<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02989493</url>
  </required_header>
  <id_info>
    <org_study_id>2015-1009</org_study_id>
    <secondary_id>R01AA024388</secondary_id>
    <secondary_id>A487400</secondary_id>
    <secondary_id>L&amp;S\PSYCHOLOGY\PSYCHOLOGY</secondary_id>
    <secondary_id>Protocol Version 11/7/2019</secondary_id>
    <nct_id>NCT02989493</nct_id>
  </id_info>
  <brief_title>Testing Doxazosin to Treat Stress Mechanisms in Alcoholism</brief_title>
  <official_title>Randomized Controlled Trial Targeting Noradrenergic Stress Mechanisms in Alcoholism With Doxazosin</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Wisconsin, Madison</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute on Alcohol Abuse and Alcoholism (NIAAA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Wisconsin, Madison</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Double-blind, placebo controlled, randomized controlled trial (RCT) for Alcohol Use Disorder&#xD;
      examining the effects of doxazosin, a norepinephrine alpha1 receptor antagonist, on stress&#xD;
      reactivity and clinical outcomes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      OBJECTIVES:&#xD;
&#xD;
        1. To translate the preclinical evidence from animal models to stress-induced relapse in&#xD;
           humans via direct pharmacological antagonism of the noradrenergic system in abstinent&#xD;
           alcoholics with doxazosin, an alpha1 noradrenergic receptor blocker.&#xD;
&#xD;
        2. To screen the efficacy of doxazosin to target stress-related relapse mechanisms in&#xD;
           abstinent alcoholics as a cost-effective first step to repurpose this alpha1&#xD;
           noradrenergic antagonist for relapse prevention in addiction.&#xD;
&#xD;
      PARTICIPANTS:&#xD;
&#xD;
      136 participants with an Alcohol Use Disorder in early abstinence.&#xD;
&#xD;
      STUDY OVERVIEW:&#xD;
&#xD;
      136 adults with an Alcohol Use Disorder in early abstinence (1-8 weeks abstinent) will&#xD;
      participate in a randomized controlled trial (RCT) to examine the efficacy of 8 mg doxazosin&#xD;
      (vs. placebo, between-subjects) on stress reactivity and clinical outcome measures (e.g.,&#xD;
      drinks/week, alcohol craving) during a 8 week treatment period. Doxazosin's impact on&#xD;
      stress-related relapse mechanisms will be assessed using a well-validated human model of&#xD;
      stressor reactivity (No Shock, Predictable Shock, Unpredictable Shock [NPU] task) at baseline&#xD;
      (pre-treatment) and after 4 weeks of treatment. The NPU task has strong translational ties to&#xD;
      both methods (e.g., unpredictable vs. predictable electric shock) and measures (e.g., startle&#xD;
      potentiation) from the preclinical literature in animals. This laboratory stress task serves&#xD;
      as an attractive early surrogate endpoint post-treatment to assess treatment efficacy and&#xD;
      examine stress mechanisms.&#xD;
&#xD;
      AIMS and HYPOTHESIS:&#xD;
&#xD;
      AIM 1: Examine effects of a therapeutic dose of doxazosin on responses to unpredictable&#xD;
      stressors in NPU task. The aim is to obtain preliminary evidence via a laboratory surrogate&#xD;
      endpoint to repurpose doxazosin for the treatment of stress-induced relapse mechanisms in&#xD;
      alcoholism.&#xD;
&#xD;
      PREDICTIONS: Following four weeks of therapeutic dosing, doxazosin (8 mg vs. placebo,&#xD;
      between-subjects) will selectively reduce response to unpredictable (vs. predictable)&#xD;
      stressors indexed by physiological defensive reactivity (startle potentiation) and&#xD;
      self-reported negative affect and craving in abstinent alcoholics.&#xD;
&#xD;
      AIM 2: Examine effects of a therapeutic dose of doxazosin on early clinical outcome measures.&#xD;
      The aim is to obtain additional evidence via clinical outcome measures to repurpose doxazosin&#xD;
      for the treatment of stress-induced relapse mechanisms in alcoholism.&#xD;
&#xD;
      PREDICTIONS: Following eight weeks of therapeutic dosing, doxazosin (8 mg vs. placebo,&#xD;
      between-subjects) will increase continuous abstinence and decrease drinking days per week and&#xD;
      drinks per week during the medication treatment period. Doxazosin will also decrease craving&#xD;
      measured during the 8th week of medication use when participants have achieved the maximum&#xD;
      dose for 4.5 weeks.&#xD;
&#xD;
      AIM 3: Examine predictive validity of pre-treatment laboratory tests of noradrenergic&#xD;
      relevant stress-reactivity on surrogate endpoint and clinical outcome measures. The aim is to&#xD;
      link individual differences in stress reactivity at baseline (i.e. pre-treatment) to&#xD;
      laboratory surrogate endpoints and early clinical outcome measures following therapeutic&#xD;
      dosing.&#xD;
&#xD;
      PREDICTIONS: Higher pre-treatment reactivity during unpredictable stressors will predict&#xD;
      poorer surrogate endpoint and clinical outcomes overall. Therapeutic 8 mg dose effects of&#xD;
      doxazosin will be greater among alcoholics who display higher pre-treatment reactivity to&#xD;
      unpredictable stressors.&#xD;
&#xD;
      AIM 4: Examine if the effects of doxazosin on clinical outcome measures are mediated by a&#xD;
