Alcohol Abuse, Alcohol Dependence, Alcoholism
Conditions
Keywords
neuroactive steroids
Brief summary
This study will examine the safety and potential benefit of the medication dutasteride to help men reduce or stop drinking alcohol.
Detailed description
Extensive preclinical studies indicate that neuroactive steroids medicate important effects of alcohol and support the examination of neuroactive steroid modulators as treatment options for alcohol use problems. Dutasteride, a widely prescribed medication for benign prostatic hypertrophy, blocks a key step in the production of neuroactive steroids and represents a promising candidate for treatment of alcohol use disorders. This study will use a 12-week randomized placebo controlled design to examine the safety and efficacy of dutasteride to reduce drinking among a sample of 160 men with hazardous levels of alcohol use. It will additionally examine the potential moderation of dutasteride treatment effects by a common missense polymorphism in a neuroactive steroid biosynthetic enzyme that we have previously reported to be associated with alcohol dependence. Identification of genetic predictors of medication response offers the potential for matching alcohol treatment medications with those most likely to respond.
Interventions
DRUGDutasteride
DRUGsugar pill
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
UConn Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* an average weekly ethanol consumption of at least 24 standard drinks; * be able to read English at the 8th grade or higher level; * no evidence of significant cognitive impairment; * be willing to provide signed, informed consent to participate in the study (including a willingness to stop or reduce drinking to non-hazardous levels); * be willing to nominate an individual who will know the patient's whereabouts to facilitate follow up during the study
Exclusion criteria
* history of significant alcohol withdrawal symptoms (e.g. substantial tremor, autonomic changes, perceptual distortions, seizures, delirium, or hallucinations); * current Diagnostic and Statistical Manual Version IV (DSM-IV) diagnosis of Alcohol Dependence who on clinical examination by a physician, are deemed to be too severely alcohol dependent to permit them to participate in a placebo-controlled study (e.g. evidence of serious adverse medical or psychiatric effects that are exacerbated by heavy drinking and would, for safety reasons, lead the physician to urge the patient to be totally abstinent and engage in an empirically supported treatment). * current, clinically significant physical disease or abnormality on the basis of medical history, physical examination, or routine laboratory evaluation,(we will not exclude patients with hypertension, diabetes mellitus, asthma or other common medical conditions, if these are adequately controlled and the patient has an ongoing relationship with a primary care provider) * serious psychiatric illness on the basis of history or psychiatric examination (i.e., schizophrenia, bipolar disorder, severe or psychotic major depression, organic mental disorder, current clinically significant eating disorder, or substantial suicide or violence risk); * current DSM-IV diagnosis of drug dependence (other than nicotine dependence); * currently taking psychotropics other than medication for depression/anxiety disorder (with stable dose for at least 4 weeks),medications for treatment of Attention Deficit/Hyperactivity Disorder (with stable dose for at least 4 weeks), a non-benzodiazepine sleep medication or a low dose of benzodiazepine equivalent to 2 mg clonazepam or lorazepam per day; * are considered by the investigators to be an unsuitable candidate for receipt of an investigational drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Heavy Drinking Days Per Week | 12-week treatment period | Number of days / study week with 5 or more drinks consumed |
| Drinks Per Week | 12-week treatment period | Total number of drinks aggregated by week |
| Number of Participants With no Heavy Drinking Days | Last 4 weeks of treatment | Number of participants with no heavy drinking days (days with 5 or more drinks) during the last 4 weeks of treatment. |
| Number of Participants With no Hazardous Drinking | Last 4 weeks of treatment | Number of participants with no hazardous drinking (not more than 4 drinks on one day and not more than 14 drinks per week) during the last 4 weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| HDD/ Week by Treatment Group and AKR1C3*2 Genotype | 12-week treatment period | Change in Number of days / week with 5 or more drinks consumed contrasting AKR1C3\*2 CC vs. G-carrier genotype and treatment group |
| Carbohydrate-deficient Transferrin | end of 12-week treatment vs. baseline | Carbohydrate-deficient transferrin (CDT) at end of treatment as percentage of baseline. Serum CDT is a biochemical measure of heavy alcohol use. |
Countries
United States
Participant flow
Pre-assignment details
47 subjects not randomized: 23 excluded at in person screening visit; 24 subjects withdrew prior to randomization
Participants by arm
| Arm | Count |
|---|---|
| Dutasteride 4 mg oral loading dose of dutasteride followed by 1 mg/day dutasteride for 12 weeks.
Dutasteride | 68 |
| Sugar Pill Placebo pills prepared to appear the same as active medication and taken in the same number as active medication for 12 weeks.
