| Age, Continuous | 47.68 years STANDARD_DEVIATION 10.35 | 48.16 years STANDARD_DEVIATION 10.15 | 48.77 years STANDARD_DEVIATION 9.86 | 48.07 years STANDARD_DEVIATION 10.34 |
| AUDIT | 21.39 scores on a scale STANDARD_DEVIATION 7.61 | 20.75 scores on a scale STANDARD_DEVIATION 7.08 | 19.40 scores on a scale STANDARD_DEVIATION 6.18 | 21.43 scores on a scale STANDARD_DEVIATION 7.23 |
| Baseline Drinking (SDU)/day | 10.02 standard drink units/day STANDARD_DEVIATION 6.76 | 9.92 standard drink units/day STANDARD_DEVIATION 6.1 | 9.88 standard drink units/day STANDARD_DEVIATION 5.96 | 9.84 standard drink units/day STANDARD_DEVIATION 5.51 |
| Baseline Smoking (CPD) | 21.34 cigarettes per day STANDARD_DEVIATION 9.96 | 20.32 cigarettes per day STANDARD_DEVIATION 10.14 | 20.33 cigarettes per day STANDARD_DEVIATION 10.02 | 19.18 cigarettes per day STANDARD_DEVIATION 10.47 |
| Employment Employed or student | 46 Participants | 143 Participants | 55 Participants | 42 Participants |
| Employment Employment unknown | 2 Participants | 11 Participants | 4 Participants | 5 Participants |
| Employment Unemployed or retired | 36 Participants | 82 Participants | 18 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 13 Participants | 3 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 76 Participants | 213 Participants | 70 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 10 Participants | 4 Participants | 3 Participants |
| Mean Fagerström Test for Cigarette Dependence (FTCD) Score | 5.32 scores on a scale STANDARD_DEVIATION 1.92 | 5.42 scores on a scale STANDARD_DEVIATION 2.21 | 5.69 scores on a scale STANDARD_DEVIATION 2.3 | 5.27 scores on a scale STANDARD_DEVIATION 2.38 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 29 Participants | 82 Participants | 22 Participants | 31 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 22 Participants | 6 Participants | 8 Participants |
| Race (NIH/OMB) White | 46 Participants | 130 Participants | 48 Participants | 36 Participants |
| Sex: Female, Male Female | 28 Participants | 76 Participants | 25 Participants | 23 Participants |
| Sex: Female, Male Male | 56 Participants | 160 Participants | 52 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 84 | 0 / 75 | 0 / 77 |
| other Total, other adverse events | 63 / 84 | 59 / 75 | 63 / 77 |
| serious Total, serious adverse events | 8 / 84 | 7 / 75 | 7 / 77 |
Outcome results
Primary
Continuous Smoking Abstinence in the Last 4 Weeks of Treatment Continuous Smoking Abstinence in the Last 4 Weeks of Treatment
No smoking in the last 4 weeks of the 18-week treatment with an expired carbon monoxide level of \<10 ppm as the biochemical verification. We used the intent-to-treat assumption, where missing smoking data were considered as smoking.
Time frame: Week 15 - 18 of the 18-week medication treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Continuous Smoking Abstinence in the Last 4 Weeks of Treatment Continuous Smoking Abstinence in the Last 4 Weeks of Treatment | 2 participants |
| Low-Dose Topiramate | Continuous Smoking Abstinence in the Last 4 Weeks of Treatment Continuous Smoking Abstinence in the Last 4 Weeks of Treatment | 5 participants |
| High-Dose Topiramate | Continuous Smoking Abstinence in the Last 4 Weeks of Treatment Continuous Smoking Abstinence in the Last 4 Weeks of Treatment | 6 participants |
Primary
Percentage of Heavy Drinking Days (PHDD) in the Last 4 Weeks of Treatment
A heavy drinking day is defined as \>= 5 standard drinking units for men and \>= 4 standard drinking units for women. We calculated the PHDD used the intent-to-treat assumption, where missing drinking data were considered as heavy drinking.
Time frame: Week 15 - 18 of the 18-week medication treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of Heavy Drinking Days (PHDD) in the Last 4 Weeks of Treatment | 62.8 percentage of heavy drinking days | Standard Deviation 45.4 |
| Low-Dose Topiramate | Percentage of Heavy Drinking Days (PHDD) in the Last 4 Weeks of Treatment | 65.1 percentage of heavy drinking days | Standard Deviation 44 |
| High-Dose Topiramate | Percentage of Heavy Drinking Days (PHDD) in the Last 4 Weeks of Treatment | 59.3 percentage of heavy drinking days | Standard Deviation 47.3 |
Secondary
Craving for Alcohol and Cigarettes in the Last 4 Weeks of Treatment
We used the Visual Analog Scales (VAS) to assess the craving levels for alcohol and cigarettes, respectively. VAS uses a 100 millimeter line, where 0 mm = no craving (minimum value) and 100 mm = strongest craving ever (maximum value). Participants are asked to make a mark on the line that best represents their current level of craving. Research staff then measure the distance in millimeters from the No Craving anchor (0 mm) to the participant's mark, which is their score. A higher score is equal to higher craving (worse outcome). Mean scores of the last 4 weeks of treatment are reported.