      reduction of stress-reactivity as measured by the NPU task. The aim is to identify whether&#xD;
      reductions in stress-reactivity (NPU task) is the mechanism through which doxazosin has its&#xD;
      effect on drinking behavior (clinical outcome).&#xD;
&#xD;
      PREDICTIONS: The direct effect of doxazosin (vs. placebo) following 8 weeks of therapeutic 8&#xD;
      mg dosing on clinical outcomes (e.g., continuous abstinence, drinking days/week, drinks/week)&#xD;
      will be partially mediated by the indirect effect of doxazosin on surrogate endpoint of NPU&#xD;
      stress reactivity at 4 weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 12, 2017</start_date>
  <completion_date type="Actual">March 13, 2020</completion_date>
  <primary_completion_date type="Actual">March 13, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Startle Potentiation During Stress Reactivity Task</measure>
    <time_frame>4 weeks</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants Reporting Any Heavy Drinking Days</measure>
    <time_frame>8 weeks</time_frame>
    <description>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 &quot;yes&quot; if participant reported any days of heavy drinking (&gt; 4/3 standard drinks for men/women) during the total 8 week assessment period; &quot;no&quot; if no heavy drinking was reported</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">61</enrollment>
  <condition>Alcoholism</condition>
  <arm_group>
    <arm_group_label>Doxazosin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants receive 8 weeks of doxazosin (8mg target dose).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will receive 8 weeks of matched placebo.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Doxazosin</intervention_name>
    <description>Doxazosin</description>
    <arm_group_label>Doxazosin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        INCLUSION CRITERIA:&#xD;
&#xD;
          -  Diagnostic and Statistical Manual (DSM-5) diagnosis of Alcohol Use Disorder,&#xD;
             Moderate-Severe&#xD;
&#xD;
          -  Alcohol abstinent for 1 - 8 weeks&#xD;
&#xD;
          -  Ages of 18 to 65&#xD;
&#xD;
        Exclusion criteria are divided into three broad categories of Medical,&#xD;
        Psychiatric/Behavioral, and Medications/Therapies.&#xD;
&#xD;
        EXCLUSION CRITERIA: Medical&#xD;
&#xD;
          -  Blood alcohol concentration above 0.00.&#xD;
&#xD;
          -  Color blind.&#xD;
&#xD;
          -  Heart rate &gt;100 beats per minute after five minutes seated.&#xD;
&#xD;
          -  Heart rate &lt;55 beats per minute after five minutes seated.&#xD;
&#xD;
          -  Systolic BP &lt;100 after five minutes seated.&#xD;
&#xD;
          -  Systolic BP drop &gt;20mm Hg or diastolic BP drop &gt;10mm Hg after two minutes standing.&#xD;
&#xD;
          -  Dizziness, lightheadedness, unsteadiness or other problems (e.g, nausea, blurry&#xD;
             vision) after two minutes standing.&#xD;
&#xD;
          -  Uncorrected auditory/vision problems.&#xD;
&#xD;
          -  Current treatment for chronic pain condition.&#xD;
&#xD;
          -  Past or current coronary artery disease, cerebrovascular accident, congestive heart&#xD;
             failure.&#xD;
&#xD;
          -  Current chronic renal insufficiency, liver insufficiency or moderate hepatic&#xD;
             impairment, pancreatitis, immunosuppressive therapy, or cancer with systemic effects&#xD;
             or therapy.&#xD;
&#xD;
          -  Benign positional vertigo, Meniere's disease, or narcolepsy.&#xD;
&#xD;
          -  Previous allergic or adverse reaction to doxazosin or other alpha1 noradrenergic&#xD;
             antagonist.&#xD;
&#xD;
          -  Scheduled or reported plans for cataract surgery prior to study completion.&#xD;
&#xD;
          -  Currently symptomatic of alcohol withdrawal [Clinical Institute Withdrawal Assessment&#xD;
             for Alcohol, revised (CIWA-Ar) Score &gt; 10, or positive for any 'visual, auditory or&#xD;
             tactile disturbances,' or for 'orientation and clouding of sensorium']&#xD;
&#xD;
          -  Discharged from inpatient treatment for Alcohol Use Disorder or alcohol detoxification&#xD;
             within past 7 days.&#xD;
&#xD;
          -  Currently medically unstable.&#xD;
&#xD;
          -  Electrocardiogram (ECG) clinical over-read indicates concerns of cardiac function.&#xD;
&#xD;
          -  Other self-reported acute or unstable illness that, in the opinion of the study team,&#xD;
             would preclude a safe and reliable study participation&#xD;
&#xD;
        EXCLUSION CRITERIA: Female Participants Only&#xD;
&#xD;
          -  Non-negative urine pregnancy test.&#xD;
&#xD;
          -  Women of childbearing potential (see definition below) must agree to use one of the&#xD;
             following forms of birth control until after study completion. Acceptable birth&#xD;
             control is defined as the following methods of contraception: abstinence; hormonal&#xD;
             contraceptives (e.g. combined oral contraceptives, patch, vaginal ring, injectables,&#xD;
             and implants); intrauterine device (IUD) or intrauterine system (IUS); vasectomy of&#xD;
             partner and tubal ligation; &quot;single&quot; barrier methods of contraception (e.g. male&#xD;
