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Testing Doxazosin to Treat Stress Mechanisms in Alcoholism

Primary Purpose

Alcoholism

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Doxazosin

Placebo

About this trial

This is an interventional treatment trial for Alcoholism focused on measuring Alcoholism, Stress, Norepinephrine, Doxazosin, Anxiety, Startle Potentiation, Relapse, Adrenergic Antagonists, Surrogate Endpoint

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA:

Diagnostic and Statistical Manual (DSM-5) diagnosis of Alcohol Use Disorder, Moderate-Severe
Alcohol abstinent for 1 - 8 weeks
Ages of 18 to 65

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

EXCLUSION CRITERIA: Medical

Blood alcohol concentration above 0.00.
Color blind.
Heart rate >100 beats per minute after five minutes seated.
Heart rate <55 beats per minute after five minutes seated.
Systolic BP <100 after five minutes seated.
Systolic BP drop >20mm Hg or diastolic BP drop >10mm Hg after two minutes standing.
Dizziness, lightheadedness, unsteadiness or other problems (e.g, nausea, blurry vision) after two minutes standing.
Uncorrected auditory/vision problems.
Current treatment for chronic pain condition.
Past or current coronary artery disease, cerebrovascular accident, congestive heart failure.
Current chronic renal insufficiency, liver insufficiency or moderate hepatic impairment, pancreatitis, immunosuppressive therapy, or cancer with systemic effects or therapy.
Benign positional vertigo, Meniere's disease, or narcolepsy.
Previous allergic or adverse reaction to doxazosin or other alpha1 noradrenergic antagonist.
Scheduled or reported plans for cataract surgery prior to study completion.
Currently symptomatic of alcohol withdrawal [Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWA-Ar) Score > 10, or positive for any 'visual, auditory or tactile disturbances,' or for 'orientation and clouding of sensorium']
Discharged from inpatient treatment for Alcohol Use Disorder or alcohol detoxification within past 7 days.
Currently medically unstable.
Electrocardiogram (ECG) clinical over-read indicates concerns of cardiac function.
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

Self-reported lifetime diagnosis of schizophrenia, schizoaffective disorder, psychotic disorder not otherwise specified, bipolar disorder (with manic episode), borderline personality disorder, or any neurocognitive disorder that may impair a reliable, safe participation.
Current suicidal ideation.
Current active substance use disorder other than alcohol or tobacco.

EXCLUSION CRITERIA: Medications/Therapies

Currently prescribed or used within past week: doxazosin or other alpha1 noradrenergic antagonist (e.g., prazosin, terazosin).
Currently prescribed or used within past week: substances with stimulant properties (e.g., d-amphetamine, methylphenidate, ephedra, pseudoephedrine).
Currently prescribed or used within past week: Sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra).
Currently prescribed or used within past week: beta-blockers (e.g., propanolol), alpha2 agonists (e.g., clonidine, guanfacine, dexmedetomidine), and serotonin and norepinephrine reuptake inhibitors (SNRI) (e.g., venlafaxine, duloxetine, atomoxetine, viloxazine).
Currently used daily or used within past week: alpha1 agonists (e.g., midodrine, metaraminol, oxymetazoline, phenylephrine).
Currently used daily or used within past week: 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 past 2 weeks: Trazodone.
Currently prescribed or used within 2 weeks: Disulfiram (Antabuse).

Sites / Locations

University of Wisconsin

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Doxazosin

Placebo

Arm Description

Participants receive 8 weeks of doxazosin (8mg target dose).

Participants will receive 8 weeks of matched placebo.

Outcomes

Primary Outcome Measures

Startle Potentiation During Stress Reactivity Task

Startle potentiation is used to study anxiety and fear with No-shock, Predictable-shock, Unpredictable-shock (NPU) task; a common, well-validated laboratory stressor task. In the Predictable condition of the NPU task, shocks are 100 percent predictable and occur at a consistent, known time. In the Unpredictable condition of the NPU task, shocks are fully unpredictable. A higher score on startle potentiation means a higher stress reactivity response for the given condition.

