Endotoxin Exposure to Examine the Role of Inflammation in Alcohol Use

Phase 2Not Yet RecruitingNCT07452146

University of California, Los Angeles64 enrolled

Overview

The study design consists of a randomized, double-blind, placebo-controlled study of low dose endotoxin. Individuals with current AUD (n=32) and matched controls without AUD (n=32) will be randomly assigned to receive a single intravenous (I.V.) infusion of either low dose endotoxin (0.8 ng/kg of body weight) or placebo (same volume of 0.9% saline solution) to determine the acute and protracted role of inflammation in alcohol use.

Participants will be recruited from the community through campaigns in radio, buses, social media, and print publications. After a telephone interview, eligible individuals will complete in-person screening to assess for presence of DSM-5 alcohol use disorder and additional inclusion/exclusion criteria. Eligible participants will complete a physical exam to assess medical safety, including EKG and laboratory tests. Participants who pass the physical exam will then be randomized to an experimental condition (i.e., endotoxin vs. placebo). Randomization will be stratified by sex (male versus female) and AUD (moderate versus severe). Participants will complete an alcohol cue-exposure paradigm in the lab 2 hours post infusion, the time of peak cytokine response. Plasma levels of inflammatory cytokines (i.e., interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α)), mood, and alcohol craving, will be assessed at baseline and then hourly for six hours post infusion. Following the infusion, all participants will complete a 7-day follow-up phase consisting of daily diary surveys of mood, alcohol craving, and alcohol consumption. The adverse events will be managed by study nurse practitioners during the endotoxin challenge.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

DIAGNOSTIC

Masking

TRIPLE

Enrollment

Conditions

Alcohol Use Disorder Inflammatory Response Craving

Interventions

EndotoxinDRUG

Bolus dose of 0.8 ng/kg

Placebo salineOTHER

Matched to endotoxin

Eligibility

Sex: ALLMin age: 21 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria (AUD Group): 1. Be between the ages of 21 and 65 2. Meet current (i.e., past month) DSM-5 diagnostic criteria for moderate to severe AUD 3. Be non-treatment seeking for AUD 4. Report drinking at least 28 drinks per week if male (21 drinks per week if female) in the 28 days prior to consent. 5. Must agree to one of the following methods of birth control (if female), unless she or partner are surgically sterile: * Oral contraceptives * Contraceptive sponge * Patch * Double barrier * Intrauterine contraceptive device * Etonogestrel implant * Medroxyprogesterone acetate contraceptive injection * Complete abstinence from sexual intercourse * Hormonal vaginal contraceptive ring Inclusion Criteria (Control Group): (1) The control group will be age-, sex-, smoking status-, and BMI-matched healthy individuals who drink at or below moderate drinking levels (≤1 drink/day for females, ≤2 drinks/day for males) and have no lifetime history of AUD. Exclusion Criteria (All Groups): 1. Have a current (last 12 months) DSM-5 diagnosis of substance use disorder for any psychoactive substances other than alcohol and nicotine 2. Have a lifetime DSM-5 diagnosis of schizophrenia, bipolar disorder, or any psychotic disorder 3. Have current moderate to severe depression as indicated by a score of ≥ 21 on the Beck Depression Inventory - II (BDI-II) 4. Have current suicidal ideation or lifetime history of suicide attempt as reported on the Columbia-Suicide Severity Rating Scale (C-SSRS) 5. Have a positive urine screen for drugs other than cannabis; 6. Have clinically significant alcohol withdrawal symptoms as indicated by a score ≥ 10 on the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-R) 7. Have an intense fear of needles or have had any adverse reactions to needle puncture 8. Be pregnant, nursing, or planning to become pregnant while taking part in the study 9. Have a body mass index (BMI) greater than 30 10. Have a medical condition that may interfere with safe study participation (e.g., unstable cardiac, renal, or liver disease, uncontrolled hypertension or diabetes, autoimmune or inflammatory disease) 11. Have clinically significant abnormal EKG 12. Have \> Grade 2 laboratory abnormalities, based on FDA Guidance Document "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials" 13. Have any other circumstances that, in the opinion of the investigators, compromises participant safety 14. To participate in the inflammatory challenge, participants must not show any of the following upon arrival to the inflammatory challenge study visit: 1. BrAC \> 0.000 g/dl 2. clinical withdrawal (CIWA-R) score ≥ 10 3. blood pressure ≤ 90/60 or ≥ 160/120 4. resting pulse ≤ 50 beats/minute or \> 100 beats/minute 5. temperature ≥ 99.5°F 6. recent (past 2 weeks) acute illness or vaccination 7. score of 10+ on Physical Sickness Symptoms Assessment

Outcomes

Primary Outcomes

Acute Phase: To determine the effect of acute inflammation on mood in AUD versus controls.

The Profile of Mood States (POMS) is a self-report questionnaire that measures dimensions of mood. Four items from the POMS were summed to calculate the negative mood subscale. The items included "discouraged," downhearted," "uneasy," and "anxious." Participants rated the extent that they felt items "right now" on a scale from 0-4, with higher scores indicating more endorsement of the items. Items were summed to calculate negative mood subscale with the score ranging from 0-16, with higher scores indicating higher negative mood. The investigators were interested in whether low dose endotoxin would increase negative mood as compared to placebo in AUD vs control.

Time frame: Mood will be collected at baseline (prior to infusion) and hourly for 6 hours post-infusion.

Acute Phase: To determine the effect of acute inflammation on cue-reactivity in AUD versus controls.

Alcohol Urge Questionnaire (AUQ) score is the primary outcome for the cue-reactivity paradigm. The AUQ is comprised of eight items rated on a 7-point Likert scale with items related to the subjective experience of alcohol craving. The minimum value is 8 and the maximum value is 56 with a higher score indicating greater subjective alcohol craving. Phasic craving for alcohol following alcohol cue exposure was assessed using the first and last items from the AUQ during an alcohol cue reactivity paradigm at baseline and at time of expected peak cytokine response (T2). This subscale of 2 items about desire to drink rated on a 7-point Likert scale provided a minimum possible value of 2 and a maximum value of 14, with higher values indicating a higher craving to drink alcohol. The investigators are primarily interested in whether low dose endotoxin increases cue-induced craving for alcohol relative to placebo in AUD vs control.

Time frame: The cue-reactivity paradigm is conducted at baseline and at 2 hours post-infusion during the experimental visit.

Acute Phase: To determine the effect of acute inflammation on biomarkers in AUD versus controls.

Plasma levels of inflammatory cytokines Interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α (TNF- α) will be collected at baseline and hourly timepoints post-infusion for 6 hours. The investigators are primarily interested in whether low dose endotoxin increases peripheral cytokines relative to placebo in AUD vs control.

Central Contacts

Lara Ray, PhD

CONTACT

(310) 794-5383 lararay@psych.ucla.edu

Jessica Jenkins, MS

CONTACT

310-206-6756 jenkinsj@ucla.edu

Data from ClinicalTrials.gov

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