             condom, female condom, cervical cap, diaphragm, contraceptive sponge) with use of&#xD;
             spermicide; or &quot;double barrier&quot; method of contraception (e.g. male condom with&#xD;
             diaphragm, male condom with cervical cap).&#xD;
&#xD;
          -  Breastfeeding.&#xD;
&#xD;
        NOTE: Women of childbearing potential are females who have experienced menarche and do not&#xD;
        meet the criteria for women not of childbearing potential. Women not of childbearing&#xD;
        potential are females who are permanently sterile (e.g., hysterectomy, bilateral&#xD;
        oophorectomy) or postmenopausal. Postmenopausal is defined as 12 consecutive months with no&#xD;
        menses without an alternative medical cause.&#xD;
&#xD;
        EXCLUSION CRITERIA: Psychological/Behavioral&#xD;
&#xD;
          -  Self-reported lifetime diagnosis of schizophrenia, schizoaffective disorder, psychotic&#xD;
             disorder not otherwise specified, bipolar disorder (with manic episode), borderline&#xD;
             personality disorder, or any neurocognitive disorder that may impair a reliable, safe&#xD;
             participation.&#xD;
&#xD;
          -  Current suicidal ideation.&#xD;
&#xD;
          -  Current active substance use disorder other than alcohol or tobacco.&#xD;
&#xD;
        EXCLUSION CRITERIA: Medications/Therapies&#xD;
&#xD;
          -  Currently prescribed or used within past week: doxazosin or other alpha1 noradrenergic&#xD;
             antagonist (e.g., prazosin, terazosin).&#xD;
&#xD;
          -  Currently prescribed or used within past week: substances with stimulant properties&#xD;
             (e.g., d-amphetamine, methylphenidate, ephedra, pseudoephedrine).&#xD;
&#xD;
          -  Currently prescribed or used within past week: Sildenafil (Viagra), tadalafil&#xD;
             (Cialis), and vardenafil (Levitra).&#xD;
&#xD;
          -  Currently prescribed or used within past week: beta-blockers (e.g., propanolol),&#xD;
             alpha2 agonists (e.g., clonidine, guanfacine, dexmedetomidine), and serotonin and&#xD;
             norepinephrine reuptake inhibitors (SNRI) (e.g., venlafaxine, duloxetine, atomoxetine,&#xD;
             viloxazine).&#xD;
&#xD;
          -  Currently used daily or used within past week: alpha1 agonists (e.g., midodrine,&#xD;
             metaraminol, oxymetazoline, phenylephrine).&#xD;
&#xD;
          -  Currently used daily or used within past week: Benzodiazepines (e.g., diazepam,&#xD;
             chlordiazepoxide, lorazepam, clonazepam, alprazolam), zolpidem (Ambien), zaleplon&#xD;
             (Sonata), zopiclone (Imovane), eszopiclone (Lunesta), doxepin (Silenor).&#xD;
&#xD;
          -  Currently prescribed and used daily or used within past 2 weeks: Trazodone.&#xD;
&#xD;
          -  Currently prescribed or used within 2 weeks: Disulfiram (Antabuse).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>John J Curtin, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Wisconsin, Madison</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Wisconsin</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <zip>53706</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://arc.psych.wisc.edu</url>
    <description>Dr. John Curtin's Addiction Research Center</description>
  </link>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>December 1, 2016</study_first_submitted>
  <study_first_submitted_qc>December 7, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 12, 2016</study_first_posted>
  <results_first_submitted>February 23, 2021</results_first_submitted>
  <results_first_submitted_qc>March 16, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">March 18, 2021</results_first_posted>
  <last_update_submitted>March 16, 2021</last_update_submitted>
  <last_update_submitted_qc>March 16, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 18, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Alcoholism</keyword>
  <keyword>Stress</keyword>
  <keyword>Norepinephrine</keyword>
  <keyword>Doxazosin</keyword>
  <keyword>Anxiety</keyword>
  <keyword>Startle Potentiation</keyword>
  <keyword>Relapse</keyword>
  <keyword>Adrenergic Antagonists</keyword>
  <keyword>Surrogate Endpoint</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alcoholism</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Doxazosin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Data will be made available online upon study completion at the Open Science Framework: https://osf.io</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>November 7, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/93/NCT02989493/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants were enrolled via community advertisement and clinical referral.</recruitment_details>
      <pre_assignment_details>61 participants were consented, passed medical screening, and were assigned to a drug group.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Doxazosin</title>
          <description>Participants receive 8 weeks of doxazosin (8mg target dose).&#xD;
Doxazosin: Doxazosin</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Participants will receive 8 weeks of matched placebo.&#xD;
Placebo: Placebo</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="29"/>
