Prazosin to Reduce Stress-Induced Alcohol/Drug Craving and Relapse

• Sponsor: Yale University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00585780
• Collaborator: National Institutes of Health (NIH) (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA) (NIH)
• Enrollment: 100
• Location: 1
• Arms: 4
• Duration (Months): 116.3
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

To test the preliminary efficacy of 16.0 mg of Prazosin daily versus placebo in treatment seeking alcohol dependent individuals. This proposal is a laboratory and treatment outcome study to examine the effects of Prazosin on brief exposure to stress, drug cues and neutral situations on alcohol and drug craving, mood and neurobiological reactivity in a sample of cocaine and/or alcohol dependent individuals. Prazosin will be beneficial for reduction in stress and alcohol cue induced craving and related arousal. In a sample of treatment-seeking alcohol dependent men and women, we propose to examine (a) differences in measures of alcohol craving, emotion state, hypothalamic-pituitary-adrenal (HPA) activation, physiological arousal and plasma catecholamine response to stress imagery and to alcohol cue imagery as compared to neutral imagery; (b) reduction in alcohol abstinence symptoms; and (c) improvement in alcohol treatment outcomes as measured by reductions in heavy drinking days, any drinking days, secondarily on drinks/day, anxiety, mood and sleep.

Condition or Disease	Intervention/Treatment	Phase
Alcohol Dependence	Drug: Prazosin Tablet; Drug: Placebo Tablet	Phase 1/Phase 2

Detailed Description

This is a proof-of-concept (POC) experimental therapeutics study with 2 arms. The first is a double-blind placebo controlled laboratory study with 40 individuals meeting current alcohol dependence criteria (DSM-IVTR) who are admitted to the Clinical Neuroscience Research Unit and initiated on Prazosin vs Placebo (16mg/day) after admission and initial detoxification (if required). Experimental laboratory sessions are conducted after subjects achieved full dose after the 2-week titration, in week 3-4 of inpatient stay. The laboratory outcomes included alcohol craving, anxiety, negative affect and neuroendocrine and sympathetic arousal measures. Individuals who wished to remain on study medication for the outpatient (Arm 2) were maintained on study medication throughout the outpatient phase for a total period of 12 weeks.

Arm 2 of the POC study is a 12-week randomized clinical trial (RCT) of Prazosin (16mg/day) versus Placebo in 100 treatment seeking alcohol dependent individuals, to assess whether high anxiety and distress, including alcohol craving, manifest as increased alcohol withdrawal symptoms at treatment entry moderates Prazosin effects on alcohol use outcomes. Primary alcohol use outcomes include heavy drinking days, any drinking days and secondarily drinks/day. Additional secondary outcomes include alcohol craving, anxiety and mood symptoms and sleep disturbances. Patients from Arm 1 who wished to continue on study medication for the outpatient phase were included in Arm 2. Arm 2 patients were initiated on study medication upon presenting with a negative breathalyzer without any minimum pre-treatment alcohol abstinence period prior to medication initiation.