Time frame: Week 15 - 18 of the 18-week medication treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Craving for Alcohol and Cigarettes in the Last 4 Weeks of Treatment | Craving for alcohol | 12.3 score on VAS scale | Standard Deviation 13.9 |
| Placebo | Craving for Alcohol and Cigarettes in the Last 4 Weeks of Treatment | Craving for cigarettes | 17.4 score on VAS scale | Standard Deviation 18 |
| Low-Dose Topiramate | Craving for Alcohol and Cigarettes in the Last 4 Weeks of Treatment | Craving for alcohol | 18.4 score on VAS scale | Standard Deviation 20.2 |
| Low-Dose Topiramate | Craving for Alcohol and Cigarettes in the Last 4 Weeks of Treatment | Craving for cigarettes | 24.6 score on VAS scale | Standard Deviation 23.3 |
| High-Dose Topiramate | Craving for Alcohol and Cigarettes in the Last 4 Weeks of Treatment | Craving for alcohol | 14.3 score on VAS scale | Standard Deviation 14.8 |
| High-Dose Topiramate | Craving for Alcohol and Cigarettes in the Last 4 Weeks of Treatment | Craving for cigarettes | 18.2 score on VAS scale | Standard Deviation 17.8 |
Secondary
Quality of Life in the Last 4 Weeks of Treatment
We used the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) to measure quality of life in the last 4 weeks of treatment. Scoring involves summing the individual item scores on a 5-point scale, with higher scores indicating greater life satisfaction and enjoyment (better outcome). We report here a percent score of subscales contained within the Q-LES-Q, with higher scores indicating a better outcome. The subscales within the questionnaire have different numbers of items, resulting in different ranges of raw scores, so using a percent score, which used the following formula: (raw\_score - scale\_min\_possible\_score) / (scale\_max\_possible\_score - scale\_min\_possible\_score), helped normalize such differences, improving interpretation using the same range (i.e., 0 - 100) between subscales.
Time frame: Week 15 - 18 of the 18-week medication treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Quality of Life in the Last 4 Weeks of Treatment | Household Duties | 43.6 percent score on a scale | Standard Deviation 5.1 |
| Placebo | Quality of Life in the Last 4 Weeks of Treatment | Work | 59.2 percent score on a scale | Standard Deviation 8.5 |
| Placebo | Quality of Life in the Last 4 Weeks of Treatment | Social Relations | 51.7 percent score on a scale | Standard Deviation 8.4 |
| Placebo | Quality of Life in the Last 4 Weeks of Treatment | Coursework | 40.2 percent score on a scale | Standard Deviation 6.9 |
| Placebo | Quality of Life in the Last 4 Weeks of Treatment | Subjective Feelings | 45.3 percent score on a scale | Standard Deviation 6.7 |
| Placebo | Quality of Life in the Last 4 Weeks of Treatment | General Activities | 57.7 percent score on a scale | Standard Deviation 8.7 |
| Placebo | Quality of Life in the Last 4 Weeks of Treatment | Physical Health | 25.2 percent score on a scale | Standard Deviation 3.7 |
| Low-Dose Topiramate | Quality of Life in the Last 4 Weeks of Treatment | Social Relations | 50.4 percent score on a scale | Standard Deviation 10.3 |
| Low-Dose Topiramate | Quality of Life in the Last 4 Weeks of Treatment | Coursework | 37.1 percent score on a scale | Standard Deviation 10.3 |
| Low-Dose Topiramate | Quality of Life in the Last 4 Weeks of Treatment | Household Duties | 42 percent score on a scale | Standard Deviation 7.2 |
| Low-Dose Topiramate | Quality of Life in the Last 4 Weeks of Treatment | Physical Health | 24.1 percent score on a scale | Standard Deviation 4.9 |
| Low-Dose Topiramate | Quality of Life in the Last 4 Weeks of Treatment | Work | 58 percent score on a scale | Standard Deviation 10.2 |
| Low-Dose Topiramate | Quality of Life in the Last 4 Weeks of Treatment | General Activities | 54.2 percent score on a scale | Standard Deviation 10.7 |
| Low-Dose Topiramate | Quality of Life in the Last 4 Weeks of Treatment | Subjective Feelings | 43.6 percent score on a scale | Standard Deviation 8.9 |
| High-Dose Topiramate | Quality of Life in the Last 4 Weeks of Treatment | Household Duties | 41.6 percent score on a scale | Standard Deviation 8.7 |
| High-Dose Topiramate | Quality of Life in the Last 4 Weeks of Treatment | Subjective Feelings | 44.5 percent score on a scale | Standard Deviation 10 |
| High-Dose Topiramate | Quality of Life in the Last 4 Weeks of Treatment | General Activities | 57.9 percent score on a scale | Standard Deviation 8.6 |
| High-Dose Topiramate | Quality of Life in the Last 4 Weeks of Treatment | Social Relations | 50.8 percent score on a scale | Standard Deviation 11.7 |
| High-Dose Topiramate | Quality of Life in the Last 4 Weeks of Treatment | Physical Health | 23.4 percent score on a scale | Standard Deviation 5.5 |
| High-Dose Topiramate | Quality of Life in the Last 4 Weeks of Treatment | Coursework | 35.4 percent score on a scale | Standard Deviation 14.4 |
| High-Dose Topiramate | Quality of Life in the Last 4 Weeks of Treatment | Work | 58.9 percent score on a scale | Standard Deviation 11.8 |