Testing Doxazosin to Treat Stress Mechanisms in Alcoholism

OBJECTIVES:

1. 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.

2. 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. We assess doxazosin's impact
on stress-related relapse mechanisms 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.

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).