Clinical trial NCT02989493: Testing Doxazosin to Treat Stress Mechanisms in Alcoholism
Official title: Randomized Controlled Trial Targeting Noradrenergic Stress Mechanisms in Alcoholism With Doxazosin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alcoholism
Keywords: Alcoholism
Stress
Norepinephrine
Doxazosin
Anxiety
Startle Potentiation
Relapse
Adrenergic Antagonists
Surrogate Endpoint
Lead sponsor: University of Wisconsin, Madison
Sponsor class: OTHER
Collaborators: name: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
First posted: 2016-12-12
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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:

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. 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.

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).

Primary outcomes:
measure: Startle Potentiation During Stress Reactivity Task
timeFrame: 4 weeks
measure: Number of Participants Reporting Any Heavy Drinking Days
timeFrame: 8 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: University of Wisconsin, Madison
name: John J Curtin, PhD
role: PRINCIPAL_INVESTIGATOR
References: