Repurposing alpha1 Noradrenergic Antagonists for Alcoholism Treatment

• Sponsor: University of Wisconsin, Madison (Other)
• Overall Status: Completed
• CT.gov ID: NCT02966340
• Collaborator: National Institute on Alcohol Abuse and Alcoholism (NIAAA) (NIH)
• Enrollment: 70
• Location: 1
• Arms: 2
• Actual Duration (Months): 16.3
• Patients Per Site Per Month: 4.3

Study Details

Study Description

Brief Summary

Double-blind, placebo-controlled, cross-over design study examining the effects of a norepinephrine alpha1 receptor antagonist (prazosin) on stress reactivity in a laboratory stressor task.

Condition or Disease	Intervention/Treatment	Phase
Alcoholism	Drug: Prazosin; Drug: Placebo	Phase 1/Phase 2

Detailed Description

OBJECTIVES

The first objective of the current study is to examine norepinephrine alpha1 (NE-alpha1) receptor involvement in reactivity to unpredictable stressors in humans, by using the NPU stress task in conjunction with an alpha1-blocker, prazosin. The second objective of the study is to provide preliminary evidence that prazosin is effective at reducing stress-reactivity in alcoholics in early abstinence.

PARTICIPANTS

Sixty-four healthy adult participants and sixty-four participants with an Alcohol Use Disorder in early abstinence.

STUDY OVERVIEW

Sixty-four healthy adult participants (32 males & 32 females) will be recruited to participate in a double-blind, placebo-controlled, cross-over design study examining the effects of a NE-alpha1 antagonist (prazosin) on the defensive (physiological and self-report affect) response to stressors using a well-validated animal-human translational stressor task. Participants will complete two overnight study visits where 2 mg prazosin and placebo are administered on separate visits separated by approximately 7 days. Drug order is randomly assigned and counterbalanced across participants (double-blind; study visits 1-2). On each of these two study visits, participants will complete the No Shock, Predictable Shock, Unpredictable Shock (NPU) task 90 minutes after drug administration. The NPU task is designed to examine stress reactivity to predictable and unpredictable stressors (i.e., electric shock). These two visits provide for a within-subject evaluation of the effect of acute antagonism of alpha1-NE receptors (via prazosin) to investigate the role of this NE mechanism in unpredictable (vs. predictable) stressor response.

After the full healthy adult/control sample has completed the study, the investigators will conduct preliminary data analysis to evaluate the first study hypothesis. These analyses are used to evaluate the sensitivity of the NPU task to NE-alpha1 mechanisms and its potential utility as an early surrogate endpoint for stress-related relapse mechanisms in alcoholism. The investigators will only recruit the sample of sixty-four alcoholic participants to complete the study if the first hypothesis is initially supported with healthy controls. These participants will meet Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria for Alcohol Use Disorder (at least moderate severity) and be in early abstinence (1-8 weeks). All other study procedures will be identical for this sample.

OUTCOME MEASURES

The primary outcome is startle potentiation during the NPU task and the secondary outcome is self-reported retrospective fear/anxiety during the NPU task.

HYPOTHESES

1. Prazosin (2mg vs. placebo) will reduce stress reactivity to unpredictable (vs. predictable) stressors measured via startle potentiation and self-report.

2. Abstinent alcoholics (vs. controls) will display elevated stress reactivity to unpredictable (vs. predictable) stressors measured via startle potentiation and self-report.

3. The predicted effects of prazosin on reducing stress reactivity to unpredictable (vs. predictable) stressors (Hypothesis 1) measured via startle potentiation and self-report will be moderated by alcoholism, such that the effects of prazosin will be larger in abstinent alcoholics than control participants.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Screening
• Official Title: Repurposing alpha1 Noradrenergic Antagonists for Alcoholism Treatment
• Actual Study Start Date: Nov 1, 2016
• Actual Primary Completion Date: Mar 12, 2018
• Actual Study Completion Date: Mar 12, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Prazosin 1st visit, Placebo 2nd visit All participants receive 2mg prazosin and placebo in a cross-over design (e.g., one pill per visit). The order of prazosin vs placebo is counterbalanced between subjects (e.g., half participants receive prazosin at study visit 1 and half participants receive placebo at study visit 1).	Drug: Prazosin; 2mg Prazosin; Drug: Placebo; Placebo
Experimental: Placebo 1st visit, Prazosin 2nd visit All participants receive 2mg prazosin and placebo in a cross-over design (e.g., one pill per visit). The order of prazosin vs placebo is counterbalanced between subjects (e.g., half participants receive prazosin at study visit 1 and half participants receive placebo at study visit 1).	Drug: Prazosin; 2mg Prazosin; Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures

