Pharmacogenetics of Alcohol: Treatment Implications

• Sponsor: UConn Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT00734656
• Collaborator: National Institutes of Health (NIH) (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA) (NIH)
• Enrollment: 94
• Location: 1
• Arms: 4
• Duration (Months): 52
• Patients Per Site Per Month: 1.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Alcohol Related Disorders; Alcoholism; Alcohol Abuse	Drug: dutasteride + ethanol; Drug: placebo medication + ethanol; Drug: dutasteride + placebo alcohol; Drug: placebo medication + placebo alcohol	N/A

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 94 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Official Title: Subjective and Physiological Effects of Alcohol: Role of Genetic Variation and Adrenal Hormones
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Oct 1, 2010
• Actual Study Completion Date: Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo medication + placebo alcohol	Drug: placebo medication + placebo alcohol; placebo medication administered 2-4 days prior to ingestion of three drinks each containing 1 cc ethanol consumed over 36 minutes
Experimental: Placebo Medication + 0.8 gr/kg Ethanol	Drug: placebo 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
Experimental: 4 mg Dutasteride + Placebo Alcohol	Drug: dutasteride + placebo alcohol; 4 mg dutasteride administered 2-4 days prior to ingestion of three drinks each containing 1 cc ethanol consumed over 36 minutes; Other Names: Avodart
Experimental: 4 mg Dutasteride + 0.8 gr/kg Ethanol	Drug: dutasteride + 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; Other Names: Avodart

Outcome Measures

Primary Outcome Measures

1. Breath Alcohol [40 minutes after beginning drink]

   Breath Alcohol level

2. 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.]

3. 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 Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 45 Years
• Sexes Eligible for Study: Male
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Connecticut Health Center	Farmington	Connecticut	United States	06030

Sponsors and Collaborators

• UConn Health
• National Institutes of Health (NIH)
• National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Investigators

• Principal Investigator: Jonathan Covault, MD, PhD, UConn Health

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jonathan Covault, Associate Professor, UConn Health
• ClinicalTrials.gov Identifier: NCT00734656
• Other Study ID Numbers: 06-218S-2; 619; 5R01AA015606-02
• First Posted: Aug 14, 2008
• Last Update Posted: Mar 28, 2012
• Last Verified: Mar 1, 2012

• Keywords provided by Jonathan Covault, Associate Professor, UConn Health: steroid 5Alpha Reductase; dutasteride; neuroactive steroid
• Additional relevant MeSH terms: Alcoholism; Alcohol-Related Disorders; Ethanol; Dutasteride

Study Results

Participant Flow

Recruitment Details	Non-treatment seeking social drinkers recruited from community settings 2007-2010.
Pre-assignment Detail	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.

Arm/Group Title	Placebo Medication + Placebo Alcohol	Placebo Medication + 0.8 gr/kg Ethanol	4 mg Dutasteride + Placebo Alcohol	4 mg Dutasteride + 0.8 mg/kg Ethanol
Arm/Group Description	placebo medication paired with placebo alcohol	placebo medication paired with active alcohol	4 mg dutasteride paired with placebo alcohol	4 mg dutasteride paired with active alcohol
Period Title: Lab Session 1
STARTED	24	23	26	21
COMPLETED	22	23	26	21
NOT COMPLETED	2	0	0	0
Period Title: Lab Session 1
STARTED	22	23	26	21
COMPLETED	21	18	24	18
NOT COMPLETED	1	5	2	3
Period Title: Lab Session 1
STARTED	19	21	21	20
COMPLETED	18	21	21	19
NOT COMPLETED	1	0	0	1
Period Title: Lab Session 1
STARTED	18	21	21	19
COMPLETED	17	20	20	19
NOT COMPLETED	1	1	1	0
Period Title: Lab Session 1
STARTED	18	19	20	19
COMPLETED	18	19	20	19
NOT COMPLETED	0	0	0	0
Period Title: Lab Session 1
STARTED	18	19	20	19
COMPLETED	17	19	20	18
NOT COMPLETED	1	0	0	1
Period Title: Lab Session 1
STARTED	20	18	16	20
COMPLETED	20	18	16	19
NOT COMPLETED	0	0	0	1

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	All study participants enrolled in Lab Session 1
Overall Participants	94
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	94 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26.1 (6.5)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	94 100%
Region of Enrollment (participants) [Number]
United States	94 100%

Outcome Measures

1. Primary Outcome

Title	Breath Alcohol
Description	Breath Alcohol level
Time Frame	40 minutes after beginning drink