Study Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Interaction effects of Alcohol withdrawal distress with Prazosin versus Placebo effects during the trial.Interaction effects of Alcohol withdrawal distress with Prazosin versus Placebo effects during the trial.
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Randomization into Prazosin/Placebo treatment was conducted by the Yale Stress Center biostatistician using an Urn randomization procedure that balanced groups on gender, age, nicotine smoking status, education years and lifetime history of DSM-IVTR anxiety disorders, including Post Traumatic Stress Disorder (PTSD). Random assignment of each patient was provided to the Yale Investigational Drug Service (IDS) Pharmacist, who formulated identical, matched tablets of Prazosin and Placebo, and provided dosing in weekly blister packs labeled by day and time of dosing for each subject to study staff for dispensing. All study personnel, including investigators, physicians, study staff and patients remained blind to medication group.
• Primary Purpose: Treatment
• Official Title: Prazosin to Reduce Stress-Induced Alcohol/Drug Craving and Relapse
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Aug 1, 2018
• Actual Study Completion Date: May 13, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: High Alcohol Withdrawal on Prazosin High AW was determined by those scoring at or above the median on Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) assessment. High AW were randomized to Prazosin 16 mg/day (tid) administered for 12 weeks with fish-bowl contingency management for weekly treatment attendance and manualized 12-Step relapse prevention counseling in a double blind manner.	Drug: Prazosin Tablet; Target medication dosing was three times/day (t.i.d. dosing) with 5 mg in the morning, 5 mg in the afternoon and 6 mg at night reached at the end of the 2-week period, and maintained at this or their highest tolerated dose until week 11, followed by a 5-day taper in week 12, as in previous research.The titration schedule was as follows: 1 mg dose at bedtime for 2 nights, followed by a 1mg dose morning and night (8 AM/8 PM) on day 3, then 2 mg dose t.i.d., on days 4-6, 3 mg dose (2 pills each) morning and afternoon, and 4 mg dose (2 pills) at night for days 7-9, increased to 4 mg dosing t.i.d. on days 10-13, and from day 14 through week 11, 5 mg (1 pill) each in the morning and afternoon, and 6 mg for the night (2 pills) dose. This was followed by a 5-day taper in week 12. Patients were initiated on study medication upon presenting with a negative breathalyzer without any minimum pre-treatment alcohol abstinence period prior to medication initiation.
Placebo Comparator: High Alcohol Withdrawal on PLA High AW was determined by those scoring at or above the median on Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) assessment. High AW were randomized to Placebo tablets administered tid for 12 weeks with fish-bowl contingency management for weekly treatment attendance and manualized 12-Step relapse prevention counseling in a double blind manner.	Drug: Placebo Tablet; Placebo tablets identical in appearance and dosing schedule as the active study medication was utilized
Active Comparator: Low Alcohol Withdrawal on Prazosin Low AW was determined by those scoring below the median on Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) assessment. Low AW were randomized to Prazosin 16 mg/day (tid) administered for 12 weeks with fish-bowl contingency management for weekly treatment attendance and manualized 12-Step relapse prevention counseling in a double blind manner.	Drug: Prazosin Tablet; Target medication dosing was three times/day (t.i.d. dosing) with 5 mg in the morning, 5 mg in the afternoon and 6 mg at night reached at the end of the 2-week period, and maintained at this or their highest tolerated dose until week 11, followed by a 5-day taper in week 12, as in previous research.The titration schedule was as follows: 1 mg dose at bedtime for 2 nights, followed by a 1mg dose morning and night (8 AM/8 PM) on day 3, then 2 mg dose t.i.d., on days 4-6, 3 mg dose (2 pills each) morning and afternoon, and 4 mg dose (2 pills) at night for days 7-9, increased to 4 mg dosing t.i.d. on days 10-13, and from day 14 through week 11, 5 mg (1 pill) each in the morning and afternoon, and 6 mg for the night (2 pills) dose. This was followed by a 5-day taper in week 12. Patients were initiated on study medication upon presenting with a negative breathalyzer without any minimum pre-treatment alcohol abstinence period prior to medication initiation.
Placebo Comparator: Low Alcohol Withdrawal on PLA Low AW was determined by those scoring below the median on Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) assessment.Placebo tablets administered tid for 12 weeks with fish-bowl contingency management for weekly treatment attendance and manualized 12-Step relapse prevention counseling in a double blind manner.	Drug: Placebo Tablet; Placebo tablets identical in appearance and dosing schedule as the active study medication was utilized

Outcome Measures

Primary Outcome Measures

1. Percentage of Heavy Drinking Days (HDD%) During the Full Dose Period From Weeks 3-12 [daily over 12 weeks]

   Percentage of heavy drinking days (HDD%) during the full dose period from weeks 3-12 where heavy drinking day (HDD) is defined as 5 or more for men and 4 or more for women in one sitting, measured as yes (1) or no(0), assessed via self reports by daily surveys and time-line follow back assessments

2. Percent of Drinkings Days During the Full Dose Period Between Weeks 3 and 12 [daily over 12 weeks]

   Percent of any drinkings days over the full dose period from weeks 3 to 12, defined as any alcoholic drink consumed each day measured as yes (1) or no(0), assessed via self reports by daily surveys and time-line follow back assessments

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female individuals, ages 18-70 with alcohol dependence, treatment seeking with varying levels of alcohol withdrawal symptoms.

