<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/NCT02989662</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00138426</org_study_id>
    <secondary_id>U01AA020890</secondary_id>
    <secondary_id>AA020890</secondary_id>
    <nct_id>NCT02989662</nct_id>
  </id_info>
  <brief_title>INIA Stress and Chronic Alcohol Interactions: Glucocorticoid Antagonists in Heavy Drinkers</brief_title>
  <official_title>Glucocorticoid Antagonists in Heavy Drinkers: Effects on fMRI Connectivity, Withdrawal and Drinking</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Johns Hopkins University</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>Johns Hopkins University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In alcohol use disorder (AUD) and matched healthy control (HC) men and women, the proposed&#xD;
      research examines the effects of MIFE, with demonstrated preclinical effects on&#xD;
      drinking-related behaviors, compared with placebo on a breadth of alcohol-related measures.&#xD;
      All subjects will be randomized to daily MIFE or placebo. Before and during medication, AUD&#xD;
      and HC subjects undergo fMRI scanning measuring resting-state functional connectivity and&#xD;
      alcohol cue-induced brain activation focused on brain reward and stress pathways. All&#xD;
      subjects are admitted to the Clinical Research Unit; AUD subjects undergo supervised alcohol&#xD;
      withdrawal with daily measurements of alcohol craving and symptom severity. Using validated&#xD;
      human laboratory procedures in AUD subjects, this study will examine the effects of stress on&#xD;
      motivation to drink and alcohol sensitivity/reward as a function of GR antagonism.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cortisol (CORT) is a glucocorticoid hormone, often associated with response to stress and&#xD;
      playing a key role in alcohol use and problems. First, acute alcohol administration increases&#xD;
      CORT, which in turn amplifies the mesolimbic dopamine reward signal. Second, alcohol&#xD;
      withdrawal elevates CORT levels in AUD compared with healthy control subjects, and CORT&#xD;
      levels in early abstinence predict subsequent relapse to drinking. Finally, the magnitude of&#xD;
      CORT response to external stressors predicts motivation to work for and consumption of&#xD;
      alcohol in the human laboratory and in the natural environment. Importantly, recent studies&#xD;
      in rodents and humans have demonstrated that blocking CORT activity using a glucocorticoid&#xD;
      receptor (GR) antagonist reduces these effects of CORT on alcohol behaviors, indicating a&#xD;
      causal role for glucocorticoids in these relationships. In alcohol use disorder (AUD) and&#xD;
      matched healthy control (HC) men and women, the proposed research examines the effects of&#xD;
      MIFE, with demonstrated preclinical effects on drinking-related behaviors, compared to&#xD;
      placebo on a breadth of alcohol-related measures. All subjects will be randomized to daily&#xD;
      MIFE or placebo. Before and during medication, AUD and HC subjects undergo fMRI scanning&#xD;
      measuring resting-state functional connectivity and alcohol cue-induced brain activation&#xD;
      focused on brain reward and stress pathways. All subjects are admitted to the Clinical&#xD;
      Research Unit; AUD subjects undergo supervised alcohol withdrawal with daily measurements of&#xD;
      alcohol craving and symptom severity. Using validated human laboratory procedures in AUD&#xD;
      subjects, this study will examine the effects of stress on motivation to drink and alcohol&#xD;
      sensitivity/reward as a function of GR antagonism. This work will help pave the way for&#xD;
      improved pharmacotherapies that target stress and reward pathways in the brain involved in&#xD;
      initiating and maintaining drinking.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date>February 2016</start_date>
  <completion_date type="Anticipated">January 2024</completion_date>
  <primary_completion_date type="Anticipated">January 2024</primary_completion_date>
  <phase>N/A</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>Basic Science</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>fMRI function connectivity</measure>
    <time_frame>Change from baseline to day 4 of MIFE dosing</time_frame>
    <description>fMRI data including resting state and alcohol cue induced measures</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Alcohol motivated responding</measure>
    <time_frame>single session on study day 5</time_frame>
    <description>Participants can earn up to 5 standard drinks during a 1-hr session.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Alcohol sensitivity</measure>
    <time_frame>single session on study day 6</time_frame>
    <description>Subjective and physiological effects of alcohol are measured repeatedly during a 4-hr session</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">150</enrollment>
  <condition>Alcohol Use Disorder</condition>
  <arm_group>
    <arm_group_label>Mifepristone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Mifepristone is a high affinity antagonist of the glucocorticoid receptor (GR). It is FDA approved to treatment hyperglycemia caused by high cortisol levels in adults with endogenous Cushing's syndrome.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo - Cap</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>This is an inactive compound which appears physically identical to active medication.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Mifepristone</intervention_name>
    <description>Participants receive 6 doses.</description>
    <arm_group_label>Mifepristone</arm_group_label>
    <other_name>Korlym</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo - Cap</intervention_name>
    <description>Participants receive 6 doses</description>
    <arm_group_label>Placebo - Cap</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Nontreatment seeking AUD volunteers&#xD;
&#xD;
          -  English speaking&#xD;
&#xD;
          -  healthy&#xD;
&#xD;
          -  Not pregnant or nursing&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Women on hormonal birth control, pregnant or nursing&#xD;
&#xD;
          -  Current health or psychiatric problems&#xD;
&#xD;
          -  Potassium level below normal&#xD;
&#xD;
          -  Any medication or health condition that is known to interact with MIFE or CORT&#xD;
             metabolism&#xD;
&#xD;
          -  History of metal implantation that would preclude MRI scan.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mary E McCaul, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Johns Hopkins University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Mary E McCaul, PhD</last_name>
    <phone>410-955-9526</phone>
    <email>mmccaul1@jhmi.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Gary S Wand, MD</last_name>
    <phone>410-955-3921</phone>
    <email>gwand1@jhmi.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Integrated Program for Substance Abuse Research</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21205</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mary E McCaul, PhD</last_name>
      <phone>410-955-9526</phone>
      <email>mmccaul1@jhmi.edu</email>
    </contact>
    <contact_backup>
      <last_name>JoAnna Mathena, MS</last_name>
      <phone>410-955-9524</phone>
      <email>jmathen5@jhmi.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>December 5, 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>
  <last_update_submitted>January 5, 2023</last_update_submitted>
  <last_update_submitted_qc>January 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alcoholism</mesh_term>
    <mesh_term>Alcoholic Intoxication</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mifepristone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT02989662
org study id: IRB00138426
secondary id: U01AA020890
secondary id: AA020890
nct id: NCT02989662
lead sponsor: 
collaborator: 
has dmc: Yes
In alcohol use disorder (AUD) and matched healthy control (HC) men and women, the proposed
      research examines the effects of MIFE, with demonstrated preclinical effects on
      drinking-related behaviors, compared with placebo on a breadth of alcohol-related measures.