1. Startle Potentiation During Stress Reactivity Task. [7 days]

   The unpredictable shock and predictable shock startle response potentiation (vs. no shock) during the administration of the NPU stressor task. Values represent point estimate of effect from unadjusted general linear model analyses with 95% confidence intervals

Secondary Outcome Measures

1. Self-reported Anxiety Potentiation During Stress Reactivity Task. [7 days]

   After the No-shock, Predictable-shock, Unpredictable-shock (NPU) task participants retrospectively reported their anxiety/fear during each condition on a 5-point likert scale (1 = 'Not at all anxious/ fearful', 5 = 'Very anxious/fearful'). The startle response is a defensive reflex that is elicited by an auditory stimuli (e.g., 50ms white noise) and measured via eyeblink electromyogram (EMG) activity over the obicularis oculi muscle. Startle potentiation is calculated as the increase in startle during unpredictable and predictable stressors relative to a no-stressor condition in the NPU task. Outcome is anxiety potentiation during unpredictable shock and predictable shock (vs. no-shock) conditions. This was assessed with a single question, total possible range was 1-5.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

INCLUSION CRITERIA: All Participants

• Can read and write in English.

• Ages of 18-50 years.

INCLUSION CRITERIA: Control Participants

• No current or lifetime history of Substance Use Disorder (except tobacco).

INCLUSION CRITERIA: Alcoholic Participants

• Current Alcohol Use Disorder with 1-8 weeks completely free from alcohol consumption.

Exclusion criteria are divided into three broad categories of Medical, Psychiatric/Behavioral, and Medications/Therapies.

EXCLUSION CRITERIA: Medical

• Colorblind

• Blood alcohol concentration (BAC) > 0.00

• Systolic BP <100 after five minutes seated.

• Systolic BP drop >20 mmHg after two minutes standing.

• Systolic BP drop >10 mgHg AND report dizziness, lightheadedness, unsteadiness or other problems (e.g, nausea, blurry vision) after two minutes standing.

• Heart rate >100 beats/ minute after two minutes seated.

• Heart rate <60 beats/ minute after two minutes seated.

• Scheduled for cataract surgery prior to study completion.

• Past or current coronary artery disease, cerebrovascular accident, congestive heart failure.

• Current renal insufficiency, liver insufficiency, pancreatitis, immunosuppressive therapy, or cancer with systemic effects or therapy.

• Benign positional vertigo, Meniere's disease or narcolepsy

• Current diabetes or polyneuropathy

• Previous allergic or adverse reaction to prazosin or other alpha1 norepinephrine antagonist.

• Other self-reported acute or unstable illness that, in the opinion of the study team, would preclude a safe and reliable study participation.

EXCLUSION CRITERIA: Female Participants Only

• Non-negative urine pregnancy test.

• Women of childbearing potential (see definition below) must agree to use one of the following forms of birth control until after study completion. Acceptable birth control is defined as the following methods of contraception: abstinence; hormonal contraceptives (e.g. combined oral contraceptives, patch, vaginal ring, injectables, and implants); intrauterine device (IUD) or intrauterine system (IUS); vasectomy of partner and tubal ligation; "single" barrier methods of contraception (e.g. male condom, female condom, cervical cap, diaphragm, contraceptive sponge) with use of spermicide; or "double barrier" method of contraception (e.g. male condom with diaphragm, male condom with cervical cap).

• Breastfeeding

NOTE: Women of childbearing potential are females who have experienced menarche and do not meet the criteria for women not of childbearing potential. Women not of childbearing potential are females who are permanently sterile (e.g., hysterectomy, bilateral oophorectomy) or postmenopausal. Postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause.

EXCLUSION CRITERIA: Psychological/Behavioral Exclusion

• Self-reported lifetime diagnosis of schizophrenia, schizoaffective disorder, psychotic disorder not otherwise specified (NOS), bipolar disorder, borderline personality disorder, or any neurocognitive disorder.