• meet current DSM-IV criteria for alcohol dependence,

• Subject has voluntarily given informed consent and signed the informed consent document.

• Able to read English and complete study evaluations.

Exclusion Criteria:

• Meet current criteria for dependence on another psychoactive substance, excluding nicotine and caffeine;

• Any current use of opiates;

• Current use of any psychoactive drugs, including anxiolytics, antidepressants, naltrexone or disulfram, except for stabilized on SSRIs

• Any psychotic disorder or current Axis I psychiatric symptoms requiring specific attention, including need for psychiatric medications for current major depression and anxiety disorders

• Significant underlying medical conditions such as cerebral, renal, thyroid or cardiac pathology which in the opinion of study physician would preclude patient from fully cooperating or be of potential harm during the course of the study;

• Hypotensive individuals with sitting blood pressure below 90/60 mmHG.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale University School of Medicine: Yale Stress Center	New Haven	Connecticut	United States	06519

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Rajita Sinha, PhD, Yale University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 15, 2018

More Information

Publications

None provided.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT00585780
• Other Study ID Numbers: 0705002691; 4R01AA020504-05
• First Posted: Jan 3, 2008
• Last Update Posted: Jul 27, 2020
• Last Verified: Jul 1, 2020

• Additional relevant MeSH terms: Alcoholism; Prazosin

Study Results

Participant Flow

Arm/Group Title	High Alcohol Withdrawal on Prazosin	High Alcohol Withdrawal on PLA	Low Alcohol Withdrawal on Prazosin	Low Alcohol Withdrawal on PLA
Arm/Group Description	High AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or above 3 randomized to Prazosin 16 mg/day (tid) for 12 weeks.	High AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or above 3 randomized to matching Placebo tablets (tid) for 12 weeks.	Low AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or below 3 randomized to Prazosin 16 mg/day (tid) for 12 weeks.	Low AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or below 2 randomized to matching Placebo tablets (tid) for 12 weeks.
Period Title: Overall Study
STARTED	21	23	34	22
COMPLETED	13	14	21	14
NOT COMPLETED	8	9	13	8

Baseline Characteristics

Arm/Group Title	High Alcohol Withdrawal on Prazosin	High Alcohol Withdrawal on PLA	Low Alcohol Withdrawal on Prazosin	Low Alcohol Withdrawal on PLA	Total
Arm/Group Description	High AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or above 3 randomized to Prazosin 16 mg/day (tid) for 12 weeks.	High AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or above 3 randomized to matching Placebo tablets (tid) for 12 weeks.	Low AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or below 3 randomized to Prazosin 16 mg/day (tid) for 12 weeks.	Low AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or below 2 randomized to matching Placebo tablets (tid) for 12 weeks.	Total of all reporting groups
Overall Participants	21	23	34	22	100
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.9 (9.8)	39.2 (11.1)	39.6 (10.8)	41.4 (11.9)	40.65 (10.86)
Sex: Female, Male (Count of Participants)
Female	8 38.1%	7 30.4%	13 38.2%	7 31.8%	35 35%
Male	13 61.9%	16 69.6%	21 61.8%	15 68.2%	65 65%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	12 57.1%	10 43.5%	20 58.8%	9 40.9%	51 51%
African American	9 42.9%	13 56.5%	14 41.2%	12 54.5%	48 48%
Other	0 0%	0 0%	0 0%	1 4.5%	1 1%

Outcome Measures

1. Primary Outcome

Title	Percentage of Heavy Drinking Days (HDD%) During the Full Dose Period From Weeks 3-12
Description	Percentage of heavy drinking days (HDD%) during the full dose period from weeks 3-12 where heavy drinking day (HDD) is defined as 5 or more for men and 4 or more for women in one sitting, measured as yes (1) or no(0), assessed via self reports by daily surveys and time-line follow back assessments
Time Frame	daily over 12 weeks