      All subjects will be randomized to daily MIFE or placebo. Before and during medication, AUD
      and HC subjects undergo fMRI scanning measuring resting-state functional connectivity and
      alcohol cue-induced brain activation focused on brain reward and stress pathways. All
      subjects are admitted to the Clinical Research Unit; AUD subjects undergo supervised alcohol
      withdrawal with daily measurements of alcohol craving and symptom severity. Using validated
      human laboratory procedures in AUD subjects, this study will examine the effects of stress on
      motivation to drink and alcohol sensitivity/reward as a function of GR antagonism.
Cortisol (CORT) is a glucocorticoid hormone, often associated with response to stress and
      playing a key role in alcohol use and problems. First, acute alcohol administration increases
      CORT, which in turn amplifies the mesolimbic dopamine reward signal. Second, alcohol
      withdrawal elevates CORT levels in AUD compared with healthy control subjects, and CORT
      levels in early abstinence predict subsequent relapse to drinking. Finally, the magnitude of
      CORT response to external stressors predicts motivation to work for and consumption of
      alcohol in the human laboratory and in the natural environment. Importantly, recent studies
      in rodents and humans have demonstrated that blocking CORT activity using a glucocorticoid
      receptor (GR) antagonist reduces these effects of CORT on alcohol behaviors, indicating a
      causal role for glucocorticoids in these relationships. In alcohol use disorder (AUD) and
      matched healthy control (HC) men and women, the proposed research examines the effects of
      MIFE, with demonstrated preclinical effects on drinking-related behaviors, compared to
      placebo on a breadth of alcohol-related measures. All subjects will be randomized to daily
      MIFE or placebo. Before and during medication, AUD and HC subjects undergo fMRI scanning
      measuring resting-state functional connectivity and alcohol cue-induced brain activation
      focused on brain reward and stress pathways. All subjects are admitted to the Clinical
      Research Unit; AUD subjects undergo supervised alcohol withdrawal with daily measurements of
      alcohol craving and symptom severity. Using validated human laboratory procedures in AUD
      subjects, this study will examine the effects of stress on motivation to drink and alcohol
      sensitivity/reward as a function of GR antagonism. This work will help pave the way for
      improved pharmacotherapies that target stress and reward pathways in the brain involved in
      initiating and maintaining drinking.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: fMRI function connectivity
time frame: Change from baseline to day 4 of MIFE dosing
description: fMRI data including resting state and alcohol cue induced measures
measure: Alcohol motivated responding
time frame: single session on study day 5
description: Participants can earn up to 5 standard drinks during a 1-hr session.
measure: Alcohol sensitivity
time frame: single session on study day 6
description: Subjective and physiological effects of alcohol are measured repeatedly during a 4-hr session
arm group label: Mifepristone
arm group type: Active Comparator
description: Mifepristone is a high affinity antagonist of the glucocorticoid receptor (GR). It is FDA approved to treatment hyperglycemia caused by high cortisol levels in adults with endogenous Cushing's syndrome.
arm group label: Placebo - Cap
arm group type: Placebo Comparator
description: This is an inactive compound which appears physically identical to active medication.
intervention type: Drug
intervention name: Mifepristone
description: Participants receive 6 doses.
arm group label: Mifepristone
other name: Korlym
intervention type: Drug
intervention name: Placebo - Cap
description: Participants receive 6 doses
arm group label: Placebo - Cap
criteria: 
gender: All
minimum age: 21 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Mary E McCaul, PhD
role: Principal Investigator
affiliation: Johns Hopkins University
last name: Mary E McCaul, PhD
phone: 410-955-9526
email: mmccaul1@jhmi.edu
last name: Gary S Wand, MD
phone: 410-955-3921
email: gwand1@jhmi.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
responsible party type: Sponsor
mesh term: Alcoholism
mesh term: Alcoholic Intoxication
mesh term: Mifepristone
sharing ipd: No