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Neuroimmune Dysfunction in Alcohol Use Disorder

Primary Purpose

Alcohol Drinking, Alcohol-Related Disorders, Disease

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Minocycline
Sugar pill
Sponsored by
University of Maryland, Baltimore
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alcohol Drinking focused on measuring Minocycline

Eligibility Criteria

25 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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 ≥ 1 times per week (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
  • Self-described daily cannabis user
  • Lifetime DSM-5 diagnosis of schizophrenia spectrum and other psychotic disorders and bipolar and related disorders
  • Positive urine toxicology screen for illicit substances (excluding marijuana)
  • 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
  • A medical condition that may interfere with safe study participation (e.g., unstable cardiac, renal, or liver disease, uncontrolled hypertension or diabetes)
  • alanine aminotransferase (ALT), aspartate aminotransferase (AST), or γ-glutamyl transferase (GGT) ≥ 3 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
  • Previously known hypersensitivity to tetracyclines
  • Current or recent (within one month) treatment with tetracycline, tetracycline derivative, or any other antibiotic
  • 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
  • History of traumatic brain injury
  • 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

Healthy Control Group Inclusion Criteria:

  • Do 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
  • 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
  • Self-described daily cannabis user
  • Positive urine toxicology screen for illicit substances (excluding marijuana)
  • If female: pregnancy, nursing, or refusal to use reliable method of birth control; if using hormonal contraceptives, refusal to use secondary birth control method
  • A medical condition that may interfere with safe study participation (e.g., unstable cardiac, renal, or liver disease, uncontrolled hypertension or diabetes)
  • AST, ALT, or GGT ≥ 3 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
  • Previously known hypersensitivity to tetracyclines
  • Current or recent (within one month) treatment with tetracycline, tetracycline derivative, or any other antibiotic
  • 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
  • History of traumatic brain injury
  • 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

Sites / Locations

  • Maryland Psychiatric Research Center (MPRC) Treatment Research Program (TRP)Recruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Placebo Comparator

Active Comparator

Placebo Comparator

Arm Label

AUD-Minocycline

AUD-Placebo

Healthy Control-Minocycline

Healthy Control-Placebo

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Neuroinflammation
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
Cue-Induced Alcohol Craving
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.
Alcohol consumption
Total drinks consumed assessed using the Timeline Follow Back
Verbal Fluency/Language
Wechsler Abbreviated Scale of Intelligence (WASI)-Vocabulary, WASI-Similarities, Verbal Fluency (Animals), with higher scores indicating greater intellectual ability.
Speed of processing
Brief Assessment of Cognition in Schizophrenia (BACS)-Symbol Coding [scored by number of correct numerals (range: 0 -110)]
Speed of processing
Trail Making Test: Part A (scored by time to complete test with lower scores being better)
Speed of processing
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)
Working Memory
Wechsler Memory Scale (WMS)-Spatial Span (scored up to 32 correct series), Letter-Number Span (scored up to 30 correct series)
Attention
Continuous Performance Test
Problem Solving/Executive Functioning
Wisconsin Card Sorting Test-64
Inhibition/Impulsivity
Stop-Signal Reaction Time
Verbal Learning
Hopkins Verbal Learning Test
Visual Learning
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.]

Secondary Outcome Measures

Peripheral Proinflammatory Marker levels
Serum level of inflammatory molecules
Alcohol Use Disorder Severity
Symptom count from the alcohol module for the Structured Clinical Interview for DSM-5
Gut microbiota
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)

Full Information

First Posted
December 17, 2019
Last Updated
November 29, 2022
Sponsor
University of Maryland, Baltimore
Collaborators
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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1. Study Identification

Unique Protocol Identification Number
NCT04210713
Brief Title
Neuroimmune Dysfunction in Alcohol Use Disorder
Official Title
Characterization of Neuroimmune Dysfunction in Alcohol Use Disorder
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Recruiting
Study Start Date
February 3, 2020 (Actual)
Primary Completion Date
August 31, 2023 (Anticipated)
Study Completion Date
August 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Maryland, Baltimore
Collaborators
National Institute on Alcohol Abuse and Alcoholism (NIAAA)

