Alcohol Abuse, Alcoholism, Alcohol Related Disorders
Conditions
Keywords
steroid 5Alpha Reductase, dutasteride, neuroactive steroid
Brief summary
This study will explore the hypothesis that effects of alcohol are in part mediated by increased production of neuroactive steroids, which interact with GABAA-receptors. We propose to study non-dependent drinkers using a 4-session within-subjects design in which alcohol / placebo is paired with dutasteride / placebo pretreatment. Dutasteride is a 5-alpha steroid reductase (5AR) inhibitor that limits the production of dihydrotestosterone and the 5a-reduced neuroactive steroids allopregnanolone, pregnanolone and 3a,5a-androstanediol.
Detailed description
Alcohol has multiple pharmacological effects, though which of these effects relate to the risk of alcohol dependence is not clear. Animal studies indicate that the neuroactive steroid allopregnanolone is an alcohol-modulated endogenous agonist at GABAA receptors and that genetic variation in steroid 5a-reductase type I gene which generates neuroactive steroids, may moderate alcohol effects. To better define the role of neuroactive steroids we will conduct a laboratory study of non-alcohol dependent drinkers using a 4-session design in which alcohol/placebo beverage is paired with dutasteride/placebo pretreatment. Dutasteride, an inhibitor of both type I and type II 5a-reductase enzymes, blocks the production of 5a-reduced neuroactive steroids. This study will extend our preliminary findings with finasteride by including a) a placebo control for alcohol, b) a more specific inhibitor of both 5a-reductase isoenzymes, c) a larger group of subjects (including both light and heavy drinkers).
Interventions
DRUGdutasteride + ethanol
4 mg dutasteride administered 2-4 days prior to ingestion of 0.8 mg/kg ethanol divided between three drinks consumed over 36 minutes
DRUGplacebo medication + ethanol
placebo medication administered 2-4 days prior to ingestion of 0.8 gr/kg ethanol divided between three drinks consumed over 36 minutes
DRUGdutasteride + placebo alcohol
4 mg dutasteride administered 2-4 days prior to ingestion of three drinks each containing 1 cc ethanol consumed over 36 minutes
DRUGplacebo medication + placebo alcohol
placebo medication administered 2-4 days prior to ingestion of three drinks each containing 1 cc ethanol consumed over 36 minutes
Sponsors
National Institutes of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
UConn Health
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
21 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Main Study: Subjects will be healthy volunteers with or without parental history of alcoholism who are 21-45 years old and who have a BMI \>18.5 and \<32.5. Drinking history: All subjects must report at least one occasion in the prior month of drinking at least 3 drinks on a single day; additionally, LD subjects will be selected if they drink 1-3 drinks, 1-3 times per week (up to 5 drinks per week on average), with no more than one occasion in the past 2 months on which they drank \>4 drinks. HD subjects will be selected if they report drinking at least 10 drinks per week, with at least one episode per week of heavy drinking.
Exclusion criteria
* Main Study: Subjects cannot have a current or past DSM-IV diagnosis of alcohol or drug dependence, current or past 24-months diagnosis of alcohol or drug abuse or another major psychiatric disorder, neurological illness, have had a hypersensitivity reaction to dutasteride, evidence of liver dysfunction, currently be using benzodiazepines, other psychotropic medications or medications that are known to influence steroid hormone levels or metabolism or modify the effects of alcohol. Nicotine-dependent subjects will be excluded to avoid the confounding effects of nicotine withdrawal during day-long laboratory sessions. Women are not allowed to participate. Subjects anticipating moving from the area during the period of their planned study participation will be excluded from study entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Breath Alcohol | 40 minutes after beginning drink | Breath Alcohol level |
| BAES Sedation Response, Average of 6 Time Points | 40, 80, 120, 160, 210 and 240 minutes after start of drinking | Biphasic Alcohol Effects Scale (BAES) Sedation items - sum of subjective responses - 0(not at all)to 10 (extremely)- for 7 sedation related questions regarding effects of alcohol. Total BAES sedation subscale score 0-70 with higher numbers indicating greater sedative effects of alcohol. \[Martin, C. S., M. Earleywine, R. E. Musty, M. W. Perrine and R. M. Swift (1993a). Development and validation of the Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res 17(1): 140-6.\] |
| BAES Stimulation Response, Average of 6 Time Points | 40, 80, 120, 160, 210 and 240 minutes after start of drinking | Biphasic Alcohol Effects Scale (BAES)Simulation items - sum of subjective responses - 0(not at all)to 10 (extremely)- for 7 stimulation related questions regarding effects of alcohol. Total BAES stimulation subscale score 0-70 with higher numbers indicating greater stimulating effects of alcohol. \[Martin, C. S., M. Earleywine, R. E. Musty, M. W. Perrine and R. M. Swift (1993a). Development and validation of the Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res 17(1): 140-6.\] |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum 3a-androstanediol Glucuronide | Baseline (pre medication administration) and 2-4 days post-medication (alcohol session) | Ratio of serum 3a-androstanediol drawn prior to alcohol administration (2-4 days after medication administration) compared to the baseline level prior to medication dose. The pharmacologic effect of dutasteride was measured by assay of serum 5a-androstan-3a,17b-diol,17-glucuronide (aka 3a-androstanediol glucuronide) as a biochemical measure of 5a-reductase enzyme inhibition. 3a-androstanediol glucuronide is the primary metabolic excretion product of 3a,5a-androstane neuroactive steroids. The |
Countries
United States
Participant flow
Recruitment details
Non-treatment seeking social drinkers recruited from community settings 2007-2010.
Pre-assignment details
A total of 148 subjects enrolled, 31 subjects were excluded for not meeting entrance criteria, 23 subjects withdrew before first dose of study medication. 94 subjects were randomized to one of 24 possible laboratory session sequences for exposure to each of 4 treatment conditions.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants All study participants enrolled in Lab Session 1 | 94 |
| Total | 94 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Lab Session 1 | Withdrawal by Subject | 2 | 0 | 0 | 0 |
| Lab Session 2 | Withdrawal by Subject | 1 | 0 | 0 | 1 |
| Lab Session 4 | Withdrawal by Subject | 0 | 0 | 0 | 1 |
| Washout 1 | Withdrawal by Subject | 1 | 5 | 2 | 3 |
| Washout 2 | Withdrawal by Subject | 1 | 1 | 1 | 0 |
| Washout 3 | Withdrawal by Subject | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 94 Participants |
| Age Continuous | 26.1 years STANDARD_DEVIATION 6.5 |
| Region of Enrollment United States | 94 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 94 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 78 | 8 / 81 | 11 / 83 | 12 / 78 |
| serious Total, serious adverse events | 0 / 78 | 0 / 81 | 0 / 83 | 0 / 78 |
Outcome results
Primary
BAES Sedation Response, Average of 6 Time Points
Biphasic Alcohol Effects Scale (BAES) Sedation items - sum of subjective responses - 0(not at all)to 10 (extremely)- for 7 sedation related questions regarding effects of alcohol. Total BAES sedation subscale score 0-70 with higher numbers indicating greater sedative effects of alcohol. \[Martin, C. S., M. Earleywine, R. E. Musty, M. W. Perrine and R. M. Swift (1993a). Development and validation of the Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res 17(1): 140-6.\]
Time frame: 40, 80, 120, 160, 210 and 240 minutes after start of drinking
Population: Subjects who completed all 4 arms of study (e.g. completed each combination of dutasteride or placebo paired with 0.8 gr/kg ethanol or alcohol flavor mask)less 3 subjects removed during data cleaning due to pharmacy errors (n=2) or protocol deviation (n=1)resulted in 70 subjects completing each condition for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Medication + Placebo Alcohol | BAES Sedation Response, Average of 6 Time Points | 0.7 units on a scale | Standard Error 0.1 |
| Placebo Medication + 0.8 gr/kg Ethanol | BAES Sedation Response, Average of 6 Time Points | 8.9 units on a scale | Standard Error 0.6 |
| 4 mg Dutasteride + Placebo Alcohol | BAES Sedation Response, Average of 6 Time Points | 1.5 units on a scale | Standard Error 0.2 |
| 4 mg Dutasteride + 0.8 mg/kg Ethanol | BAES Sedation Response, Average of 6 Time Points | 7.4 units on a scale | Standard Error 0.5 |
Comparison: null hypothesis: dutasteride pre-treatment does not reduce the sedative effect of alcoholp-value: 0.01Mixed Models Analysis
Primary
BAES Stimulation Response, Average of 6 Time Points
Biphasic Alcohol Effects Scale (BAES)Simulation items - sum of subjective responses - 0(not at all)to 10 (extremely)- for 7 stimulation related questions regarding effects of alcohol. Total BAES stimulation subscale score 0-70 with higher numbers indicating greater stimulating effects of alcohol. \[Martin, C. S., M. Earleywine, R. E. Musty, M. W. Perrine and R. M. Swift (1993a). Development and validation of the Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res 17(1): 140-6.\]
Time frame: 40, 80, 120, 160, 210 and 240 minutes after start of drinking
