Minocycline for Alcohol Use Disorder

Study Overview
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Brief Summary
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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
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The research objective of this project is to advance medication development for AUD by conducting a randomized, double blind, placebo-controlled, neuroimaging study to examine the effects of minocycline on neuroinflammation, alcohol cue reactivity, neurocognitive performance, and alcohol use. In the proposed study, non-treatment seeking individuals with a current DSM-5 AUD diagnosis (N = 32) will be randomized to receive either 200 mg of minocycline per day or placebo for 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 28 days. Within each laboratory session, participants will complete a cue reactivity paradigm, neurocognitive performance tasks, and a positron emission tomography (PET) imaging session. Neuroinflammation will be assessed by using PET imaging with the radiotracer N-(2,5-dimethoxy-benzyl)-N-(5-fluoro-2-phenoxyphenyl) acetamide, labeled with carbon-11 ([11C]-DAA1106), which binds to the mitochondrial translocator protein, a marker of activated microglia in brain. Additionally, blood samples will be drawn on days 0, 7, 14, 21, and 28 to measure circulating levels of proinflammatory markers and alcohol use over the four weeks of treatment will also be measured.

Official Title
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Development of Minocycline as a Neuroimmune Therapy for Alcohol Use Disorder

Conditions
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Alcohol Use Disorder, Inflammation, Neurocognitive Dysfunction, Craving, Alcohol Drinking

Intervention / Treatment
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* Drug: Minocycline
* Drug: Sugar pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 25 - 45 Meet DSM-5 diagnostic criteria for an AUD [n.b., only participants with moderate or severe AUD will be enrolled] Drink ≥ 48 standard drinks in a 30-day period before enrollment Exclusion Criteria: Currently in treatment for AUD, a history of treatment in the 30 days before enrollment, or currently treatment seeking Current (last 12 months) DSM-V diagnosis of substance use disorder for any psychoactive substances other than alcohol and nicotine Lifetime DSM-V diagnosis of schizophrenia, bipolar disorder, or any psychotic disorder Positive urine screen for narcotics, amphetamines, or sedative hypnotics Serious alcohol withdrawal symptoms as indicated by a score ≥ 10 on the Clinical Institute Withdrawal Assessment for Alcohol-Revised Pregnancy, nursing, or refusal to use reliable method of birth control (if female) 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 MINO Any other circumstances that, in the opinion of the investigators, compromises participant safety. Claustrophobia Participating in any other research study involving exposure to ionizing radiation in the past year will be excluded if the total cumulative exposure from the past research studies and the current research study would exceed the limits set by the FDA in 21 CFR 361.1. Specifically, the total cumulated dose to the whole body, active blood-forming organs, lens of the eye, and gonads must remain below 5 rems, and the cumulated dose to all other organs must remain below 15 rems. Potential participants who have had exposure to ionizing radiation in the past year will not be allowed to participate if we are unable to obtain proper documentation quantifying the amount of past exposure. Presence of a metal device in the body (e.g., pacemaker, infusion pump, aneurysm clip, metal prosthesis or plate): Those devices could either interfere with the acquisition of the MRI scan of the brain or for whom the MRI scan would pose a potential risk. If participants have a non-removable device in their body, they must acquire and show a document exhibiting the device is MRI-compatible. low affinity rs6971 genotype

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Minocycline<br>200 mg/day | Drug: Minocycline<br>* 200 mg/day<br>|
| Placebo Comparator: Sugar Pill<br>Matched placebo | Drug: Sugar pill<br>* Matched placebo<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microglial Activation | Level of [11C]DAA1106 binding during PET imaging | Change from baseline after 28 days of medication dosing | 
| Cue-Induced Alcohol Craving | Alcohol Urge Questionnaire (AUQ) | Change from baseline after 28 days of medication dosing | 
| Alcohol consumption | Total drinks consumed | Day 28 of medication dosing period | 
| Verbal Learning and Memory | Hopkins Verbal Learning Test | Change from baseline after 28 days of medication dosing | 
| Set-Shifting | Wisconsin Card Sorting Test | Change from baseline after 28 days of medication dosing | 
| Response Inhibition | Stop Signal Task | Change from baseline after 28 days of medication dosing | 
| Manipulative Dexterity | Grooved Pegboard Test | Change from baseline after 28 days of medication dosing | 
| Executive Function | Digit Symbol Substitution Test | Change from baseline after 28 days of medication dosing | 
| Memory | Digit Span | Change from baseline after 28 days of medication dosing | 
| Vocabulary | WAIS Vocabulary | Change from baseline after 28 days of medication dosing | 
| Executive Function | Rey Complex Figure Copy | Change from baseline after 28 days of medication dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peripheral Proinflammatory Marker levels | Serum level of cytokines and innate immune receptors | At baseline (day zero) and after 7, 14, and 21 and 28 days of medication dosing | 
| Alcohol Use Disorder Severity | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Minocycline