EXCLUSION CRITERIA: Medications/Therapies

• Currently prescribed or used within 72 hours: prazosin or other alpha1-NE antagonist (e.g., doxazosin, terazosin).

• Previous adequate trial of prazosin for alcohol use disorder or PTSD.

• Currently prescribed or used within 72 hours: Stimulants (e.g., d-amphetamine, methylphenidate) or alternative medications with stimulant properties (e.g., ephedra, pseudoephedrine).

• Currently prescribed or used within 72 hours: Sildenafil (Viagra), tadalafil (Cialis), or vardenafil (Levitra).

• Currently prescribed or used within 72 hours: beta-blockers (e.g., propranolol), alpha2 agonists (e.g., clonidine, guanfacine), or Serotonin-norepinephrine reuptake inhibitor (SNRI) anti-depressants (e.g., venlafaxine, duloxetine).

• Currently used daily or used within 72 hours: alpha1 agonists (e.g., midodrine, metaraminol, oxymetazoline, phenylephrine).

• Currently used daily or used within 72 hours: Benzodiazepines (e.g., diazepam, chlordiazepoxide, lorazepam, clonazepam, alprazolam), zolpidem (Ambien), zaleplon (Sonata), zopiclone (Imovane), eszopiclone (Lunesta), doxepin (Silenor).

• Currently prescribed and used daily or used within 72 hours: Trazodone (males only)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Wisconsin	Madison	Wisconsin	United States	53706

Sponsors and Collaborators

• University of Wisconsin, Madison
• National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Investigators

• Principal Investigator: John J Curtin, PhD, University of Wisconsin, Madison

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 26, 2017

More Information

Additional Information:

• Dr. John Curtin's Addiction Research Center

Publications

None provided.

• Responsible Party: University of Wisconsin, Madison
• ClinicalTrials.gov Identifier: NCT02966340
• Other Study ID Numbers: 2014-0966; F31AA022845-01; Kaye2
• First Posted: Nov 17, 2016
• Last Update Posted: May 28, 2019
• Last Verified: May 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of Wisconsin, Madison: Alcoholism; Prazosin; Startle Potentiation; Norepinephrine; Anxiety; Fear; Stress
• Additional relevant MeSH terms: Alcoholism; Prazosin

Study Results

Participant Flow

Pre-assignment Detail	In order to enroll 64 participants with valid data, 70 participants were randomized to account for 4 lost early in study flow (one data collection error, two startle non-responders, and one withdrawn after visit 1).

Arm/Group Title	Prazosin 1st Visit, Placebo 2nd Visit	Placebo 1st Visit, Prazosin 2nd Visit
Arm/Group Description	All participants receive 2mg prazosin and placebo in a cross-over design (e.g., one pill per visit). The order of prazosin vs placebo is counterbalanced between subjects (e.g., half participants receive prazosin at study visit 1 and half participants receive placebo at study visit 1). Prazosin: 2mg Prazosin Placebo: Placebo	All participants receive 2mg prazosin and placebo in a cross-over design (e.g., one pill per visit). The order of prazosin vs placebo is counterbalanced between subjects (e.g., half participants receive prazosin at study visit 1 and half participants receive placebo at study visit 1). Prazosin: 2mg Prazosin Placebo: Placebo
Period Title: Overall Study
STARTED	37	33
COMPLETED	34	30
NOT COMPLETED	3	3

Baseline Characteristics

Arm/Group Title	All Participants Who Completed the Study
Arm/Group Description	All participants receive 2mg prazosin and placebo in a cross-over design (e.g., one pill per visit). The order of prazosin vs placebo is counterbalanced between subjects (e.g., half participants receive prazosin at study visit 1 and half participants receive placebo at study visit 1). Results are to be reported by treatment (placebo vs prazosin) each of which include results for all participants. Therefore we report baseline characteristics for the entire group.
Overall Participants	64
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	64 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	23 (5.3)
Sex: Female, Male (Count of Participants)
Female	32 50%
Male	32 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 7.8%
Not Hispanic or Latino	59 92.2%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.6%
Asian	12 18.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 6.3%
White	41 64.1%
More than one race	6 9.4%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	64 100%

