An Inflammatory Challenge Using Endotoxin

• Status: Recruiting
• Trial end date: 2022-12-01
• Target enrollment: 0
• Participant gender: All

Summary

The study design consists of a randomized, double-blind, placebo-controlled trial of low dose endotoxin. The low dose endotoxin challenge induces a transient systemic inflammatory response with normalization of cytokine levels within hours. This "phasic" inflammation is distinct from chronic ("tonic") levels of inflammation that may be present with AUD. A total of 38 non-treatment seeking heavy drinking men and women and 38 light drinking healthy controls will participate in the study. Recruitment will be monitored to ensure the two groups are matched by gender. Eligible participants will be randomly assigned, stratified by gender and BDI-II severity, to receive a single I.V. infusion of either low dose endotoxin (0.8 ng/kg of body weight) or placebo (same volume of 0.9% saline solution) at the UCLA Outpatient Clinical and Translational Research Center (CTRC). All participants will complete an alcohol cue-exposure paradigm and reward responsiveness assessment 2 hours post infusion, which is the time of expected peak cytokine response. All participants will also complete an fMRI alcohol cue-reactivity paradigm at 3 hours post infusion. Plasma levels of proinflammatory 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 four hours post infusion.

• Phase: Phase 2
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: University of California, Los Angeles

Criteria

Inclusion Criteria:

1. Be between the ages of 21 and 45

2. Be non-treatment seeking for AUD

3. Have had at least one alcoholic beverage in the last 30 days

4. FOR HEAVY DRINKERS: Alcohol Use Disorder Identification Test (AUDIT) score between 8 - 15; FOR LIGHT DRINKERS: AUDIT score < 4

5. FOR HEAVY DRINKERS: Report drinking at binge levels at least 1 time in the past month (5+ drinks/day for men, 4+ drinks/day for women); FOR LIGHT DRINKERS: report no occasions of binge drinking in the past month

Exclusion Criteria:

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 ≥ 8 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; and 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

9. 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)

10. Have clinically significant abnormal EKG

11. 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"

12. Have any other circumstances that, in the opinion of the investigators, compromises participant safety

13. Have non-removable ferromagnetic objects in body

14. Have claustrophobia

15. Have serious head injury or prolonged period of unconsciousness (>30 minutes)

Exclusionary Criteria for Inflammatory Challenge Visits:

1. BrAC > 0.000 g/dl

2. clinical withdrawal (CIWA-R) score ≥ 8

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