Population: Subjects who completed all 4 arms of study (e.g. completed each combination of dutasteride or placebo paired with 0.8 gr/kg ethanol or alcohol flavor mask)less 3 subjects removed during data cleaning due to pharmacy errors (n=2) or protocol deviation (n=1)resulted in 70 subjects completing each condition for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Medication + Placebo Alcohol | BAES Stimulation Response, Average of 6 Time Points | 0.7 units on a scale | Standard Error 0.1 |
| Placebo Medication + 0.8 gr/kg Ethanol | BAES Stimulation Response, Average of 6 Time Points | 4.2 units on a scale | Standard Error 0.4 |
| 4 mg Dutasteride + Placebo Alcohol | BAES Stimulation Response, Average of 6 Time Points | 1.7 units on a scale | Standard Error 0.3 |
| 4 mg Dutasteride + 0.8 mg/kg Ethanol | BAES Stimulation Response, Average of 6 Time Points | 4.8 units on a scale | Standard Error 0.4 |
Comparison: null hypothesis: dutasteride pre-treatment does not reduce the stimulating effect of alcoholp-value: 0.17Mixed Models Analysis
Primary
Breath Alcohol
Breath Alcohol level
Time frame: 40 minutes after beginning drink
Population: Subjects who completed all 4 arms of study (e.g. completed each combination of dutasteride or placebo paired with 0.8 gr/kg ethanol or alcohol flavor mask)less 3 subjects removed during data cleaning due to pharmacy errors (n=2) or protocol deviation (n=1)resulted in 70 subjects completing each condition for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Medication + Placebo Alcohol | Breath Alcohol | 0.001 gr/dL | Standard Error 0.0004 |
| Placebo Medication + 0.8 gr/kg Ethanol | Breath Alcohol | 0.075 gr/dL | Standard Error 0.003 |
| 4 mg Dutasteride + Placebo Alcohol | Breath Alcohol | 0.001 gr/dL | Standard Error 0.0005 |
| 4 mg Dutasteride + 0.8 mg/kg Ethanol | Breath Alcohol | 0.071 gr/dL | Standard Error 0.003 |
Comparison: null hypothesis - dutasteride does not affect blood alcohol following standardized dose of alcohol (0.8 gr/kg)p-value: 0.28t-test, 2 sided
Secondary
Change in Serum 3a-androstanediol Glucuronide
Ratio of serum 3a-androstanediol drawn prior to alcohol administration (2-4 days after medication administration) compared to the baseline level prior to medication dose. The pharmacologic effect of dutasteride was measured by assay of serum 5a-androstan-3a,17b-diol,17-glucuronide (aka 3a-androstanediol glucuronide) as a biochemical measure of 5a-reductase enzyme inhibition. 3a-androstanediol glucuronide is the primary metabolic excretion product of 3a,5a-androstane neuroactive steroids. The
Time frame: Baseline (pre medication administration) and 2-4 days post-medication (alcohol session)
Population: Subjects who completed all 4 arms of study (e.g. completed each combination of dutasteride or placebo paired with 0.8 gr/kg ethanol or alcohol flavor mask)less 3 subjects removed during data cleaning due to pharmacy errors (n=2) or protocol deviation (n=1)resulted in 70 subjects completing each condition for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Medication + Placebo Alcohol | Change in Serum 3a-androstanediol Glucuronide | 1.04 ratio | Standard Error 0.033 |
| Placebo Medication + 0.8 gr/kg Ethanol | Change in Serum 3a-androstanediol Glucuronide | 1.11 ratio | Standard Error 0.03 |
| 4 mg Dutasteride + Placebo Alcohol | Change in Serum 3a-androstanediol Glucuronide | 0.31 ratio | Standard Error 0.02 |
| 4 mg Dutasteride + 0.8 mg/kg Ethanol | Change in Serum 3a-androstanediol Glucuronide | 0.31 ratio | Standard Error 0.02 |
Comparison: null hypothesis - A single 4 mg dose of dutasteride does not reduce serum 3a-androstanediol glucuronide levelsp-value: <0.001t-test, 2 sided