                <participants group_id="P2" count="32"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="29"/>
                <participants group_id="P2" count="32"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Doxazosin</title>
          <description>Participants receive 8 weeks of doxazosin (8mg target dose).&#xD;
Doxazosin: Doxazosin</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Participants will receive 8 weeks of matched placebo.&#xD;
Placebo: Placebo</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="29"/>
            <count group_id="B2" value="32"/>
            <count group_id="B3" value="61"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <description>self report age</description>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="45.6" spread="11.9"/>
                    <measurement group_id="B2" value="39.7" spread="10.8"/>
                    <measurement group_id="B3" value="42.5" spread="11.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                    <measurement group_id="B2" value="23"/>
                    <measurement group_id="B3" value="46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="28"/>
                    <measurement group_id="B2" value="30"/>
                    <measurement group_id="B3" value="58"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="27"/>
                    <measurement group_id="B2" value="27"/>
                    <measurement group_id="B3" value="54"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <description>All participants were enrolled in Madison, WI, USA</description>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="29"/>
                    <measurement group_id="B2" value="32"/>
                    <measurement group_id="B3" value="61"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Startle Potentiation During Stress Reactivity Task</title>
        <description>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.</description>
        <time_frame>4 weeks</time_frame>
        <population>Although all 61 participants were able to provide TLFB data through the end of 8 weeks, the NPU task required that they attend a study visit at 4 weeks. 24 participants (10 in doxazosin, 13 in placebo) did not complete that study visit and so have data missing for this outcome measure. 1 (doxazosin) attended the visit but chose not to complete the NPU task. 2 participants (both placebo) completed NPU at this visit, but their NPU data was unusable for this analysis due to technical issues.</population>
        <group_list>
          <group group_id="O1">
            <title>Doxazosin</title>
            <description>Participants receive 8 weeks of doxazosin (8mg target dose).&#xD;
Doxazosin: Doxazosin</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants will receive 8 weeks of matched placebo.&#xD;
Placebo: Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Startle Potentiation During Stress Reactivity Task</title>
          <description>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.</description>
          <population>Although all 61 participants were able to provide TLFB data through the end of 8 weeks, the NPU task required that they attend a study visit at 4 weeks. 24 participants (10 in doxazosin, 13 in placebo) did not complete that study visit and so have data missing for this outcome measure. 1 (doxazosin) attended the visit but chose not to complete the NPU task. 2 participants (both placebo) completed NPU at this visit, but their NPU data was unusable for this analysis due to technical issues.</population>
          <units>microvolts</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="17"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Unpredictable startle potentiation</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.25" spread="20.18"/>
                    <measurement group_id="O2" value="20.76" spread="23.21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Predictable startle potentiation</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26.22" spread="30.90"/>
                    <measurement group_id="O2" value="22.21" spread="35.93"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants Reporting Any Heavy Drinking Days</title>
        <description>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 &quot;yes&quot; if participant reported any days of heavy drinking (&gt; 4/3 standard drinks for men/women) during the total 8 week assessment period; &quot;no&quot; if no heavy drinking was reported</description>
        <time_frame>8 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Doxazosin</title>
            <description>Participants receive 8 weeks of doxazosin (8mg target dose).&#xD;
Doxazosin: Doxazosin</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants will receive 8 weeks of matched placebo.&#xD;
Placebo: Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Reporting Any Heavy Drinking Days</title>
          <description>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 &quot;yes&quot; if participant reported any days of heavy drinking (&gt; 4/3 standard drinks for men/women) during the total 8 week assessment period; &quot;no&quot; if no heavy drinking was reported</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="29"/>