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo Medication + Placebo Alcohol	Placebo Medication + 0.8 gr/kg Ethanol	4 mg Dutasteride + Placebo Alcohol	4 mg Dutasteride + 0.8 mg/kg Ethanol
Arm/Group Description	placebo medication paired with placebo alcohol	placebo medication paired with active alcohol	4 mg dutasteride paired with placebo alcohol	4 mg dutasteride paired with active alcohol
Measure Participants	70	70	70	70
Mean (Standard Error) [gr/dL]	0.001 (0.0004)	0.075 (0.003)	0.001 (0.0005)	0.071 (0.003)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Medication + 0.8 gr/kg Ethanol, 4 mg Dutasteride + 0.8 mg/kg Ethanol
	Comments	null hypothesis - dutasteride does not affect blood alcohol following standardized dose of alcohol (0.8 gr/kg)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	BAES Sedation Response, Average of 6 Time Points
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo Medication + Placebo Alcohol	Placebo Medication + 0.8 gr/kg Ethanol	4 mg Dutasteride + Placebo Alcohol	4 mg Dutasteride + 0.8 mg/kg Ethanol
Arm/Group Description	placebo medication paired with placebo alcohol	placebo medication paired with active alcohol	4 mg dutasteride paired with placebo alcohol	4 mg dutasteride paired with active alcohol
Measure Participants	70	70	70	70
Mean (Standard Error) [units on a scale]	0.7 (0.1)	8.9 (0.6)	1.5 (0.2)	7.4 (0.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Medication + 0.8 gr/kg Ethanol, 4 mg Dutasteride + 0.8 mg/kg Ethanol
	Comments	null hypothesis: dutasteride pre-treatment does not reduce the sedative effect of alcohol
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	Mixed Models Analysis
	Comments

3. Primary Outcome

Title	BAES Stimulation Response, Average of 6 Time Points
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo Medication + Placebo Alcohol	Placebo Medication + 0.8 gr/kg Ethanol	4 mg Dutasteride + Placebo Alcohol	4 mg Dutasteride + 0.8 mg/kg Ethanol
Arm/Group Description	placebo medication paired with placebo alcohol	placebo medication paired with active alcohol	4 mg dutasteride paired with placebo alcohol	4 mg dutasteride paired with active alcohol
Measure Participants	70	70	70	70
Mean (Standard Error) [units on a scale]	0.7 (0.1)	4.2 (0.4)	1.7 (0.3)	4.8 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Medication + 0.8 gr/kg Ethanol, 4 mg Dutasteride + 0.8 mg/kg Ethanol
	Comments	null hypothesis: dutasteride pre-treatment does not reduce the stimulating effect of alcohol
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.17
	Comments
	Method	Mixed Models Analysis
	Comments

4. Secondary Outcome

Title	Change in Serum 3a-androstanediol Glucuronide
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo Medication + Placebo Alcohol	Placebo Medication + 0.8 gr/kg Ethanol	4 mg Dutasteride + Placebo Alcohol	4 mg Dutasteride + 0.8 mg/kg Ethanol
Arm/Group Description	placebo medication paired with placebo alcohol	placebo medication paired with active alcohol	4 mg dutasteride paired with placebo alcohol	4 mg dutasteride paired with active alcohol
Measure Participants	70	70	70	70
Mean (Standard Error) [ratio]	1.04 (0.033)	1.11 (0.03)	0.31 (0.02)	0.31 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Medication + 0.8 gr/kg Ethanol, 4 mg Dutasteride + 0.8 mg/kg Ethanol
	Comments	null hypothesis - A single 4 mg dose of dutasteride does not reduce serum 3a-androstanediol glucuronide levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	2-11 days following medication administration. In person at time of alcohol laboratory session (2-4 days after medication dose)and by phone 1-day and 1-week following alcohol laboratory session.
Arm/Group Title	Placebo Medication + Placebo Alcohol		Placebo Medication + 0.8 gr/kg Ethanol		4 mg Dutasteride + Placebo Alcohol		4 mg Dutasteride + 0.8 mg/kg Ethanol
Arm/Group Description	placebo medication paired with placebo alcohol		placebo medication paired with active alcohol		4 mg dutasteride paired with placebo alcohol		4 mg dutasteride paired with active alcohol
All Cause Mortality
	Placebo Medication + Placebo Alcohol		Placebo Medication + 0.8 gr/kg Ethanol		4 mg Dutasteride + Placebo Alcohol		4 mg Dutasteride + 0.8 mg/kg Ethanol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo Medication + Placebo Alcohol		Placebo Medication + 0.8 gr/kg Ethanol		4 mg Dutasteride + Placebo Alcohol		4 mg Dutasteride + 0.8 mg/kg Ethanol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/78 (0%)		0/81 (0%)		0/83 (0%)		0/78 (0%)
Other (Not Including Serious) Adverse Events
	Placebo Medication + Placebo Alcohol		Placebo Medication + 0.8 gr/kg Ethanol		4 mg Dutasteride + Placebo Alcohol		4 mg Dutasteride + 0.8 mg/kg Ethanol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/78 (11.5%)		8/81 (9.9%)		11/83 (13.3%)		12/78 (15.4%)
Gastrointestinal disorders
Nausea	1/78 (1.3%)	1	0/81 (0%)	0	2/83 (2.4%)	2	2/78 (2.6%)	2
Stomach discomfort	2/78 (2.6%)	2	2/81 (2.5%)	2	4/83 (4.8%)	5	6/78 (7.7%)	7
General disorders
Fatigue	2/78 (2.6%)	2	2/81 (2.5%)	2	2/83 (2.4%)	3	1/78 (1.3%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain	1/78 (1.3%)	1	1/81 (1.2%)	1	1/83 (1.2%)	1	0/78 (0%)	0
Nervous system disorders
Headace	2/78 (2.6%)	2	3/81 (3.7%)	3	1/83 (1.2%)	1	3/78 (3.8%)	3
Reproductive system and breast disorders
Libido, reduced	1/78 (1.3%)	1	0/81 (0%)	0	1/83 (1.2%)	1	0/78 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.