Minocycline for Alcohol Use Disorder

Development of Minocycline as a Neuroimmune Therapy for 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• Status: Withdrawn
• Conditions: Alcohol Drinking; Inflammation; Alcohol Use Disorder; Craving; Neurocognitive Dysfunction
• Intervention / Treatment: Drug: Minocycline; Drug: Sugar pill

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Ages 25 - 45
2. Meet DSM-5 diagnostic criteria for an AUD [n.b., only participants with moderate or severe AUD will be enrolled]
3. Drink ≥ 48 standard drinks in a 30-day period before enrollment

Exclusion Criteria:

1. Currently in treatment for AUD, a history of treatment in the 30 days before enrollment, or currently treatment seeking
2. Current (last 12 months) DSM-V diagnosis of substance use disorder for any psychoactive substances other than alcohol and nicotine
3. Lifetime DSM-V diagnosis of schizophrenia, bipolar disorder, or any psychotic disorder
4. Positive urine screen for narcotics, amphetamines, or sedative hypnotics
5. Serious alcohol withdrawal symptoms as indicated by a score ≥ 10 on the Clinical Institute Withdrawal Assessment for Alcohol-Revised
6. Pregnancy, nursing, or refusal to use reliable method of birth control (if female)
7. A medical condition that may interfere with safe study participation (e.g., unstable cardiac, renal, or liver disease, uncontrolled hypertension or diabetes)
8. AST, ALT, or GGT ≥ 3 times upper normal limit
9. Attempted suicide in the past 3 years and/or serious suicidal intention or plan within the past year
10. Currently on prescription medication that contraindicates use of MINO
11. Any other circumstances that, in the opinion of the investigators, compromises participant safety.
12. Claustrophobia
13. 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.
14. 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.
15. low affinity rs6971 genotype

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Minocycline; 200 mg/day	Drug: Minocycline; 200 mg/day
Placebo Comparator: Sugar Pill; Matched placebo	Drug: Sugar pill; Matched placebo; Other Names: Placebo

What is the study measuring?

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
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
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

Collaborators and Investigators

• Sponsor: University of California, Los Angeles
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Investigators: Principal Investigator: Daniel Roche, PhD, University of California, Los Angeles

Study record dates

Study Major Dates

• Study Start (Anticipated): January 15, 2018
• Primary Completion (Actual): March 1, 2018
• Study Completion (Actual): March 1, 2018

Study Registration Dates

• First Submitted: July 28, 2017
• First Submitted That Met QC Criteria: August 6, 2017
• First Posted (Actual): August 9, 2017

Study Record Updates

• Last Update Posted (Actual): January 24, 2019
• Last Update Submitted That Met QC Criteria: January 22, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Minocycline
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Pathologic Processes; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Neurocognitive Disorders; Cognition Disorders; Alcohol Drinking; Alcoholism; Inflammation; Cognitive Dysfunction; Anti-Infective Agents; Anti-Bacterial Agents; Minocycline
• Other Study ID Numbers: K01AA026005 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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