AlcoholismPhase 2NCT02989493
Testing Doxazosin to Treat Stress Mechanisms in Alcoholism
A Phase 2 study testing Doxazosin in people with Alcoholism, run by University of Wisconsin, Madison at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Alcoholism
- What is being tested?
- Doxazosin
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 61 participants
- Where
- 1 siteUnited States
- Study dates
- 12 Apr 2017to 13 Mar 2020
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 34Show fewer
- 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
- 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.
- 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.
- 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).
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Randomized Controlled Trial Targeting Noradrenergic Stress Mechanisms in Alcoholism With Doxazosin
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.
Read the 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.
- Conditions
- Alcoholism
- Being tested
- Doxazosin, Placebo
- Keywords
- Alcoholism, Stress, Norepinephrine, Doxazosin, Anxiety, Startle Potentiation, Relapse, Adrenergic Antagonists, Surrogate Endpoint
- Medical subject headings
- Alcoholism, Anxiety Disorders, Recurrence
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DoxazosinDrug
Doxazosin
PlaceboOther
Placebo
| Study group | Role | What they receive |
|---|---|---|
| Doxazosin | Experimental | Participants receive 8 weeks of doxazosin (8mg target dose). Receives: Drug: Doxazosin |
| Placebo | Placebo comparator | Participants will receive 8 weeks of matched placebo. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 4 weeks
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
Measured: 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Dec 2016 (estimated)
- Study start12 Apr 2017
- Primary completion13 Mar 2020
- Study completion13 Mar 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for AlcoholismStudies of the same condition, open and under way.
- More trials run by University of Wisconsin, MadisonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 61 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Wisconsin, Madison
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Alcohol Abuse and Alcoholism (NIAAA)
- Responsible party
- Sponsor
- Investigators
- John J Curtin, PhD, Principal investigator, University of Wisconsin, Madison
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02989493
- Sponsor's protocol ID
- 2015-1009
- Other IDs
- R01AA024388, A487400, L&S\PSYCHOLOGY\PSYCHOLOGY, Protocol Version 11/7/2019
- Status last verified
- Mar 2021
- First submitted
- 1 Dec 2016
- Last updated
- 18 Mar 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data will be made available online upon study completion at the Open Science Framework: https://osf.io
Study at a glance
From the registry record, last updated by the sponsor on 18 Mar 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Controlled Trial Targeting Noradrenergic Stress Mechanisms in Alcoholism With Doxazosin
- ClinicalTrials.gov ID
- NCT02989493
- Acronym / sponsor ID
- 2015-1009
- Conditions
- Alcoholism
- Keywords
- Alcoholism, Stress, Norepinephrine, Doxazosin, Anxiety, Startle Potentiation, Relapse, Adrenergic Antagonists
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 61 participants (actual)
- Lead sponsor
- University of Wisconsin, MadisonUniversity, hospital or other
- Collaborators
- National Institute on Alcohol Abuse and Alcoholism (NIAAA)
- Study start
- 12 Apr 2017 (actual)
- Primary completion
- 13 Mar 2020 (actual)
- Study completion
- 13 Mar 2020 (actual)
- First posted
- 12 Dec 2016 (estimated)
- Results
- Posted 18 Mar 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Doxazosin | Experimental | Drug: DoxazosinParticipants receive 8 weeks of doxazosin (8mg target dose). |
| Placebo | Placebo comparator | Other: PlaceboParticipants will receive 8 weeks of matched placebo. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (34 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DoxazosinDoxazosin | Drug | Doxazosin |
| PlaceboPlacebo | Other | Placebo |
Primary outcome
Startle Potentiation During Stress Reactivity Task
Time frame: 4 weeks
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
Time frame: 8 weeks
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Mar 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Dr. John Curtin's Addiction Research CenterLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. Data will be made available online upon study completion at the Open Science Framework: https://osf.io
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
John J Curtin, PhD principal investigator
University of Wisconsin, Madison
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Doxazosin in people with Alcoholism, run by University of Wisconsin, Madison at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 34 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Mar 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Startle Potentiation During Stress Reactivity Task (time frame: 4 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Mar 2021.