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alcohol Drinking, Alcohol-Related Disorders, Disease, Inflammation, Alcoholism, Cognitive Dysfunction, Pathologic Processes, Drinking Behavior, Substance-Related Disorders, Chemically-Induced Disorders, Mental Disorder, Cognition Disorder, Neurocognitive Disorders, Minocycline, Anti-Bacterial Agents, Anti-Infective Agents
Keywords
Minocycline

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
Double Blind
Allocation
Randomized
Enrollment
72 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
AUD-Minocycline
Arm Type
Active Comparator
Arm Description
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.
Arm Title
AUD-Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Healthy Control-Minocycline
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Healthy Control-Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Minocycline
Intervention Description
200 mg/day
Intervention Type
Drug
Intervention Name(s)
Sugar pill
Other Intervention Name(s)
Placebo
Intervention Description
Matched placebo
Primary Outcome Measure Information:
Title
Neuroinflammation
Description
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
Time Frame
Change from baseline after 28 days of medication dosing
Title
Cue-Induced Alcohol Craving
Description
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.
Time Frame
Change from baseline after 28 days of medication dosing
Title
Alcohol consumption
Description
Total drinks consumed assessed using the Timeline Follow Back
Time Frame
Change from baseline after 28 days of medication dosing
Title
Verbal Fluency/Language
Description
Wechsler Abbreviated Scale of Intelligence (WASI)-Vocabulary, WASI-Similarities, Verbal Fluency (Animals), with higher scores indicating greater intellectual ability.
Time Frame
Change from baseline after 28 days of medication dosing
Title
Speed of processing
Description
Brief Assessment of Cognition in Schizophrenia (BACS)-Symbol Coding [scored by number of correct numerals (range: 0 -110)]
Time Frame
Change from baseline after 28 days of medication dosing
Title
Speed of processing
Description
Trail Making Test: Part A (scored by time to complete test with lower scores being better)
Time Frame
Change from baseline after 28 days of medication dosing
Title
Speed of processing
Description
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)
Time Frame
Change from baseline after 28 days of medication dosing
Title
Working Memory
Description
Wechsler Memory Scale (WMS)-Spatial Span (scored up to 32 correct series), Letter-Number Span (scored up to 30 correct series)
Time Frame
Change from baseline after 28 days of medication dosing
Title
Attention
Description
Continuous Performance Test
Time Frame
Change from baseline after 28 days of medication dosing
Title
Problem Solving/Executive Functioning
Description
Wisconsin Card Sorting Test-64
Time Frame
Change from baseline after 28 days of medication dosing
Title
Inhibition/Impulsivity
Description
Stop-Signal Reaction Time
Time Frame
Change from baseline after 28 days of medication dosing
Title
Verbal Learning
Description
Hopkins Verbal Learning Test
Time Frame
Change from baseline after 28 days of medication dosing
Title
Visual Learning
Description
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.]
Time Frame
Change from baseline after 28 days of medication dosing
Secondary Outcome Measure Information:
Title
Peripheral Proinflammatory Marker levels
Description
Serum level of inflammatory molecules
Time Frame
At baseline (day zero) and after 7, 14, and 21 and 28 days of medication dosing
Title
Alcohol Use Disorder Severity
Description
Symptom count from the alcohol module for the Structured Clinical Interview for DSM-5
Time Frame
At baseline (day zero) and after 28 days of medication dosing
Title
Gut microbiota
Description
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)
Time Frame
At baseline (day zero) and after 7, 14, and 21 and 28 days of medication dosing

10. Eligibility

Sex
All
Minimum Age & Unit of Time
25 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Brian Brandler, MA
Phone
410-402-6425
Email
bbrandler@som.umaryland.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Ann Kearns, BS
Phone
410-402-6854
Email
akearns@mprc.umaryland.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Daniel Roche, PhD
Organizational Affiliation
University of Maryland, Baltimore
Official's Role
Principal Investigator
Facility Information:
Facility Name
Maryland Psychiatric Research Center (MPRC) Treatment Research Program (TRP)
City
Catonsville
State/Province
Maryland
ZIP/Postal Code
21228
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Brian Brandler, MA
Phone
410-402-6425
Email
bbrandler@som.umaryland.edu
First Name & Middle Initial & Last Name & Degree
Daniel Roche, PhD

12. IPD Sharing Statement

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Neuroimmune Dysfunction in Alcohol Use Disorder

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