Neuroimmune Dysfunction in Alcohol Use Disorder

Sponsor

University of Maryland, Baltimore (Other)

Overall Status

Recruiting

CT.gov ID

NCT04210713

Collaborator

National Institute on Alcohol Abuse and Alcoholism (NIAAA) (NIH)

Enrollment

Location

Arms

30.9

Anticipated Duration (Months)

2.3

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Minocycline Drug: Sugar pill	Phase 1

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 Design

Study Type:

Interventional

Anticipated Enrollment :

72 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Masking Description:

Double Blind

Primary Purpose:

Treatment

Official Title:

Characterization of Neuroimmune Dysfunction in Alcohol Use Disorder

Actual Study Start Date :

Feb 3, 2020

Anticipated Primary Completion Date :

Aug 31, 2022

Anticipated Study Completion Date :

Aug 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
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

Outcome Measures

Primary Outcome Measures

Neuroinflammation [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
Cue-Induced Alcohol Craving [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.
Alcohol consumption [Change from baseline after 28 days of medication dosing]
Total drinks consumed assessed using the Timeline Follow Back
Verbal Fluency/Language [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.
Speed of processing [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)]
Speed of processing [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)
Speed of processing [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)
Working Memory [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)
Attention [Change from baseline after 28 days of medication dosing]
Continuous Performance Test
Problem Solving/Executive Functioning [Change from baseline after 28 days of medication dosing]
Wisconsin Card Sorting Test-64
Inhibition/Impulsivity [Change from baseline after 28 days of medication dosing]
Stop-Signal Reaction Time
Verbal Learning [Change from baseline after 28 days of medication dosing]
Hopkins Verbal Learning Test
Visual Learning [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.]

Secondary Outcome Measures

Peripheral Proinflammatory Marker levels [At baseline (day zero) and after 7, 14, and 21 and 28 days of medication dosing]
Serum level of inflammatory molecules
Alcohol Use Disorder Severity [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
Gut microbiota [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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

25 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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