                <count group_id="O2" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17"/>
                    <measurement group_id="O2" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>8 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Doxazosin</title>
          <description>Participants receive 8 weeks of doxazosin (8mg target dose).&#xD;
Doxazosin: Doxazosin</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Participants will receive 8 weeks of matched placebo.&#xD;
Placebo: Placebo</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="32"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="24" subjects_at_risk="29"/>
                <counts group_id="E2" subjects_affected="28" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cardiac arrhythmia</sub_title>
                <counts group_id="E1" events="12" subjects_affected="8" subjects_at_risk="29"/>
                <counts group_id="E2" events="7" subjects_affected="6" subjects_at_risk="32"/>
              </event>
              <event>
                <sub_title>Chest pains</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="32"/>
              </event>
              <event>
                <sub_title>Edema</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="17" subjects_affected="9" subjects_at_risk="29"/>
                <counts group_id="E2" events="9" subjects_affected="7" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurry vision</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea or diarrhea</sub_title>
                <counts group_id="E1" events="14" subjects_affected="9" subjects_at_risk="29"/>
                <counts group_id="E2" events="9" subjects_affected="8" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="38" subjects_affected="15" subjects_at_risk="29"/>
                <counts group_id="E2" events="36" subjects_affected="17" subjects_at_risk="32"/>
              </event>
              <event>
                <sub_title>Rhinitis</sub_title>
                <counts group_id="E1" events="29" subjects_affected="13" subjects_at_risk="29"/>
                <counts group_id="E2" events="9" subjects_affected="5" subjects_at_risk="32"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="25" subjects_affected="9" subjects_at_risk="29"/>
                <counts group_id="E2" events="17" subjects_affected="11" subjects_at_risk="32"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="30" subjects_affected="10" subjects_at_risk="29"/>
                <counts group_id="E2" events="15" subjects_affected="8" subjects_at_risk="32"/>
              </event>
              <event>
                <sub_title>General symptoms, nonspecific</sub_title>
                <counts group_id="E1" events="9" subjects_affected="8" subjects_at_risk="29"/>
                <counts group_id="E2" events="10" subjects_affected="6" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Polyurea</sub_title>
                <counts group_id="E1" events="6" subjects_affected="2" subjects_at_risk="29"/>
                <counts group_id="E2" events="8" subjects_affected="4" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Priapism</sub_title>
                <description>This was only assessed in men</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="29"/>
                <counts group_id="E2" events="5" subjects_affected="3" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Orthostatic hypertension</sub_title>
                <counts group_id="E1" events="24" subjects_affected="14" subjects_at_risk="29"/>
                <counts group_id="E2" events="18" subjects_affected="7" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>John Curtin</name_or_title>
      <organization>University of Wisconsin</organization>
      <phone>608-262-0387</phone>
      <email>jjcurtin@wisc.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02989493
org study id: 2015-1009
secondary id: R01AA024388
secondary id: A487400
secondary id: L&S\PSYCHOLOGY\PSYCHOLOGY
secondary id: Protocol Version 11/7/2019
nct id: NCT02989493
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Startle Potentiation During Stress Reactivity Task
time frame: 4 weeks
description: 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.
measure: Number of Participants Reporting Any Heavy Drinking Days
time frame: 8 weeks
description: 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
arm group label: Doxazosin
arm group type: Experimental
description: Participants receive 8 weeks of doxazosin (8mg target dose).
arm group label: Placebo
arm group type: Placebo Comparator
description: Participants will receive 8 weeks of matched placebo.
intervention type: Drug
intervention name: Doxazosin
description: Doxazosin
arm group label: Doxazosin
intervention type: Other
intervention name: Placebo
description: Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: John J Curtin, PhD
role: Principal Investigator
affiliation: University of Wisconsin, Madison
facility: 
country: United States
url: http://arc.psych.wisc.edu
description: Dr. John Curtin's Addiction Research Center
responsible party type: Sponsor
mesh term: Alcoholism
mesh term: Doxazosin
sharing ipd: Yes
ipd description: Data will be made available online upon study completion at the Open Science Framework: https://osf.io
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 