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Repurposing alpha1 Noradrenergic Antagonists for Alcoholism Treatment

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ClinicalTrials.gov Identifier: NCT02966340
Recruitment Status : Completed
First Posted : November 17, 2016
Last Update Posted : April 12, 2018
Sponsor:
Collaborator:
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Information provided by (Responsible Party):
University of Wisconsin, Madison

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 DSM5 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 Type : Interventional  (Clinical Trial)
Actual Enrollment : 64 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 : November 1, 2016
Actual Primary Completion Date : March 12, 2018
Actual Study Completion Date : March 12, 2018

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Startle potentiation during stress reactivity task. [ Time Frame: 7 days ]

Secondary Outcome Measures :
  1. Self-reported anxiety during stress reactivity task. [ Time Frame: 7 days ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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 >20mmHg after two minutes standing.
  • Systolic BP drop >10mgHG 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 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 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02966340


Locations
United States, Wisconsin
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

Additional Information:
Responsible Party: University of Wisconsin, Madison
ClinicalTrials.gov Identifier: NCT02966340     History of Changes
Other Study ID Numbers: 2014-0966
F31AA022845-01 ( U.S. NIH Grant/Contract )
Kaye2 ( Other Identifier: Study Team )
First Posted: November 17, 2016    Key Record Dates
Last Update Posted: April 12, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The investigators will share on Open Science Framework de-identified and anonymous physiology (e.g., EMG startle response) and self-report survey/questionnaire data collected from participants during the study.

Keywords provided by University of Wisconsin, Madison:
Alcoholism
Prazosin
Startle Potentiation
Norepinephrine
Anxiety
Fear
Stress

Additional relevant MeSH terms:
Alcoholism
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Prazosin
Antihypertensive Agents
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs