Alcoholism
Conditions
Keywords
alcohol, treatment, nicotinic acetylcholine receptors, pharmacotherapy, outpatient
Brief summary
The purpose of this study is to determine the efficacy of varenicline (Chantix™) for the treatment of alcohol dependence.
Detailed description
By both providing a low level of reinforcement and down-grading any high associated with concurrent administration of the abused drug, combined agonist/antagonist therapies promote both initial and sustained abstinence. Based on varenicline's specific affinity for the nicotinic acetylcholine receptors that are implicated in alcohol reward circuitry, it appears to be a good candidate for treatment of alcohol dependence. Alcohol can exert its reinforcing and dopamine-enhancing effects through activation of nicotinic receptors. In addition to its partial agonist activity at heteromeric α4β2 nicotinic acetylcholine receptors, varenicline has also been shown to be a full agonist at homomeric α7 nicotinic acetylcholine receptors. That full agonism at α7 may be key in reducing alcohol withdrawal and craving during early alcohol abstinence, and thus reducing relapse, as α7 receptors are implicated in the neural reward circuitry activated by alcohol use.
Interventions
DRUGvarenicline
1.0 mg BID for 12 weeks
DRUGplacebo
BID 12 weeks
Sponsors
National Institute on Drug Abuse (NIDA)
University of Pennsylvania
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 70 Years
Healthy volunteers
No
Inclusion criteria
* 1\. Males and females, 18-70 years old. * 2\. Meets DSM-IV criteria for current diagnoses of alcohol dependence, determined by the SCID-IV (First, 1996). * 3\. Meets the following drinking criteria as measured by the Timeline Followback (TLFB) (Sobell, 1995) * drank within 30 days of intake day, * reports a minimum of 48 standard alcoholic drinks (avg. 12 drinks/wk) in a consecutive 30-day period over the 90-day period prior to starting intake (i.e., a minimum of 40% days drinking), and * has 2 or more days of heavy drinking (defined as 5 or more drinks per day in males and 4 or more drinks per day in females) in this same pre-treatment period. * 4\. Three consecutive days of abstinence from alcohol, determined by self-reports and confirmed by a negative breathalyzer tests immediately before the day of randomization, and a Clinical Institute Withdrawal Scale for Alcohol (CIWA-AR) (Sullivan, 1989) score below eight on the day of randomization. * 5\. Lives a commutable distance from the TRC and agrees to attend all research visits including follow-up visits. * Speaks, understands, and prints in English.
Exclusion criteria
* Has evidence of dependence on a substance other than alcohol (except nicotine or marijuana); or tests positive on the urine drug screen and on a single allowed retest, during the screening week, with the exception of a THC positive urine, and/or a).positive result for benzodiazepines prescribed by a doctor for medically indicated detox (prescription required). * Has hepatocellular disease indicated by elevations of SGPT (ALT) and SGOT (AST) of at least 4.5 times normal after the required 3 days of abstinence, or elevated bilirubin (\>1.3) (one retest allowed at the discretion of the Medical Director). * Meets diagnostic criteria for a current unstable or serious psychiatric or medical illness. For example, bipolar affective disorder, schizophrenia or any other psychotic disorder, or organic mental disorder; has serious heart, lung, kidney, immune system, GI tract (ulcerative colitis, regional enteritis, or gastrointestinal bleeding) disease. * Has taken any psychotropic medications (including disulfiram, naltrexone or acamprosate) regularly within the last 2 weeks or needs immediate treatment with a psychotropic medication (with the exception of detoxification medications or benadryl used sparingly for sleep). * Tests positive on a pregnancy test, is contemplating pregnancy in the next 12 months, is nursing, or is not using an effective contraceptive method if the subject is of child-bearing potential. * Has participated in any investigational drug trial within 30 days prior to the study. Subjects mandated to treatment based upon a legal decision or as a condition of employment. This will be assessed by the subject's self-report. * Known hypersensitivity to varenicline. * Subjects with known AIDS or other serious illnesses that may require hospitalization during the study. * Clinical laboratory tests (CBC, blood chemistries, urinalysis) outside normal limits that are clinically unacceptable to the Principal Investigator. (ECG 1st degree heart block, sinus tachycardia, left axis deviation, and nonspecific ST or T wave changes are allowed; liver function tests \[LFTs\] \<5 x ULN are acceptable).