Neuroimmune Dysfunction in Alcohol Use Disorder

November 30, 2023 updated by: Daniel Roche, University of Maryland, Baltimore

Characterization of Neuroimmune Dysfunction in Alcohol Use Disorder

The objective of this proposal is to advance medication development for alcohol use disorder by examining the efficacy and mechanisms of action of minocycline, a neuroimmune modulator, as a potential treatment. This study has important clinical implications, as the available treatments for alcohol use disorder are only modestly effective and testing novel medications is a high research priority.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The research objective of this project is to characterize the role of the neuroimmune system in alcohol use disorder (AUD). The proposed study employs a randomized, double-blind, and placebo-controlled design to examine how neuroinflammation, as measured via neuroimaging [e.g., magnetic resonance imaging (MRI)], relates to alcohol craving, neurocognitive impairment (e.g., memory, attention, etc.), and alcohol use in non-treatment seeking individuals with AUD. The study will also determine whether minocycline (MINO), an FDA-approved antibiotic medication, affects any of the above listed measures. In the proposed study, healthy controls (n = 36) and non-treatment seeking individuals with a current Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 AUD diagnosis (n = 36) will be randomized to receive either 200 mg of minocycline per day or placebo for approximately 28 days and complete two laboratory sessions. The first laboratory session will be performed immediately before commencing the medication regimen (day 0) and the second will be completed after taking the medication daily for approximately 28 days. Within each laboratory session, participants will complete a cue reactivity paradigm, neurocognitive performance tasks, and a magnetic resonance imaging (MRI) session. Additionally, blood samples will be drawn on days 0, 7, 14, 21, and 28 of treatment to measure circulating levels of proinflammatory molecules in order to identify the specific immune signaling pathways underlying neuroinflammation in AUD. Clinical labs (e.g., blood chemistry, liver function tests) and adverse events (AEs) will also be assessed at these five visits.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
142

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • United States
    • Maryland
      • Catonsville, Maryland, United States, 21228
        • Maryland Psychiatric Research Center (MPRC) Treatment Research Program (TRP)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

21 years to 61 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

AUD Group Inclusion Criteria:

  • Meet DSM-5 diagnostic criteria for an AUD
  • In the 30-day period before enrollment, consume ≥ 14 and ≥ 7 standard drinks per week for men and women, respectively, AND
  • In the 30-day period before enrollment, engage in heavy drinking (5 or more drinks for men, 4 or more drinks for women) and ≥ 5 times per month

AUD Group Exclusion Criteria:

  • Currently in treatment for AUD, a history of treatment within the 30 days before enrollment, or currently seeking immediate treatment
  • Current (last 12 months) DSM-5 diagnosis of substance use disorder for any psychoactive substances other than alcohol and nicotine
  • Currently prescribed a psychotropic medication for the treatment of schizophrenia spectrum and other psychotic disorders, bipolar and related disorders, depressive disorders, anxiety disorders, and mood disorders.
  • Lifetime DSM-5 diagnosis of schizophrenia spectrum and other psychotic disorders and bipolar and related disorders
  • Positive urine toxicology screen for the following substances: cocaine, opiates, amphetamines, methamphetamine, phencyclidine, barbiturates, benzodiazepine, methadone, and tricyclic antidepressants.
  • Self-reported daily use of cannabidiol (CBD) or opioids (including prescribed)
  • Serious alcohol withdrawal symptoms as indicated by a score ≥ 10 on the Clinical Institute Withdrawal Assessment for Alcohol-Revised
  • If female: pregnancy, nursing, or refusal to use reliable method of birth control; if using hormonal contraceptives, refusal to use secondary birth control method
  • Any autoimmune or inflammatory medical disorder or medical condition that may interfere with safe study participation and/or study aims (e.g., unstable cardiac, renal, or liver disease, uncontrolled hypertension or diabetes)
  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or γ-glutamyl transferase (GGT) ≥ 4 times upper normal limit
  • Attempted suicide in the past 3 years and/or serious suicidal intention or plan within the past year
  • Currently on prescription medication that contraindicates use of minocycline, including but not necessarily limited to: isoretinoin, ergot alkaloids, and anti-coagulants.
  • Previously known hypersensitivity to tetracyclines
  • Current or recent (within one month) treatment with any antibiotic
  • Regular use of a prebiotic or probiotic supplement
  • Claustrophobia or physical issues preventing MRI scan
  • Presence of a metal device in the body (e.g., pacemaker, infusion pump, aneurysm clip, metal prosthesis or plate)
  • Current or recent (within 3 months) participation in a clinical trial involving medication administration
  • Suffered a mild or moderate traumatic brain injury (TBI) within the last 12 months, a severe TBI at any point in their life, or a moderate TBI before the age of 12.
  • Having below a 6th grade reading level
  • Within the last 3 months, tested positive for COVID-19 (i.e. the SARS-CoV-2 virus) and experienced common related symptoms.
  • Any other circumstances that, in the opinion of the investigators, compromises participant safety, ability of the investigators to conduct the study as designed, and/or study integrity.

Healthy Control Group Inclusion Criteria:

  • Does not meet DSM-5 diagnostic criteria for an AUD (current or lifetime)
  • In the 30-day period before enrollment, consume ≤ 14 and ≤ 7 standard drinks per week for men and women, respectively
  • Engage in infrequent heavy drinking during the past 6 months (≤ 2 heavy drinking events in past 6 months)

Healthy Control Group Exclusion Criteria:

  • Lifetime DSM-5 diagnosis of substance use disorder for any psychoactive substances other than nicotine
  • Self-reported daily use of cannabidiol (CBD) or opioids (including prescribed)
  • Lifetime DSM-5 diagnosis of schizophrenia spectrum and other psychotic disorders, bipolar and related disorders, depressive disorders, anxiety disorders (panic disorder, agoraphobia, social anxiety, and generalized anxiety), obsessive-compulsive and related disorders, trauma- and stressor-related disorders, feeding and eating disorders (binge eating, anorexia, and bulimia), conduct disorders, and gambling disorder
  • Positive urine toxicology screen for the following substances: cocaine, opiates, amphetamines, methamphetamine, phencyclidine, barbiturates, benzodiazepine, methadone, and tricyclic antidepressants.
  • Serious alcohol withdrawal symptoms as indicated by a score ≥ 10 on the Clinical Institute Withdrawal Assessment for Alcohol-Revised
  • If female: pregnancy, nursing, or refusal to use reliable method of birth control; if using hormonal contraceptives, refusal to use secondary birth control method
  • Any autoimmune or inflammatory medical disorder or medical condition that may interfere with safe study participation and/or study aims (e.g., unstable cardiac, renal, or liver disease, uncontrolled hypertension or diabetes)
  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or γ-glutamyl transferase (GGT) ≥ 4 times upper normal limit
  • Attempted suicide in the past 3 years and/or serious suicidal intention or plan within the past year
  • Currently on prescription medication that contraindicates use of minocycline, including but not necessarily limited to: isoretinoin, ergot alkaloids, and anti-coagulants.
  • Previously known hypersensitivity to tetracyclines
  • Current or recent (within one month) treatment with any antibiotic
  • Regular use of a prebiotic or probiotic supplement
  • Claustrophobia or physical issues preventing MRI scan
  • Presence of a metal device in the body (e.g., pacemaker, infusion pump, aneurysm clip, metal prosthesis or plate)
  • Current or recent (within 3 months) participation in a clinical trial involving medication administration
  • Suffered a mild or moderate traumatic brain injury (TBI) within the last 12 months, a severe TBI at any point in their life, or a moderate TBI before the age of 12.
  • Having below a 6th grade reading level
  • Within the last 3 months, tested positive for COVID-19 (i.e. the SARS-CoV-2 virus) and experienced common related symptoms.
  • Any other circumstances that, in the opinion of the investigators, compromises participant safety, ability of the investigators to conduct the study as designed, and/or study integrity.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: AUD-Minocycline
Participants diagnosed with alcohol use disorder will be randomly assigned to take minocycline for 4 weeks. The randomization is double-blinded and will alternate between minocycline and placebo.
Drug: Minocycline
200 mg/day
Placebo Comparator: AUD-Placebo
Participants diagnosed with alcohol use disorder will be randomly assigned to take placebo for 4 weeks. The randomization is double-blinded and will alternate between minocycline and placebo.
Drug: Sugar pill
Matched placebo
Other Names:
  • Placebo
Active Comparator: Healthy Control-Minocycline
Healthy control participants will be randomly assigned to take minocycline for 4 weeks. The randomization is double-blinded and will alternate between minocycline and placebo.
Drug: Minocycline
200 mg/day
Placebo Comparator: Healthy Control-Placebo
Healthy control participants will be randomly assigned to take placebo for 4 weeks. The randomization is double-blinded and will alternate between minocycline and placebo.
Drug: Sugar pill
Matched placebo
Other Names:
  • Placebo

