INIA Stress and Chronic Alcohol Interactions: Glucocorticoid Antagonists in Heavy Drinkers

• ClinicalTrials.gov Identifier: NCT02989662
• Recruitment Status: Recruiting
• First Posted: December 12, 2016
• Last Update Posted: August 6, 2020
• Sponsor: Johns Hopkins University
• Collaborator: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Information provided by (Responsible Party): Johns Hopkins University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Alcohol Use Disorder	Drug: Mifepristone; Drug: Placebo - Cap	Not Applicable

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Glucocorticoid Antagonists in Heavy Drinkers: Effects on fMRI Connectivity, Withdrawal and Drinking
• Study Start Date: February 2016
• Estimated Primary Completion Date: January 2022
• Estimated Study Completion Date: January 2022

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Mifepristone; 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.	Drug: Mifepristone; Participants receive 6 doses.; Other Name: Korlym
Placebo Comparator: Placebo - Cap; This is an inactive compound which appears physically identical to active medication.	Drug: Placebo - Cap; Participants receive 6 doses

Outcome Measures

Primary Outcome Measures :

1. fMRI function connectivity [ Time Frame: Change from baseline to day 4 of MIFE dosing ]
   fMRI data including resting state and alcohol cue induced measures

Secondary Outcome Measures :

1. Alcohol motivated responding [ Time Frame: single session on study day 5 ]
   Participants can earn up to 5 standard drinks during a 1-hr session.
2. Alcohol sensitivity [ Time Frame: single session on study day 6 ]
   Subjective and physiological effects of alcohol are measured repeatedly during a 4-hr session

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Nontreatment seeking AUD volunteers
• English speaking
• healthy
• Not pregnant or nursing

Exclusion Criteria:

• Women on hormonal birth control, pregnant or nursing
• Current health or psychiatric problems
• Potassium level below normal
• Any medication or health condition that is known to interact with MIFE or CORT metabolism
• History of metal implantation that would preclude MRI scan.

Contacts and Locations

Contacts

Contact: Gary Wand, MD; 410-955-3921; gwand1@jhmi.edu

Contact: Mary E McCaul, PhD; 410-955-9526; mmccaul1@jhmi.edu

Locations

United States, Maryland

Integrated Program for Substance Abuse Research; Recruiting

Baltimore, Maryland, United States, 21205

Contact: Mary E McCaul, PhD 410-955-9526 mmccaul1@jhmi.edu

Contact: JoAnna Mathena, MS 410-955-9524 jmathen5@jhmi.edu

Sponsors and Collaborators

Johns Hopkins University

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Investigators

• Principal Investigator: Gary Wand, MD; Johns Hopkins University

More Information

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT02989662
• Other Study ID Numbers: IRB00138426; U01AA020890 ( U.S. NIH Grant/Contract ); AA020890 ( Other Identifier: Other )
• First Posted: December 12, 2016
• Last Update Posted: August 6, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Additional relevant MeSH terms:

Mifepristone; Alcoholism; Alcoholic Intoxication; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Abortifacient Agents, Steroidal; Abortifacient Agents; Reproductive Control Agents; Physiological Effects of Drugs; Contraceptives, Oral, Synthetic; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptive Agents; Contraceptives, Postcoital, Synthetic; Contraceptives, Postcoital; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Luteolytic Agents; Menstruation-Inducing Agents