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Repurposing alpha1 Noradrenergic Antagonists for Alcoholism Treatment

Primary Purpose

Alcoholism

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Prazosin
Placebo
Sponsored by
University of Wisconsin, Madison
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional screening trial for Alcoholism focused on measuring Alcoholism, Prazosin, Startle Potentiation, Norepinephrine, Anxiety, Fear, Stress

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesAccepts Healthy Volunteers

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)

Sites / Locations

  • University of Wisconsin

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Prazosin 1st visit, Placebo 2nd visit

Placebo 1st visit, Prazosin 2nd visit

Arm 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).

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).

Outcomes

Primary Outcome Measures

Startle Potentiation During Stress Reactivity Task.
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

Self-reported Anxiety Potentiation During Stress Reactivity Task.
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.

Full Information

First Posted
November 15, 2016
Last Updated
May 2, 2019
Sponsor
University of Wisconsin, Madison
Collaborators
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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1. Study Identification

Unique Protocol Identification Number
NCT02966340
Brief Title
Repurposing alpha1 Noradrenergic Antagonists for Alcoholism Treatment
Official Title
Repurposing alpha1 Noradrenergic Antagonists for Alcoholism Treatment
Study Type
Interventional

2. Study Status

Record Verification Date
May 2019
Overall Recruitment Status
Completed
Study Start Date
November 1, 2016 (Actual)
Primary Completion Date
March 12, 2018 (Actual)
Study Completion Date
March 12, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Wisconsin, Madison
Collaborators
National Institute on Alcohol Abuse and Alcoholism (NIAAA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. 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.
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 Prazosin (2mg vs. placebo) will reduce stress reactivity to unpredictable (vs. predictable) stressors measured via startle potentiation and self-report. Abstinent alcoholics (vs. controls) will display elevated stress reactivity to unpredictable (vs. predictable) stressors measured via startle potentiation and self-report. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alcoholism
Keywords
Alcoholism, Prazosin, Startle Potentiation, Norepinephrine, Anxiety, Fear, Stress

7. Study Design

Primary Purpose
Screening
Study Phase
Phase 1, Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
70 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Prazosin 1st visit, Placebo 2nd visit
Arm Type
Experimental
Arm 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).
Arm Title
Placebo 1st visit, Prazosin 2nd visit
Arm Type
Experimental
Arm 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).
Intervention Type
Drug
Intervention Name(s)
Prazosin
Intervention Description
2mg Prazosin
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John J Curtin, PhD
Organizational Affiliation
University of Wisconsin, Madison
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Wisconsin
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53706
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
The investigators will share on Open Science Framework de-identified and anonymous physiology (e.g., Electromyography (EMG) startle response) and self-report survey/questionnaire data collected from participants during the study.
Links:
URL
http://dionysus.psych.wisc.edu
Description
Dr. John Curtin's Addiction Research Center

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Repurposing alpha1 Noradrenergic Antagonists for Alcoholism Treatment

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