Clinical trial NCT04210713: Neuroimmune Dysfunction in Alcohol Use Disorder
Official title: Characterization of Neuroimmune Dysfunction in Alcohol Use Disorder
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
Collaborators: name: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
First posted: 2019-12-26
Enrollment: 142
Sex: ALL
Minimum age (years): 25
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Neuroinflammation
timeFrame: Change from baseline after 28 days of medication dosing
measure: Cue-Induced Alcohol Craving
timeFrame: Change from baseline after 28 days of medication dosing
measure: Alcohol consumption
timeFrame: Change from baseline after 28 days of medication dosing
measure: Verbal Fluency/Language
timeFrame: Change from baseline after 28 days of medication dosing
measure: Speed of processing
timeFrame: Change from baseline after 28 days of medication dosing
measure: Speed of processing
timeFrame: Change from baseline after 28 days of medication dosing
measure: Speed of processing
timeFrame: Change from baseline after 28 days of medication dosing
measure: Working Memory
timeFrame: Change from baseline after 28 days of medication dosing
measure: Attention
timeFrame: Change from baseline after 28 days of medication dosing
measure: Problem Solving/Executive Functioning
timeFrame: Change from baseline after 28 days of medication dosing
measure: Inhibition/Impulsivity
timeFrame: Change from baseline after 28 days of medication dosing
measure: Verbal Learning
timeFrame: Change from baseline after 28 days of medication dosing
measure: Visual Learning
timeFrame: Change from baseline after 28 days of medication dosing
Secondary outcomes:
measure: Peripheral Proinflammatory Marker levels
timeFrame: At baseline (day zero) and after 7, 14, and 21 and 28 days of medication dosing
measure: Alcohol Use Disorder Severity
timeFrame: At baseline (day zero) and after 28 days of medication dosing
measure: Gut microbiota
timeFrame: At baseline (day zero) and after 7, 14, and 21 and 28 days of medication dosing
Other outcomes:
Locations:
city: Catonsville
country: United States
facility: Maryland Psychiatric Research Center (MPRC) Treatment Research Program (TRP)
state: Maryland
Study officials:
affiliation: University of Maryland, Baltimore
name: Daniel Roche, PhD
role: PRINCIPAL_INVESTIGATOR
References: