Alcoholism
Conditions
Keywords
Baclofen, Alcohol Dependence
Brief summary
The proposed study will carefully test the hypothesis that a robust dose of baclofen (90 mg/day) has efficacy and is safe in individuals with alcohol dependence. Furthermore, the proposal will test whether an indicator of physical dependence, i.e. drinks/drinking day, predicts response to baclofen. Additionally, the proposal will examine the anti-anxiety effects of baclofen within an alcohol dependent population and ascertain whether baseline levels of anxiety predict response to baclofen.
Detailed description
Alcohol dependence (AD) is a common problem with significant health consequences. Treatment of AD is evolving to include both counseling methods and medications. Several medications have been discovered, that show efficacy in AD, e.g. naltrexone, acamprosate. However, the overall effect of existing medications is modest leaving a clear need for the development of new pharmacotherapies. The gamma-aminobutyric acid (GABA)-B receptor agonist baclofen has attracted attention as a potential new medication for AD based on preclinical data and early clinical trials. Baclofen is an FDA approved medication with an excellent safety profile even for patients with liver cirrhosis-a not uncommon consequence of AD. Questions have arisen with regards to the efficacy of baclofen and whether higher doses of baclofen are safe and more effective than the prior tested dose of 30 mg/ day. There is emerging evidence that severity of dependence is positively associated with baclofen response. The main goal of the present proposal is to test the efficacy and safety of 30 mg/d and 90 mg/d of baclofen compared to placebo controlling for severity of dependence as assessed by drinks/drinking day. A primary secondary goal will examine for an anxiolytic effect of baclofen. The study proposes to enroll 120 men and women with AD in a randomized, placebo-controlled trial to include at least 60 individuals with more severe AD (≥14 drinks/drinking day for men; ≥10 drinks/drinking day for women) with randomization to baclofen or placebo balanced for this variable. Baclofen will be titrated to 10 mg t.i.d over 3 days and to 30 mg t.i.d over 12 days and maintained at that level for 12 weeks and then downtitrated for a total study time of 16 weeks. Medical Management will be provided to encourage progress towards drinking goals and to enhance retention and compliance. Drinking patterns, anxiety levels, sleep patterns, craving for alcohol, gamma-glutamyl transferase (GGT) and carbohydrate deficient transferring (CDT) will be assessed. Trough blood levels of R & S-baclofen will be assessed in all individuals at week 4. In summary, the present proposal is innovative and of clinical significance as it will test and compare standard and high-dose baclofen for efficacy and safety in individuals with AD. The proposal is adequately powered to test the primary hypothesis and provides good power to assess whether drinks/drinking day is predictive of baclofen response. Adequate power is also present to examine the anxiolytic effect of baclofen. Ascertaining the effects of standard and high-dose baclofen, the predictive value of heavy drinking on baclofen response and the anxiolytic effect of baclofen are important goals towards determining whether baclofen has true value for the clinical management of the patient with alcohol dependence.
Interventions
DRUGBaclofen
Baclofen is a GABA-B agonist
DRUGPlacebo
Pill containing no pharmacologically active substance.
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
University of North Carolina, Chapel Hill
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 65 Years
Healthy volunteers
No
Inclusion criteria
1. Men and women between the ages of 18 and 65 meeting Diagnostic and Statistical Manual (DSM)-IV criteria for current alcohol dependence. 2. More than 14 drinks (women) or 21 drinks (men) per week including at least 2 heavy drinking days (men \> 5 drinks/day; women \> 4 drinks/day) per week in the 30-day period prior to screening. In addition we will recruit 50% of individuals who have a mean of ≥14 drinks/drinking day (men) or ≥10 drinks/drinking day (women) in the 30 days prior to screening. 3. Ability to understand and sign written informed consent. 4. Must have a 0.0 gms/dL breathalyzer reading on the day of screening and 0.0 gms/dL on the day of randomization. 5. Express a desire to achieve abstinence or to greatly reduce alcohol consumption 6. Must have a stable residence and be able to identify an individual who could contact participant if needed.