Outcome Measures

1. Primary Outcome

Title	Startle Potentiation During Stress Reactivity Task.
Description	The unpredictable shock and predictable shock startle response potentiation (vs. no shock) during the administration of the NPU stressor task. Values represent point estimate of effect from unadjusted general linear model analyses with 95% confidence intervals
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prazosin 2mg Trials	Placebo Trials
Arm/Group Description	All participants receive 2mg prazosin and placebo in a cross-over design (e.g., one pill per visit). The order of prazosin vs placebo is counterbalanced between subjects (e.g., half participants receive prazosin at study visit 1 and half participants receive placebo at study visit 1). Prazosin: 2mg Prazosin Placebo: Placebo	All participants receive 2mg prazosin and placebo in a cross-over design (e.g., one pill per visit). The order of prazosin vs placebo is counterbalanced between subjects (e.g., half participants receive prazosin at study visit 1 and half participants receive placebo at study visit 1). Prazosin: 2mg Prazosin Placebo: Placebo
Measure Participants	64	64
Predictable Shock	45.7	40.1
Unpredictable Shock	33.2	25.2

2. Secondary Outcome

Title	Self-reported Anxiety Potentiation During Stress Reactivity Task.
Description	After the No-shock, Predictable-shock, Unpredictable-shock (NPU) task participants retrospectively reported their anxiety/fear during each condition on a 5-point likert scale (1 = 'Not at all anxious/ fearful', 5 = 'Very anxious/fearful'). The startle response is a defensive reflex that is elicited by an auditory stimuli (e.g., 50ms white noise) and measured via eyeblink electromyogram (EMG) activity over the obicularis oculi muscle. Startle potentiation is calculated as the increase in startle during unpredictable and predictable stressors relative to a no-stressor condition in the NPU task. Outcome is anxiety potentiation during unpredictable shock and predictable shock (vs. no-shock) conditions. This was assessed with a single question, total possible range was 1-5.
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prazosin 2mg Trials	Placebo Trials
Arm/Group Description	All participants receive 2mg prazosin and placebo in a cross-over design (e.g., one pill per visit). The order of prazosin vs placebo is counterbalanced between subjects (e.g., half participants receive prazosin at study visit 1 and half participants receive placebo at study visit 1). Prazosin: 2mg Prazosin Placebo: Placebo	All participants receive 2mg prazosin and placebo in a cross-over design (e.g., one pill per visit). The order of prazosin vs placebo is counterbalanced between subjects (e.g., half participants receive prazosin at study visit 1 and half participants receive placebo at study visit 1). Prazosin: 2mg Prazosin Placebo: Placebo
Measure Participants	64	64
Predictable Shock	2.0	2.1
Unpredictable Shock	2.3	2.4

Adverse Events

Time Frame	Up to 24 hours
Adverse Event Reporting Description	Nurses completed Adverse Events (AE) evaluations at 1, 3, 4, 5, and 6 hours post-dose at each study visit.
Arm/Group Title	Prazosin 2mg Trials		Placebo Trials
Arm/Group Description	All participants receive 2mg prazosin and placebo in a cross-over design (e.g., one pill per visit). The order of prazosin vs placebo is counterbalanced between subjects (e.g., half participants receive prazosin at study visit 1 and half participants receive placebo at study visit 1). Prazosin: 2mg Prazosin Placebo: Placebo		All participants receive 2mg prazosin and placebo in a cross-over design (e.g., one pill per visit). The order of prazosin vs placebo is counterbalanced between subjects (e.g., half participants receive prazosin at study visit 1 and half participants receive placebo at study visit 1). Prazosin: 2mg Prazosin Placebo: Placebo
All Cause Mortality
	Prazosin 2mg Trials		Placebo Trials
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/64 (0%)		0/64 (0%)
Serious Adverse Events
	Prazosin 2mg Trials		Placebo Trials
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/64 (0%)		0/64 (0%)
Other (Not Including Serious) Adverse Events
	Prazosin 2mg Trials		Placebo Trials
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/64 (46.9%)		3/64 (4.7%)
Gastrointestinal disorders
Nausea	6/64 (9.4%)	6	0/64 (0%)	0
Vascular disorders
Dizzyness	16/64 (25%)	16	0/64 (0%)	0
Lightheadedness	12/64 (18.8%)	12	0/64 (0%)	0
Headache	3/64 (4.7%)	3	1/64 (1.6%)	1
Drowsiness	4/64 (6.3%)	4	2/64 (3.1%)	2

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.