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Neuroinflammation
Time Frame: Change from baseline after 28 days of medication dosing
A multimodal MRI approach consisting of Diffusion Tensor Imaging (DTI) with free water imaging and Magnetic Resonance Spectroscopy (MRS) will be utilized to assess neuroinflammation
Change from baseline after 28 days of medication dosing
Cue-Induced Alcohol Craving
Time Frame: Change from baseline after 28 days of medication dosing
Participants will listen to a 5-minute guided cue exposure script, during which they are exposed to both a neutral and their preferred alcoholic beverage. Prior to beginning the paradigm and after each cue exposure participants will rate their alcohol craving using the "Alcohol Urge Questionnaire (AUQ)" and cigarette craving using the "Brief Questionnaire on Smoking Urges (BQSU)." Both scales range from 1 to 7 with higher scores reflecting more craving.
Change from baseline after 28 days of medication dosing
Alcohol consumption
Time Frame: Change from baseline after 28 days of medication dosing
Total drinks consumed assessed using the Timeline Follow Back
Change from baseline after 28 days of medication dosing
Verbal Fluency/Language
Time Frame: Change from baseline after 28 days of medication dosing
Wechsler Abbreviated Scale of Intelligence (WASI)-Vocabulary, WASI-Similarities, Verbal Fluency (Animals), with higher scores indicating greater intellectual ability.
Change from baseline after 28 days of medication dosing
Speed of processing
Time Frame: Change from baseline after 28 days of medication dosing
Brief Assessment of Cognition in Schizophrenia (BACS)-Symbol Coding [scored by number of correct numerals (range: 0 -110)]
Change from baseline after 28 days of medication dosing
Speed of processing
Time Frame: Change from baseline after 28 days of medication dosing
Trail Making Test: Part A (scored by time to complete test with lower scores being better)
Change from baseline after 28 days of medication dosing
Speed of processing
Time Frame: Change from baseline after 28 days of medication dosing
Grooved Pegboard (scored as a sum of the total time, total number of drops, and the total number of pegs correctly placed in the board with higher scores corresponding to worse performance)
Change from baseline after 28 days of medication dosing
Working Memory
Time Frame: Change from baseline after 28 days of medication dosing
Wechsler Memory Scale (WMS)-Spatial Span (scored up to 32 correct series), Letter-Number Span (scored up to 30 correct series)
Change from baseline after 28 days of medication dosing
Attention
Time Frame: Change from baseline after 28 days of medication dosing
Continuous Performance Test
Change from baseline after 28 days of medication dosing
Problem Solving/Executive Functioning
Time Frame: Change from baseline after 28 days of medication dosing
Wisconsin Card Sorting Test-64
Change from baseline after 28 days of medication dosing
Inhibition/Impulsivity
Time Frame: Change from baseline after 28 days of medication dosing
Stop-Signal Reaction Time
Change from baseline after 28 days of medication dosing
Verbal Learning
Time Frame: Change from baseline after 28 days of medication dosing
Hopkins Verbal Learning Test
Change from baseline after 28 days of medication dosing
Visual Learning
Time Frame: Change from baseline after 28 days of medication dosing
Brief Visuospatial Memory Test [scoring is as follows, 1) Total recall: The sum of all valid items generated across learning trials 1-3, 2) Delayed recall: The number of valid items generated after a delay (trial 4), 3) Percent retained: Delayed recall score divided by the higher of trial 2 or 3 × 100, and 4) Recognition Discrimination Index: True positive responses minus false positive responses.]
Change from baseline after 28 days of medication dosing

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Peripheral Proinflammatory Marker levels
Time Frame: At baseline (day zero) and after 7, 14, and 21 and 28 days of medication dosing
Serum level of inflammatory molecules
At baseline (day zero) and after 7, 14, and 21 and 28 days of medication dosing
Alcohol Use Disorder Severity
Time Frame: At baseline (day zero) and after 28 days of medication dosing
Symptom count from the alcohol module for the Structured Clinical Interview for DSM-5
At baseline (day zero) and after 28 days of medication dosing
Gut microbiota
Time Frame: At baseline (day zero) and after 7, 14, and 21 and 28 days of medication dosing
Gut microbiota from stool samples using the following parameters: 1) diversity and evenness (Shannon, Simpson index) and 2) similarity (phylogenetic UniFrac distance, Jensen-Shannon divergence)
At baseline (day zero) and after 7, 14, and 21 and 28 days of medication dosing

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Maryland, Baltimore

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Daniel Roche, PhD, University of Maryland, Baltimore

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
February 3, 2020

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 20, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 20, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 17, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 21, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 26, 2019

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 1, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 30, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • HP-00080891
  • 5K01AA026005-03 (U.S. NIH Grant/Contract)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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