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Heavy Drinking Days Per Week. | 12 weeks of treatment and one month follow-up | Rate of heavy drinking days per week (defined as five drinks per day for men, four drinks per day for women) as determined by self-report on the time-line follow-back (TLFB). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Addiction Severity Index (ASI) Alcohol Composite Score at End of Study. | 12 weeks of treatment, with a follow-up one month after treatment | The Addiction Severity Index (ASI) is a semistructured interview that measures the severity of addiction in 25 questions concerning seven problem areas: medical problems, employment problems, drug use, alcohol use, family and social problems, criminality, and psychiatric problems. Each problem area is measured as its own Compsite Score. Each Composite Score total ranges between 0 (no endorsement of any problems) and 1 (maximal endorsement of all problems). Higher scores (i.e., those closer to 1) on each Composite Score indicate more difficulty/lower functioning in that area, while lower scores (i.e., those closer to 0) indicate higher functioning/less difficulty in that area. As such, the Addiction Severity Index (ASI) Alcohol Composite Total Score must fall between 0 and 1, and scores closer to 1 suggest continued problem drinking. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Varenicline Titrated 0.5mg o.d. for days 1-3, 0.5mg b.i.d. for days 4-7, up to full dose of 1 mg/day by the end of the first week. Then 1 mg/day for remaining weeks. | 19 |
| Placebo placebo : BID 12 weeks | 21 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 3 |
Baseline characteristics
| Characteristic | Varenicline | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 21 Participants | 40 Participants |
| Age, Continuous | 44.8 years STANDARD_DEVIATION 12.3 | 48.1 years STANDARD_DEVIATION 10.5 | 46.5 years STANDARD_DEVIATION 11.7 |
| ASI Alcohol Composite Score, Baseline | 0.61 Alcohol Composite Score STANDARD_DEVIATION 0.16 | 0.60 Alcohol Composite Score STANDARD_DEVIATION 0.15 | 0.61 Alcohol Composite Score STANDARD_DEVIATION 0.16 |
| Days of Alcohol Use in Past 30 Days | 18.4 Drinking Days STANDARD_DEVIATION 8.8 | 17.6 Drinking Days STANDARD_DEVIATION 9.1 | 18.0 Drinking Days STANDARD_DEVIATION 8.95 |
| Region of Enrollment United States | 19 participants | 21 participants | 40 participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 15 Participants | 19 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 17 / 19 | 19 / 21 |
| serious Total, serious adverse events | 0 / 19 | 0 / 21 |
Outcome results
Primary
Rate of Heavy Drinking Days Per Week.
Rate of heavy drinking days per week (defined as five drinks per day for men, four drinks per day for women) as determined by self-report on the time-line follow-back (TLFB).
Time frame: 12 weeks of treatment and one month follow-up
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Varenicline | Rate of Heavy Drinking Days Per Week. | .89 rate of heavy drinking days per week | Standard Deviation 0.18 |
| Placebo | Rate of Heavy Drinking Days Per Week. | 1.21 rate of heavy drinking days per week | Standard Deviation 0.31 |
Comparison: Self-reported drinking results, as gathered by the TLFB, were compared by the generalized estimating equations (GEE) (Diggle et al., 1994), using Poisson models for counts of drinking and heavy drinking days, and logistic regression models for absence/presence binary indicators of drinking. In the GEE model, the pre-treatment of the response was included as a covariate, together with the treatment group indicator, and a linear time effect.p-value: 0.1Regression, Logistic
Secondary
Addiction Severity Index (ASI) Alcohol Composite Score at End of Study.
The Addiction Severity Index (ASI) is a semistructured interview that measures the severity of addiction in 25 questions concerning seven problem areas: medical problems, employment problems, drug use, alcohol use, family and social problems, criminality, and psychiatric problems. Each problem area is measured as its own Compsite Score. Each Composite Score total ranges between 0 (no endorsement of any problems) and 1 (maximal endorsement of all problems). Higher scores (i.e., those closer to 1) on each Composite Score indicate more difficulty/lower functioning in that area, while lower scores (i.e., those closer to 0) indicate higher functioning/less difficulty in that area. As such, the Addiction Severity Index (ASI) Alcohol Composite Total Score must fall between 0 and 1, and scores closer to 1 suggest continued problem drinking.
Time frame: 12 weeks of treatment, with a follow-up one month after treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Varenicline | Addiction Severity Index (ASI) Alcohol Composite Score at End of Study. | 0.12 alcohol composite score | Standard Deviation 0.2 |
| Placebo | Addiction Severity Index (ASI) Alcohol Composite Score at End of Study. | 0.29 alcohol composite score | Standard Deviation 0.23 |