Outcome Measure Data

Analysis Population Description

Mean percentage of heavy drinking days (HDD%) during the full dose period from weeks 3-12

Arm/Group Title	High Alcohol Withdrawal (AW) on Prazosin	High Alcohol Withdrawal (AW) on PLA	Low Alcohol Withdrawal (AW) on Prazosin	Low Alcohol Withdrawal (AW) on PLA
Arm/Group Description	High AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or above 3 randomized to Prazosin 16 mg/day (tid) for 12 weeks.	High AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or above 3 randomized to matching Placebo tablets (tid) for 12 weeks.	Low AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or below 3 randomized to Prazosin 16 mg/day (tid) for 12 weeks.	Low AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or below 2 randomized to matching Placebo tablets (tid) for 12 weeks.
Measure Participants	21	23	34	22
Mean (Standard Error) [percentage of heavy drinking days]	8.2 (4.09)	27.11 (7.97)	31.29 (7.42)	7.32 (3.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Alcohol Withdrawal (AW) on Prazosin, High Alcohol Withdrawal (AW) on PLA
	Comments	Intent-to-treat (ITT) analyses with baseline AW severity (mean-centered continuous CIWA-Ar scores) as a moderator of Time (Pre-Full Dose(FD): weeks 1-2; Post FD: weeks 3-12) were conducted with linear or generalized linear mixed effect (LME/GLME) piecewise growth models for continuous and binary outcomes. Control variables that were modeled in all analyses. As hypothesized, significant interactions were tested using AW median cut-offs for high and Low AW groups.
	Type of Statistical Test	Other
	Comments	Expected outcome was that Prazosin will be better than placebo in reducing HDD% among High AW individuals but no differences by medication treatment in the Low AW individuals.
Statistical Test of Hypothesis	p-Value	0.016
	Comments	This is for the apriori hypothesis of significant AWX Treatment X Time effect.
	Method	Mixed Models Analysis
	Comments	Simple effects were conducted to assess source of the interaction.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.23
	Confidence Interval	(2-Sided) 95%; 0.1 to 0.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Percent of Drinkings Days During the Full Dose Period Between Weeks 3 and 12
Description	Percent of any drinkings days over the full dose period from weeks 3 to 12, defined as any alcoholic drink consumed each day measured as yes (1) or no(0), assessed via self reports by daily surveys and time-line follow back assessments
Time Frame	daily over 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Alcohol Withdrawal on Prazosin	High Alcohol Withdrawal on PLA	Low Alcohol Withdrawal on Prazosin	Low Alcohol Withdrawal on PLA
Arm/Group Description	High AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or above 3 randomized to Prazosin 16 mg/day (tid) for 12 weeks.	High AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or above 3 randomized to matching Placebo tablets (tid) for 12 weeks.	Low AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or below 3 randomized to Prazosin 16 mg/day (tid) for 12 weeks.	Low AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or below 2 randomized to matching Placebo tablets (tid) for 12 weeks.
Measure Participants	21	23	34	22
Mean (Standard Error) [Mean percent of any drinking days]	26.89 (7.45)	41.21 (9.36)	53.35 (7.74)	23.71 (6.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Alcohol Withdrawal (AW) on Prazosin, High Alcohol Withdrawal (AW) on PLA
	Comments	Intent-to-treat (ITT) analyses with baseline AW severity (mean-centered continuous CIWA-Ar scores) as a moderator of Time (Pre-Full Dose(FD): weeks 1-2; Post FD: weeks 3-12) were conducted with linear or generalized linear mixed effect (LME/GLME) piecewise growth models for continuous and binary outcomes. Control variables that were modeled in all analyses. As hypothesized, significant interactions were tested using AW median cut-offs for high and Low AW groups.
	Type of Statistical Test	Other