Exclusion criteria
1. Clinically significant medical disease that might interfere with the evaluation of the study medication or present a safety concern (e.g., renal insufficiency, cirrhosis, unstable hypertension, diabetes mellitus, seizure disorder). Clinically significant psychiatric illness including any psychotic disorder, bipolar disorder, severe depression, or suicidal ideation. 2. Other substance abuse or dependence disorder other than nicotine or alcohol or cannabis abuse. Occasional use of cocaine is acceptable. 3. Concurrent use of any psychotropic medication including antidepressants, mood stabilizers, antipsychotics, anxiolytics, stimulants, or hypnotics with the exception of stable doses of antidepressants for one month. Concurrent use of anticonvulsants, insulin, or oral hypoglycemics. 4. Prior history of adverse reaction to baclofen. 5. Creatinine level \> Upper Limit of Normal (ULN) or Estimated Glomerular Filtration Rate \< age norm. 6. aspartate aminotransferase (AST), or alanine transaminase (ALT) \> 5 times ULN or bilirubin \> 1.5 X ULN. 7. Positive urine toxicology screen with the exception of cannabis. Individuals with positive cannabis screens will be excluded only if they have a history of cannabis dependence. 8. Pregnant women and women of childbearing potential who do not practice a medically acceptable form of birth control (oral or depot contraceptive, or barrier methods such as diaphragm or condom with spermicidal). 9. Women who are breastfeeding. 10. Individuals requiring inpatient treatment or more intense outpatient treatment for their alcohol dependence. 11. Participation in any clinical trial within the past 60 days. 12. Court-mandated participation in alcohol treatment or pending incarceration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percentage of Heavy Drinking Days | Every 1-2 weeks up to 16 weeks of active trial | The frequency of heavy drinking days (5 or more drinks for a man and 4 or more drinks for a woman) as percentage during the treatment phase. |
| Mean Percentage of Abstinent Drinking Days | Every 1-2 weeks up to 16 weeks of active trial | Percent of abstinent days over the course of the trial. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Spielberger State-Trait Anxiety Inventory Score [State] | Every 1-2 weeks up to 16 weeks of active trial | The Spielberger State and Trait Anxiety Inventory (STAI) is a validated self-reporting instrument used to assess anxiety in adults.The inventory consists of state anxiety, which evaluates how the subject feels currently (transient anxiety). The State scale consists of 20 questions, each question rated 1-4, and a higher score indicates greater anxiety. Total score ranges from 20 (no anxiety) to 80 (maximum anxiety). The scores are averaged over the trial. |
| Mean Penn Alcohol Craving Scale Score | Every 1-2 weeks up to 16 weeks of active trial | Penn Alcohol Craving Scale (PACS) is a five-item self administered instrument for assessing craving, frequency, intensity, and duration of thoughts about drinking as well as the ability to resist drinking. Scores range from a minimum of zero to a maximum of 30. Lower scores are associated with lower level of craving for alcohol. Scores are averaged over the trial. |
| Carbohydrate-deficient Transferrin | End of trial, generally 16 weeks | Lab test assessing history of heavy drinking with greater specificity than GGT. Higher levels are indicative of greater levels of drinking. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Self-reported Sedation on at Least One Occasion by a Participant | Every 1-2 weeks up to 16 weeks of active trial | Any reporting of feeling sedated/sleepy/drowsy |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants will take placebo for 16 weeks, 3 times per day. Placebo will be given in blister packs.
Placebo: Pill containing no pharmacologically active substance. | 40 |
| 30 Mg Baclofen Participants will take baclofen/placebo for 16 weeks, 3 times per day. Baclofen will be given in blister packs. The 30 mg/d arm will reach 30 mg/d at day 3 and titrate down starting at day 101.
Baclofen: Baclofen is a GABA-B agonist | 43 |
| 90 mg Baclofen Participants will take baclofen/placebo for 16 weeks, 3 times per day. Baclofen will be given in blister packs. The 90 mg/d arm will reach 90 mg/d at day 12 and titrate down starting at day 95.
