Alcohol Abuse, Alcoholism
Conditions
Keywords
Alcoholism, Alcohol dependence, Quetiapine
Brief summary
The purpose of this study is to determine whether quetiapine fumarate extended release is effective in the treatment of alcohol dependence in very heavy drinkers.
Detailed description
This study will investigate quetiapine fumarate XR (SEROQUEL XR®), a dibenzothiazepine derivative, as a potential medication for treating alcohol dependence. The immediate release form of quetiapine fumarate, SEROQUEL XR®, is approved by the FDA for treatment of schizophrenia and acute manic episodes associated with bipolar disorder. The extended release formulation (SEROQUEL XR®) is also approved by the FDA and is undergoing clinical investigation for the treatment of major depressive disorders, schizophrenia, generalized anxiety disorder, and alcohol dependence. Treatment with other atypical antipsychotics such as clozapine and olanzapine has resulted in decreases in alcohol use in alcohol dependent patients with and without comorbid psychiatric diagnoses. Quetiapine, like clozapine, appears to have efficacy in reducing drug and alcohol use among alcoholics and drug dependent patients with co-morbid psychiatric illness.
Interventions
DRUGQuetiapine fumarate
Quetiapine fumarate- taken daily, for 12 weeks
OTHERPlacebo
Placebo
Sponsors
National Institute on Drug Abuse (NIDA)
AstraZeneca
US Department of Veterans Affairs
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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
* Between the ages of 18 and 65 years old * DSM-IV diagnosis of current alcohol dependence as supported by SCID Module E * Report very heavy drinking (10 or more drinks per drinking day for men or 8 or more drinks per drinking day for women) at least 40% of the days during the interval from day 31 to 90 prior to the initial screening visit (i.e. a total of 24 days of this 60-day period), with at least one day of very heavy drinking occurring within the last 2 weeks before screening * Seeking treatment for alcohol dependence and desire reduction or cessation of drinking * Able to verbalize understanding of the consent form, able to provide written informed consent, and verbalize willingness to complete study procedures * Females of child bearing potential must agree to use of at least one approved method of birth control, or must be surgically sterile or postmenopausal * Able to take oral medication, willing to adhere to the medication regimen, and willing to return for regular visits * Able to understand written and oral instructions in English and to complete the questionnaires required by the protocol * Can complete all psychological assessments required at screening and baseline * Able to provide evidence of stable residence in the last 2 months prior to randomization, have reasonable transportation arrangements to study site, and have no plans to move within the next 3 months or unresolved legal problems; must provide contact information of family member, spouse, or significant other who can contact subject in case of missed appointment * Breath alcohol concentration (BAC) equal to 0.00 when s/he signed the informed consent document * Must have an absolute neutrophil count of 1.5 x 109/L or greater.
Exclusion criteria
Please contact site for additional information.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Heavy Drinking Days | Weeks 3 - 11 | A heavy drinking day is defined as 5 or more drinks for men and 4 or more drinks for women during a 24 hour period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Drinks Per Drinking Day | Study Weeks 3-11 | Timeline Follow Back daily drinking data used to calculate the weekly mean drinks per drinking day |
| Drinks Per Day | Study Weeks 3-11 | Timeline Follow Back daily drinking data used to calculate the weekly mean drinks per day |
| Percent Very Heavy Drinking Day | Study Weeks 3-11 | Timeline Follow Back data used to calculate the % of very heavy drinking days per week. Heavy drinking is 10+ drinks per day for females and 12+ drinks per day for males |
| Percent Subjects Abstinent | Study Weeks 3-11 | Timeline Follow Back data used to calculate the % of subjects that maintained abstinence weeks 3-11. |
| Percent Subjects With no Heavy Drinking Day | Study Weeks 3-11 | Timeline Follow Back data used to calculate the % of subjects that didn't have a heavy drinking day during study weeks 3-11. |