	Comments	Expected outcome was that Prazosin will be better than placebo in reducing percent of drinking days (DD%) among High AW individuals but no differences by medication treatment in the Low AW individuals.
Statistical Test of Hypothesis	p-Value	0.002
	Comments	This is for apriori hypothesized significant AW X Treatment X Post-full dose time interaction effect.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.50
	Confidence Interval	(2-Sided) 95%; 0.28 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse event data obtained weekly for 12 week treatment period using a modified version of the Systematic Assessment for Treatment Emergent Effects (SAFTEE) assessing expected and unexpected side effects and serious adverse events.
Arm/Group Title	High Alcohol Withdrawal on Prazosin		High Alcohol Withdrawal on PLA		Low Alcohol Withdrawal on Prazosin		Low Alcohol Withdrawal on PLA
Arm/Group Description	High AW scoring at or above 3 on Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) assessment randomized to Prazosin 16 mg/day (tid) administered for 12 weeks. Prazosin Tablet: Target medication dosing was three times/day (t.i.d. dosing) with 5 mg in the morning, 5 mg in the afternoon and 6 mg at night reached at the end of the 2-week period, and maintained at this or their highest tolerated dose until week 11, followed by a 5-day taper in week 12, as in previous research.		High AW scoring at or above 3 on Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) assessment randomized to Placebo tablets administered tid for 12 weeks in a double blind manner. Placebo Tablet: Placebo tablets identical in appearance and dosing schedule as the active study medication was utilized		Low AW scoring at or below 2 on Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) assessment randomized to Prazosin 16 mg/day (tid) administered for 12 weeks in a double blind manner. Prazosin Tablet: Target medication dosing was three times/day (t.i.d. dosing) with 5 mg in the morning, 5 mg in the afternoon and 6 mg at night reached at the end of the 2-week period, and maintained at this or their highest tolerated dose until week 11, followed by a 5-day taper in week 12, as in previous research.		Low AW scoring at or below 2 on Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) assessment and randomized to Placebo tablets administered tid for 12 weeks in a double blind manner. Placebo Tablet: Placebo tablets identical in appearance and dosing schedule as the active study medication was utilized
All Cause Mortality
	High Alcohol Withdrawal on Prazosin		High Alcohol Withdrawal on PLA		Low Alcohol Withdrawal on Prazosin		Low Alcohol Withdrawal on PLA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/23 (0%)		0/34 (0%)		0/22 (0%)
Serious Adverse Events
	High Alcohol Withdrawal on Prazosin		High Alcohol Withdrawal on PLA		Low Alcohol Withdrawal on Prazosin		Low Alcohol Withdrawal on PLA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/23 (0%)		1/34 (2.9%)		1/22 (4.5%)
Psychiatric disorders
Alcohol intoxication	0/21 (0%)		0/23 (0%)		1/34 (2.9%)	1	0/22 (0%)	1
Social circumstances
weakness and fainting	0/21 (0%)		0/23 (0%)		0/34 (0%)		1/22 (4.5%)	1
Other (Not Including Serious) Adverse Events
	High Alcohol Withdrawal on Prazosin		High Alcohol Withdrawal on PLA		Low Alcohol Withdrawal on Prazosin		Low Alcohol Withdrawal on PLA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/21 (19%)		3/23 (13%)		9/34 (26.5%)		2/22 (9.1%)
Cardiac disorders
Ligtheadedness/dizzy	1/21 (4.8%)	2	1/23 (4.3%)	1	2/34 (5.9%)	4	1/22 (4.5%)	1
Infections and infestations
Cold and Flu	1/21 (4.8%)	5	2/23 (8.7%)	4	3/34 (8.8%)	4	2/22 (9.1%)	2
Nervous system disorders
Pain	2/21 (9.5%)	6	1/23 (4.3%)	3	4/34 (11.8%)	4	2/22 (9.1%)	7
Headache	1/21 (4.8%)	1	1/23 (4.3%)	3	2/34 (5.9%)	4	2/22 (9.1%)	4

Limitations/Caveats

There was not adequate power to assess sex differences, and specific sensitivity and specificity data for apriori AW cutoffs for Prazosin benefit in high AW group needs to be determined in future studies.

More Information

Certain Agreements

Principal Investigators are NOT 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.