sugar pill | 67 |
| Total | 135 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Lack of Efficacy | 4 | 2 |
| Overall Study | Lost to Follow-up | 3 | 4 |
| Overall Study | Withdrawal by Subject | 12 | 7 |
Baseline characteristics
| Characteristic | Dutasteride | Sugar Pill | Total |
|---|---|---|---|
| AbstinentDays/week | 0.67 days STANDARD_DEVIATION 1.1 | 0.62 days STANDARD_DEVIATION 1.1 | 0.64 days STANDARD_DEVIATION 1.1 |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 5 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 64 Participants | 62 Participants | 126 Participants |
| Age, Continuous | 53.0 years STANDARD_DEVIATION 7.9 | 53.1 years STANDARD_DEVIATION 9.4 | 53.0 years STANDARD_DEVIATION 8.6 |
| Drinks/week | 48.8 drinks/week STANDARD_DEVIATION 24 | 47.3 drinks/week STANDARD_DEVIATION 20.4 | 48.0 drinks/week STANDARD_DEVIATION 22.2 |
| DSM-IV Alcohol Dependence criteria | 4.3 units on a scale STANDARD_DEVIATION 1.6 | 4.0 units on a scale STANDARD_DEVIATION 1.6 | 4.2 units on a scale STANDARD_DEVIATION 1.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 67 Participants | 67 Participants | 134 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Heavy Drinking Days (HDD)/wk | 5.2 heavy drinking days / week STANDARD_DEVIATION 2.2 | 5.2 heavy drinking days / week STANDARD_DEVIATION 2.1 | 5.2 heavy drinking days / week STANDARD_DEVIATION 2.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 66 Participants | 65 Participants | 131 Participants |
| Region of Enrollment United States | 68 participants | 67 participants | 135 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 68 Participants | 67 Participants | 135 Participants |
| Short Inventory of Problems | 17.2 units on a scale STANDARD_DEVIATION 8.2 | 16.8 units on a scale STANDARD_DEVIATION 8.8 | 17.0 units on a scale STANDARD_DEVIATION 8.4 |
| Smoker | 12 Participants | 12 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 68 | 0 / 67 |
| other Total, other adverse events | 37 / 68 | 27 / 67 |
| serious Total, serious adverse events | 4 / 68 | 2 / 67 |
Outcome results
Primary
Drinks Per Week
Total number of drinks aggregated by week
Time frame: 12-week treatment period
Population: Modified ITT (all subjects who attended one or more post-randomization visit)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dutasteride | Drinks Per Week | 22.0 drinks/week | Standard Error 2.6 |
| Sugar Pill | Drinks Per Week | 27.2 drinks/week | Standard Error 2.4 |
p-value: 0.028Mixed Models Analysis
Primary
Heavy Drinking Days Per Week
Number of days / study week with 5 or more drinks consumed
Time frame: 12-week treatment period
Population: Modified Intention to Treat (ITT) all subjects who attended one or more post-randomization visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dutasteride | Heavy Drinking Days Per Week | 1.75 heavy drinking days/week | Standard Error 0.33 |
| Sugar Pill | Heavy Drinking Days Per Week | 2.67 heavy drinking days/week | Standard Error 0.34 |
p-value: 0.002Mixed Models Analysis
Primary
Number of Participants With no Hazardous Drinking
Number of participants with no hazardous drinking (not more than 4 drinks on one day and not more than 14 drinks per week) during the last 4 weeks of treatment.
Time frame: Last 4 weeks of treatment
Population: Per protocol 12 week treatment completers
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dutasteride | Number of Participants With no Hazardous Drinking | 13 Participants |
| Sugar Pill | Number of Participants With no Hazardous Drinking | 3 Participants |
p-value: 0.00795% CI: [1.5, 20.7]Fisher Exact
Primary
Number of Participants With no Heavy Drinking Days
Number of participants with no heavy drinking days (days with 5 or more drinks) during the last 4 weeks of treatment.
Time frame: Last 4 weeks of treatment
Population: Per protocol 12-week completer
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dutasteride | Number of Participants With no Heavy Drinking Days | 16 Participants |
| Sugar Pill | Number of Participants With no Heavy Drinking Days | 8 Participants |
p-value: 0.05795% CI: [0.96, 6.45]Chi-squared
Secondary
Carbohydrate-deficient Transferrin
Carbohydrate-deficient transferrin (CDT) at end of treatment as percentage of baseline. Serum CDT is a biochemical measure of heavy alcohol use.
Time frame: end of 12-week treatment vs. baseline
Population: Per protocol 12-week completers (serum sample not available for 1 placebo subject).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dutasteride | Carbohydrate-deficient Transferrin | 94 percentage of baseline CDT | Standard Error 3.8 |
| Sugar Pill | Carbohydrate-deficient Transferrin | 107 percentage of baseline CDT | Standard Error 4 |
p-value: 0.03t-test, 2 sided
Secondary
HDD/ Week by Treatment Group and AKR1C3*2 Genotype
Change in Number of days / week with 5 or more drinks consumed contrasting AKR1C3\*2 CC vs. G-carrier genotype and treatment group
Time frame: 12-week treatment period
Population: Modified ITT (all subjects who attended one or more post-randomization visit)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dutasteride | HDD/ Week by Treatment Group and AKR1C3*2 Genotype | 1.06 heavy drinking days/week | Standard Error 0.48 |
| Sugar Pill | HDD/ Week by Treatment Group and AKR1C3*2 Genotype | 2.9 heavy drinking days/week | Standard Error 0.53 |
| Dutasteride - AKR1C3*2 G-carrier | HDD/ Week by Treatment Group and AKR1C3*2 Genotype | 2.05 heavy drinking days/week | Standard Error 0.42 |
| Sugar Pill - AKR1C3*2 G-carrier | HDD/ Week by Treatment Group and AKR1C3*2 Genotype | 2.5 heavy drinking days/week | Standard Error 0.44 |
p-value: 0.87Mixed Models Analysis