| Drinking Consequences Score | Weeks 6 & 12 | Drinkers Inventory of Consequences (DrInC) - Alcohol-related problems are determined using the DrInC (Miller et al., 1995). The DrInC is a self-administered 50-item questionnaire designed to measure adverse consequences of alcohol abuse in five areas: Interpersonal, Physical, Social, Impulsive, and Intrapersonal. Each scale provides a lifetime and past 3-month measure of adverse consequences, and scales can be combined to assess total adverse consequences. We used a modified version of the DrInC that just included the 45-items that summed the Interpersonal, Physical, Social, and Impulsivity items. This total score (min=0, max=135) was analyzed in this study with high scores indicative of more alcohol-related consequences (a poor outcome for a given study participant). The DrInC was assessed at study weeks 6 and 12. Analyses averaged across these weeks. |
| Percent Days Abstinent | Weeks 3-11 | Timeline Follow-back drinking data is used to calculate the % of days abstinent per week during Weeks 3-11 |
| Montgomery-Asberg Depression Rating Scale (MADRS) | Weeks 3-11 | The MADRS is an observer rating scale that has proven to be an efficient and practical measure of depression (Montgomery and Asberg, 1979). The scale was constructed to be sensitive to changes in treatment effects. Its capacity to differentiate between responders and non-responders to antidepressant treatment has been shown to be comparable to the Hamilton Rating Scale for Depression, another established measure of depressive symptomatology, but the MADRS has greater sensitivity to change during the course of a depressive phase. It has exhibited high inter-rater reliability and appears to be oriented more towards psychic as opposed to somatic aspects of depression. The MADRS is the sum of the 10-item in a checklist where items are rated on a scale of 0 to 6 with anchors at 2-point intervals. Scores range from 0 to 60. Higher scores are indicative of greater depressive symptoms (a poor outcome). The MADRS was assessed at weeks 4, 6, 8, 10, and 12. Analyses averaged across these weeks. |
| Hamilton Anxiety Scale (HAM-A) | Weeks 4, 6, 8, 10, and 12 | The Hamilton Anxiety Scale consists of 14 items, each defined by a series of symptoms. Similar to the HAM-D, each item is rated on a 5-point scale, ranging from 0 (not present) to 4 (severe) (Guy, 1976). A total score is derived from the summed items (min=0, max=56) with higher scores indicative of greater anxiety (a poor outcome). The HAM-A was assessed at study weeks 4, 6, 8, 10, and 12. Analyses averaged across these weeks. |
| Pittsburgh Sleep Quality Score | Weeks 4, 8, 12 | The PSQI is a 19-item questionnaire assessing the subject's overall sleep experience in the past 30 days (Buysse et al-1989). The lower the overall score, the better the person sleeps. The tool has an adequate internal reliability, validity and consistency for clinical and community samples of the various populations. Range is (0-21); \>6 indicative of poor sleep quality. The PSQI was assessed at study weeks 4,8, and 12. Analyses averaged across these weeks. |
| Quality of Life SF - 12 - Mental Aggregate Score | Week 12 | The SF-12 will be used to assess overall health status. The SF-12 is a 12-item questionnaire developed in 1994 as a shorter alternative to the SF-36 to reproduce the physical and mental health summary measures with at least 90% accuracy. We calculated the physical and mental component summary scores which were both converted to T-scores (min=0, max=100) normed to the general population such that a T=50 is the average score in the general population. Higher scores are indicative of better health status. |
| Quality of Life SF-12 - Physical Aggregate Score | Week 12 | The SF-12 will be used to assess overall health status. The SF-12 is a 12-item questionnaire developed in 1994 as a shorter alternative to the SF-36 to reproduce the physical and mental health summary measures with at least 90% accuracy. We calculated the physical and mental component summary scores which were both converted to T-scores (min=0, max=100) normed to the general population such that a T=50 is the average score in the general population. Higher scores are indicative of better health status. |
| Penn Alcohol Craving Score (PACS_ | Weeks 4, 6, 8, 10, and 12 | The Penn Alcohol Craving Scale (PACS) is a five-item, self-report measure that includes questions about the frequency, intensity, and duration of craving, the ability to resist drinking, and asks for an overall rating of craving for alcohol for the previous week (Flannery et al., 1999). The summed total score of the 5 items was used in the analysis (min=0, max=30) with higher scores indicative of higher craving for alcohol (a poor outcome). Based on clinical study results, the PACS has been shown to be a reliable and valid measure of alcohol craving and can predict subjects at risk for subsequent relapse. The PACS was assessed at study weeks 4, 6, 8, 10, and 12. Analyses averaged across these weeks. |
Countries
United States
Participant flow
Recruitment details
Interested candidates responded by telephone to advertisements at 5 academic centers in the United States between December 2007 and May 2009.
Pre-assignment details
218 comprises the Modified Intent To Treat group (MITT)
Participants by arm
| Arm | Count |
|---|---|
| Quetiapine Fumerate Plus Medical Management Quetiapine fumarate - target dose 400mg/day plus medical management | 105 |
| Sugar Pill Plus Medical Management Medical management plus placebo comparator | 113 |
| Total | 218 |
Baseline characteristics
| Characteristic | Sugar Pill Plus Medical Management | Total | Quetiapine Fumerate Plus Medical Management |
|---|---|---|---|
| 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 | 113 Participants | 218 Participants | 105 Participants |
| Age, Continuous | 45.5 years STANDARD_DEVIATION 9.8 | 45.4 years STANDARD_DEVIATION 9.4 | 45.4 years STANDARD_DEVIATION 9.3 |
| Region of Enrollment United States | 113 participants | 218 participants | 105 participants |
| Sex: Female, Male Female | 26 Participants | 43 Participants | 17 Participants |
| Sex: Female, Male Male | 87 Participants | 175 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 105 / 105 | 110 / 113 |
| serious Total, serious adverse events | 6 / 105 | 5 / 113 |
Outcome results
Primary
Percent Heavy Drinking Days
A heavy drinking day is defined as 5 or more drinks for men and 4 or more drinks for women during a 24 hour period.
Time frame: Weeks 3 - 11
Population: Intention to Treat
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Quetiapine Fumerate Plus Medical Management | Percent Heavy Drinking Days | 37.1 percentage of heavy drinking days | Standard Error 3.5 |
| Sugar Pill Plus Medical Management | Percent Heavy Drinking Days | 37.9 percentage of heavy drinking days | Standard Error 3.34 |
Secondary
Drinking Consequences Score
Drinkers Inventory of Consequences (DrInC) - Alcohol-related problems are determined using the DrInC (Miller et al., 1995). The DrInC is a self-administered 50-item questionnaire designed to measure adverse consequences of alcohol abuse in five areas: Interpersonal, Physical, Social, Impulsive, and Intrapersonal. Each scale provides a lifetime and past 3-month measure of adverse consequences, and scales can be combined to assess total adverse consequences. We used a modified version of the DrInC that just included the 45-items that summed the Interpersonal, Physical, Social, and Impulsivity items. This total score (min=0, max=135) was analyzed in this study with high scores indicative of more alcohol-related consequences (a poor outcome for a given study participant). The DrInC was assessed at study weeks 6 and 12. Analyses averaged across these weeks.
Time frame: Weeks 6 & 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Quetiapine Fumerate Plus Medical Management | Drinking Consequences Score | 18.5 score on a scale | Standard Error 1.87 |
| Sugar Pill Plus Medical Management | Drinking Consequences Score | 22.5 score on a scale | Standard Error 1.78 |
Secondary
Drinks Per Day
Timeline Follow Back daily drinking data used to calculate the weekly mean drinks per day
Time frame: Study Weeks 3-11
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Quetiapine Fumerate Plus Medical Management | Drinks Per Day | 4.3 drinks per day | Standard Error 0.43 |
| Sugar Pill Plus Medical Management | Drinks Per Day | 4.4 drinks per day | Standard Error 0.41 |
Secondary
Drinks Per Drinking Day
Timeline Follow Back daily drinking data used to calculate the weekly mean drinks per drinking day
Time frame: Study Weeks 3-11
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Quetiapine Fumerate Plus Medical Management | Drinks Per Drinking Day | 6.2 drinks per drinking day | Standard Error 0.47 |
| Sugar Pill Plus Medical Management | Drinks Per Drinking Day | 6.3 drinks per drinking day | Standard Error 0.45 |
Secondary
Hamilton Anxiety Scale (HAM-A)
The Hamilton Anxiety Scale consists of 14 items, each defined by a series of symptoms. Similar to the HAM-D, each item is rated on a 5-point scale, ranging from 0 (not present) to 4 (severe) (Guy, 1976). A total score is derived from the summed items (min=0, max=56) with higher scores indicative of greater anxiety (a poor outcome). The HAM-A was assessed at study weeks 4, 6, 8, 10, and 12. Analyses averaged across these weeks.
Time frame: Weeks 4, 6, 8, 10, and 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Quetiapine Fumerate Plus Medical Management | Hamilton Anxiety Scale (HAM-A) | 2.4 score on a scale | Standard Error 0.26 |
| Sugar Pill Plus Medical Management | Hamilton Anxiety Scale (HAM-A) | 3.0 score on a scale | Standard Error 0.24 |
Secondary
Montgomery-Asberg Depression Rating Scale (MADRS)
The MADRS is an observer rating scale that has proven to be an efficient and practical measure of depression (Montgomery and Asberg, 1979). The scale was constructed to be sensitive to changes in treatment effects. Its capacity to differentiate between responders and non-responders to antidepressant treatment has been shown to be comparable to the Hamilton Rating Scale for Depression, another established measure of depressive symptomatology, but the MADRS has greater sensitivity to change during the course of a depressive phase. It has exhibited high inter-rater reliability and appears to be oriented more towards psychic as opposed to somatic aspects of depression. The MADRS is the sum of the 10-item in a checklist where items are rated on a scale of 0 to 6 with anchors at 2-point intervals. Scores range from 0 to 60. Higher scores are indicative of greater depressive symptoms (a poor outcome). The MADRS was assessed at weeks 4, 6, 8, 10, and 12. Analyses averaged across these weeks.
Time frame: Weeks 3-11
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Quetiapine Fumerate Plus Medical Management | Montgomery-Asberg Depression Rating Scale (MADRS) | 2.8 score on a scale | Standard Error 0.39 |
| Sugar Pill Plus Medical Management | Montgomery-Asberg Depression Rating Scale (MADRS) | 4.1 score on a scale | Standard Error 0.37 |
Secondary
Penn Alcohol Craving Score (PACS_
The Penn Alcohol Craving Scale (PACS) is a five-item, self-report measure that includes questions about the frequency, intensity, and duration of craving, the ability to resist drinking, and asks for an overall rating of craving for alcohol for the previous week (Flannery et al., 1999). The summed total score of the 5 items was used in the analysis (min=0, max=30) with higher scores indicative of higher craving for alcohol (a poor outcome). Based on clinical study results, the PACS has been shown to be a reliable and valid measure of alcohol craving and can predict subjects at risk for subsequent relapse. The PACS was assessed at study weeks 4, 6, 8, 10, and 12. Analyses averaged across these weeks.
Time frame: Weeks 4, 6, 8, 10, and 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Quetiapine Fumerate Plus Medical Management | Penn Alcohol Craving Score (PACS_ | 12.1 score on a scale | Standard Error 0.63 |
| Sugar Pill Plus Medical Management | Penn Alcohol Craving Score (PACS_ | 12.8 score on a scale | Standard Error 0.6 |
Secondary
Percent Days Abstinent
Timeline Follow-back drinking data is used to calculate the % of days abstinent per week during Weeks 3-11
Time frame: Weeks 3-11
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Quetiapine Fumerate Plus Medical Management | Percent Days Abstinent | 49.5 percentage of days abstinent | Standard Error 3.71 |
| Sugar Pill Plus Medical Management | Percent Days Abstinent | 47.1 percentage of days abstinent | Standard Error 3.54 |
Secondary
Percent Subjects Abstinent
Timeline Follow Back data used to calculate the % of subjects that maintained abstinence weeks 3-11.