Baclofen: Baclofen is a GABA-B agonist | 37 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 5 |
| Overall Study | Lost to Follow-up | 3 | 4 | 3 |
| Overall Study | miscellaneous | 4 | 5 | 3 |
| Overall Study | Withdrawal by Subject | 9 | 6 | 2 |
Baseline characteristics
| Characteristic | 30 Mg Baclofen | Total | Placebo | 90 mg Baclofen |
|---|---|---|---|---|
| Age, Continuous | 46.1 years STANDARD_DEVIATION 10.4 | 46.0 years STANDARD_DEVIATION 10.1 | 47.1 years STANDARD_DEVIATION 9.6 | 44.8 years STANDARD_DEVIATION 10.3 |
| Baseline Drinks/drinking day | 10.7 drinks per drinking day STANDARD_DEVIATION 7.7 | 10.0 drinks per drinking day STANDARD_DEVIATION 5.6 | 9.3 drinks per drinking day STANDARD_DEVIATION 3.9 | 10.0 drinks per drinking day STANDARD_DEVIATION 4.2 |
| Baseline Percentage of Abstinent Days | 17 Percentage of Abstinent Days STANDARD_DEVIATION 19 | 16 Percentage of Abstinent Days STANDARD_DEVIATION 19 | 13 Percentage of Abstinent Days STANDARD_DEVIATION 17 | 18 Percentage of Abstinent Days STANDARD_DEVIATION 20 |
| Baseline Percentage of Heavy Drinking Days | 73 percentage of heavy drinking days STANDARD_DEVIATION 23 | 74 percentage of heavy drinking days STANDARD_DEVIATION 23 | 79 percentage of heavy drinking days STANDARD_DEVIATION 21 | 70 percentage of heavy drinking days STANDARD_DEVIATION 26 |
| Carbohydrate Deficient Transferrin (CDT) | 1.72 % CDT STANDARD_DEVIATION 0.63 | 2.07 % CDT STANDARD_DEVIATION 1.46 | 2.31 % CDT STANDARD_DEVIATION 1.95 | 2.22 % CDT STANDARD_DEVIATION 1.46 |
| Craving for Alcohol | 15.5 units on a scale STANDARD_DEVIATION 7.2 | 15.1 units on a scale STANDARD_DEVIATION 6.7 | 14.5 units on a scale STANDARD_DEVIATION 6.8 | 15.3 units on a scale STANDARD_DEVIATION 6.1 |
| Goal of Abstinence | 24 Participants | 52 Participants | 16 Participants | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 14 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 36 Participants | 102 Participants | 36 Participants | 30 Participants |
| Region of Enrollment United States | 43 Participants | 120 Participants | 40 Participants | 37 Participants |
| Sex: Female, Male Female | 21 Participants | 58 Participants | 20 Participants | 17 Participants |
| Sex: Female, Male Male | 22 Participants | 62 Participants | 20 Participants | 20 Participants |
| Speilberger State Anxiety | 36.3 units on a scale STANDARD_DEVIATION 12.4 | 35.7 units on a scale STANDARD_DEVIATION 10.9 | 35.0 units on a scale STANDARD_DEVIATION 10.5 | 35.7 units on a scale STANDARD_DEVIATION 9.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 43 | 0 / 37 |
| other Total, other adverse events | 16 / 40 | 28 / 43 | 21 / 37 |
| serious Total, serious adverse events | 0 / 40 | 0 / 43 | 1 / 37 |
Outcome results
Primary
Mean Percentage of Abstinent Drinking Days
Percent of abstinent days over the course of the trial.
Time frame: Every 1-2 weeks up to 16 weeks of active trial
Population: Post-randomization data were unavailable for 2 participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Percentage of Abstinent Drinking Days | 47 percentage of days | Standard Error 4 |
| 30 Mg Baclofen | Mean Percentage of Abstinent Drinking Days | 48 percentage of days | Standard Error 4 |
| 90 mg Baclofen | Mean Percentage of Abstinent Drinking Days | 59 percentage of days | Standard Error 4 |
p-value: 0.028Mixed Models Analysis
Primary
Mean Percentage of Heavy Drinking Days
The frequency of heavy drinking days (5 or more drinks for a man and 4 or more drinks for a woman) as percentage during the treatment phase.