Number of Participants Reporting Any Heavy Drinking Days

Timeline-followback (TLFB) was administered twice at 4 weeks and 8 weeks. Participants reported the number of drinks per day for each previous 30 day period. Any heavy drinking was scored "yes" if participant reported any days of heavy drinking (> 4/3 standard drinks for men/women) during the total 8 week assessment period; "no" if no heavy drinking was reported

Secondary Outcome Measures

Full Information

NCT ID

NCT02989493

First Posted

December 1, 2016

Last Updated

March 16, 2021

Sponsor

University of Wisconsin, Madison

Collaborators

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

1. Study Identification

Unique Protocol Identification Number

NCT02989493

Brief Title

Testing Doxazosin to Treat Stress Mechanisms in Alcoholism

Official Title

Randomized Controlled Trial Targeting Noradrenergic Stress Mechanisms in Alcoholism With Doxazosin

Study Type

Interventional

2. Study Status

Record Verification Date

March 2021

Overall Recruitment Status

Completed

Study Start Date

April 12, 2017 (Actual)

Primary Completion Date

March 13, 2020 (Actual)

Study Completion Date

March 13, 2020 (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

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

Brief Summary

Double-blind, placebo controlled, randomized controlled trial (RCT) for Alcohol Use Disorder examining the effects of doxazosin, a norepinephrine alpha1 receptor antagonist, on stress reactivity and clinical outcomes.

Detailed Description

OBJECTIVES: To translate the preclinical evidence from animal models to stress-induced relapse in humans via direct pharmacological antagonism of the noradrenergic system in abstinent alcoholics with doxazosin, an alpha1 noradrenergic receptor blocker. To screen the efficacy of doxazosin to target stress-related relapse mechanisms in abstinent alcoholics as a cost-effective first step to repurpose this alpha1 noradrenergic antagonist for relapse prevention in addiction. PARTICIPANTS: 136 participants with an Alcohol Use Disorder in early abstinence. STUDY OVERVIEW: 136 adults with an Alcohol Use Disorder in early abstinence (1-8 weeks abstinent) will participate in a randomized controlled trial (RCT) to examine the efficacy of 8 mg doxazosin (vs. placebo, between-subjects) on stress reactivity and clinical outcome measures (e.g., drinks/week, alcohol craving) during a 8 week treatment period. Doxazosin's impact on stress-related relapse mechanisms will be assessed using a well-validated human model of stressor reactivity (No Shock, Predictable Shock, Unpredictable Shock [NPU] task) at baseline (pre-treatment) and after 4 weeks of treatment. The NPU task has strong translational ties to both methods (e.g., unpredictable vs. predictable electric shock) and measures (e.g., startle potentiation) from the preclinical literature in animals. This laboratory stress task serves as an attractive early surrogate endpoint post-treatment to assess treatment efficacy and examine stress mechanisms. AIMS and HYPOTHESIS: AIM 1: Examine effects of a therapeutic dose of doxazosin on responses to unpredictable stressors in NPU task. The aim is to obtain preliminary evidence via a laboratory surrogate endpoint to repurpose doxazosin for the treatment of stress-induced relapse mechanisms in alcoholism. PREDICTIONS: Following four weeks of therapeutic dosing, doxazosin (8 mg vs. placebo, between-subjects) will selectively reduce response to unpredictable (vs. predictable) stressors indexed by physiological defensive reactivity (startle potentiation) and self-reported negative affect and craving in abstinent alcoholics. AIM 2: Examine effects of a therapeutic dose of doxazosin on early clinical outcome measures. The aim is to obtain additional evidence via clinical outcome measures to repurpose doxazosin for the treatment of stress-induced relapse mechanisms in alcoholism. PREDICTIONS: Following eight weeks of therapeutic dosing, doxazosin (8 mg vs. placebo, between-subjects) will increase continuous abstinence and decrease drinking days per week and drinks per week during the medication treatment period. Doxazosin will also decrease craving measured during the 8th week of medication use when participants have achieved the maximum dose for 4.5 weeks. AIM 3: Examine predictive validity of pre-treatment laboratory tests of noradrenergic relevant stress-reactivity on surrogate endpoint and clinical outcome measures. The aim is to link individual differences in stress reactivity at baseline (i.e. pre-treatment) to laboratory surrogate endpoints and early clinical outcome measures following therapeutic dosing. PREDICTIONS: Higher pre-treatment reactivity during unpredictable stressors will predict poorer surrogate endpoint and clinical outcomes overall. Therapeutic 8 mg dose effects of doxazosin will be greater among alcoholics who display higher pre-treatment reactivity to unpredictable stressors. AIM 4: Examine if the effects of doxazosin on clinical outcome measures are mediated by a reduction of stress-reactivity as measured by the NPU task. The aim is to identify whether reductions in stress-reactivity (NPU task) is the mechanism through which doxazosin has its effect on drinking behavior (clinical outcome). PREDICTIONS: The direct effect of doxazosin (vs. placebo) following 8 weeks of therapeutic 8 mg dosing on clinical outcomes (e.g., continuous abstinence, drinking days/week, drinks/week) will be partially mediated by the indirect effect of doxazosin on surrogate endpoint of NPU stress reactivity at 4 weeks.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alcoholism