Time frame: Study Weeks 3-11
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Quetiapine Fumerate Plus Medical Management | Percent Subjects Abstinent | 12 Participants |
| Sugar Pill Plus Medical Management | Percent Subjects Abstinent | 12 Participants |
Secondary
Percent Subjects With no Heavy Drinking Day
Timeline Follow Back data used to calculate the % of subjects that didn't have a heavy drinking day during study weeks 3-11.
Time frame: Study Weeks 3-11
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Quetiapine Fumerate Plus Medical Management | Percent Subjects With no Heavy Drinking Day | 17 Participants |
| Sugar Pill Plus Medical Management | Percent Subjects With no Heavy Drinking Day | 24 Participants |
Secondary
Percent Very Heavy Drinking Day
Timeline Follow Back data used to calculate the % of very heavy drinking days per week. Heavy drinking is 10+ drinks per day for females and 12+ drinks per day for males
Time frame: Study Weeks 3-11
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Quetiapine Fumerate Plus Medical Management | Percent Very Heavy Drinking Day | 16.5 percentage heavy drinking days | Standard Error 2.56 |
| Sugar Pill Plus Medical Management | Percent Very Heavy Drinking Day | 18.8 percentage heavy drinking days | Standard Error 2.44 |
Secondary
Pittsburgh Sleep Quality Score
The PSQI is a 19-item questionnaire assessing the subject's overall sleep experience in the past 30 days (Buysse et al-1989). The lower the overall score, the better the person sleeps. The tool has an adequate internal reliability, validity and consistency for clinical and community samples of the various populations. Range is (0-21); \>6 indicative of poor sleep quality. The PSQI was assessed at study weeks 4,8, and 12. Analyses averaged across these weeks.
Time frame: Weeks 4, 8, 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Quetiapine Fumerate Plus Medical Management | Pittsburgh Sleep Quality Score | 4.1 score | Standard Error 0.27 |
| Sugar Pill Plus Medical Management | Pittsburgh Sleep Quality Score | 5.1 score | Standard Error 0.26 |
Secondary
Quality of Life SF - 12 - Mental Aggregate Score
The SF-12 will be used to assess overall health status. The SF-12 is a 12-item questionnaire developed in 1994 as a shorter alternative to the SF-36 to reproduce the physical and mental health summary measures with at least 90% accuracy. We calculated the physical and mental component summary scores which were both converted to T-scores (min=0, max=100) normed to the general population such that a T=50 is the average score in the general population. Higher scores are indicative of better health status.
Time frame: Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Quetiapine Fumerate Plus Medical Management | Quality of Life SF - 12 - Mental Aggregate Score | 51.5 score on a scale | Standard Error 1.12 |
| Sugar Pill Plus Medical Management | Quality of Life SF - 12 - Mental Aggregate Score | 50.7 score on a scale | Standard Error 1.08 |
Secondary
Quality of Life SF-12 - Physical Aggregate Score
The SF-12 will be used to assess overall health status. The SF-12 is a 12-item questionnaire developed in 1994 as a shorter alternative to the SF-36 to reproduce the physical and mental health summary measures with at least 90% accuracy. We calculated the physical and mental component summary scores which were both converted to T-scores (min=0, max=100) normed to the general population such that a T=50 is the average score in the general population. Higher scores are indicative of better health status.
Time frame: Week 12
Population: mITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Quetiapine Fumerate Plus Medical Management | Quality of Life SF-12 - Physical Aggregate Score | 51.0 score on a scale | Standard Error 0.82 |
| Sugar Pill Plus Medical Management | Quality of Life SF-12 - Physical Aggregate Score | 50.6 score on a scale | Standard Error 0.93 |