Time frame: Every 1-2 weeks up to 16 weeks of active trial
Population: Post-randomization data were unavailable for 2 participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Percentage of Heavy Drinking Days | 39 percentage of heavy drinking days | Standard Error 4 |
| 30 Mg Baclofen | Mean Percentage of Heavy Drinking Days | 42 percentage of heavy drinking days | Standard Error 4 |
| 90 mg Baclofen | Mean Percentage of Heavy Drinking Days | 28 percentage of heavy drinking days | Standard Error 4 |
p-value: 0.018Mixed Models Analysis
Secondary
Carbohydrate-deficient Transferrin
Lab test assessing history of heavy drinking with greater specificity than GGT. Higher levels are indicative of greater levels of drinking.
Time frame: End of trial, generally 16 weeks
Population: Post-randomization CDT was not collected for all participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Carbohydrate-deficient Transferrin | 1.81 % CDT | Standard Error 0.26 |
| 30 Mg Baclofen | Carbohydrate-deficient Transferrin | 2.19 % CDT | Standard Error 0.26 |
| 90 mg Baclofen | Carbohydrate-deficient Transferrin | 1.96 % CDT | Standard Error 0.28 |
p-value: 0.6ANCOVA
Secondary
Mean Penn Alcohol Craving Scale Score
Penn Alcohol Craving Scale (PACS) is a five-item self administered instrument for assessing craving, frequency, intensity, and duration of thoughts about drinking as well as the ability to resist drinking. Scores range from a minimum of zero to a maximum of 30. Lower scores are associated with lower level of craving for alcohol. Scores are averaged over the trial.
Time frame: Every 1-2 weeks up to 16 weeks of active trial
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Penn Alcohol Craving Scale Score | 10.1 units on a scale | Standard Error 0.91 |
| 30 Mg Baclofen | Mean Penn Alcohol Craving Scale Score | 10.8 units on a scale | Standard Error 0.88 |
| 90 mg Baclofen | Mean Penn Alcohol Craving Scale Score | 9.4 units on a scale | Standard Error 0.92 |
p-value: 0.43Mixed Models Analysis
Secondary
Mean Spielberger State-Trait Anxiety Inventory Score [State]
The Spielberger State and Trait Anxiety Inventory (STAI) is a validated self-reporting instrument used to assess anxiety in adults.The inventory consists of state anxiety, which evaluates how the subject feels currently (transient anxiety). The State scale consists of 20 questions, each question rated 1-4, and a higher score indicates greater anxiety. Total score ranges from 20 (no anxiety) to 80 (maximum anxiety). The scores are averaged over the trial.
Time frame: Every 1-2 weeks up to 16 weeks of active trial
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Spielberger State-Trait Anxiety Inventory Score [State] | 35.2 units on a scale | Standard Error 1.16 |
| 30 Mg Baclofen | Mean Spielberger State-Trait Anxiety Inventory Score [State] | 33.8 units on a scale | Standard Error 1.12 |
| 90 mg Baclofen | Mean Spielberger State-Trait Anxiety Inventory Score [State] | 33.6 units on a scale | Standard Error 1.18 |
p-value: 0.52Mixed Models Analysis
Other Pre-specified
Self-reported Sedation on at Least One Occasion by a Participant
Any reporting of feeling sedated/sleepy/drowsy
Time frame: Every 1-2 weeks up to 16 weeks of active trial
Population: Post-randomization data were unavailable for 2 participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Self-reported Sedation on at Least One Occasion by a Participant | 14 Participants |
| 30 Mg Baclofen | Self-reported Sedation on at Least One Occasion by a Participant | 25 Participants |
| 90 mg Baclofen | Self-reported Sedation on at Least One Occasion by a Participant | 20 Participants |
p-value: 0.07Fisher Exact