Keywords

Alcoholism, Stress, Norepinephrine, Doxazosin, Anxiety, Startle Potentiation, Relapse, Adrenergic Antagonists, Surrogate Endpoint

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

61 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Doxazosin

Arm Type

Experimental

Arm Description

Participants receive 8 weeks of doxazosin (8mg target dose).

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Participants will receive 8 weeks of matched placebo.

Intervention Type

Drug

Intervention Name(s)

Doxazosin

Intervention Description

Doxazosin

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

Placebo

Primary Outcome Measure Information:

Title

Startle Potentiation During Stress Reactivity Task

Description

Time Frame

4 weeks

Title

Number of Participants Reporting Any Heavy Drinking Days

Description

Time Frame

8 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

INCLUSION CRITERIA: Diagnostic and Statistical Manual (DSM-5) diagnosis of Alcohol Use Disorder, Moderate-Severe Alcohol abstinent for 1 - 8 weeks Ages of 18 to 65 Exclusion criteria are divided into three broad categories of Medical, Psychiatric/Behavioral, and Medications/Therapies. EXCLUSION CRITERIA: Medical Blood alcohol concentration above 0.00. Color blind. Heart rate >100 beats per minute after five minutes seated. Heart rate <55 beats per minute after five minutes seated. Systolic BP <100 after five minutes seated. Systolic BP drop >20mm Hg or diastolic BP drop >10mm Hg after two minutes standing. Dizziness, lightheadedness, unsteadiness or other problems (e.g, nausea, blurry vision) after two minutes standing. Uncorrected auditory/vision problems. Current treatment for chronic pain condition. Past or current coronary artery disease, cerebrovascular accident, congestive heart failure. Current chronic renal insufficiency, liver insufficiency or moderate hepatic impairment, pancreatitis, immunosuppressive therapy, or cancer with systemic effects or therapy. Benign positional vertigo, Meniere's disease, or narcolepsy. Previous allergic or adverse reaction to doxazosin or other alpha1 noradrenergic antagonist. Scheduled or reported plans for cataract surgery prior to study completion. Currently symptomatic of alcohol withdrawal [Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWA-Ar) Score > 10, or positive for any 'visual, auditory or tactile disturbances,' or for 'orientation and clouding of sensorium'] Discharged from inpatient treatment for Alcohol Use Disorder or alcohol detoxification within past 7 days. Currently medically unstable. Electrocardiogram (ECG) clinical over-read indicates concerns of cardiac function. 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 Self-reported lifetime diagnosis of schizophrenia, schizoaffective disorder, psychotic disorder not otherwise specified, bipolar disorder (with manic episode), borderline personality disorder, or any neurocognitive disorder that may impair a reliable, safe participation. Current suicidal ideation. Current active substance use disorder other than alcohol or tobacco. EXCLUSION CRITERIA: Medications/Therapies Currently prescribed or used within past week: doxazosin or other alpha1 noradrenergic antagonist (e.g., prazosin, terazosin). Currently prescribed or used within past week: substances with stimulant properties (e.g., d-amphetamine, methylphenidate, ephedra, pseudoephedrine). Currently prescribed or used within past week: Sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra). Currently prescribed or used within past week: beta-blockers (e.g., propanolol), alpha2 agonists (e.g., clonidine, guanfacine, dexmedetomidine), and serotonin and norepinephrine reuptake inhibitors (SNRI) (e.g., venlafaxine, duloxetine, atomoxetine, viloxazine). Currently used daily or used within past week: alpha1 agonists (e.g., midodrine, metaraminol, oxymetazoline, phenylephrine). Currently used daily or used within past week: 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 past 2 weeks: Trazodone. Currently prescribed or used within 2 weeks: Disulfiram (Antabuse).

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

Data will be made available online upon study completion at the Open Science Framework: https://osf.io

Links:

URL

http://arc.psych.wisc.edu

Description

Dr. John Curtin's Addiction Research Center

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Testing Doxazosin to Treat Stress Mechanisms in Alcoholism

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