An Inflammatory Challenge Using Endotoxin

NCT04310423 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 19-001561
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Alcohol Use Disorder; Inflammatory Response; Craving; Depressed Mood

Outcome Measures

Primary Outcomes (2)

• Cue-induced Craving

  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 in non-treatment-seeking heavy drinkers, relative to placebo.

  The cue-reactivity paradigm is conducted at baseline and at 2 hours post-infusion of placebo or low dose endotoxin during the experimental visit.

• Change in Negative Mood

  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.

  The POMS will be completed at 5 timepoints during the experimental visit. Specifically, negative mood will be assessed at baseline (prior to infusion) and 1 hour, 2 hours, 3 hours, and 4 hours post-infusion of placebo or low dose endotoxin.

Secondary Outcomes (3)

• Change in Reward Responsiveness

  The RRS will be completed at 2 timepoints during the experimental visit. Specifically, reward responsiveness will be assessed at baseline (prior to infusion) and 2 hours post-infusion of placebo or low dose endotoxin.

• Change in Reward Responsiveness

  The PRT will be completed at 2 timepoints during the experimental visit. Specifically, reward responsiveness will be assessed at baseline (prior to infusion) and 2 hours post-infusion of placebo or low dose endotoxin.

• Effect on Neural Alcohol Cue-reactivity

  The fMRI scan will be completed during the experimental visit. Specifically, participants will undergo the neuroimaging scan at 3 hours post-infusion of placebo or low dose endotoxin.

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Matched to endotoxin

Drug: Placebo

Endotoxin

EXPERIMENTAL

Bolus dose of endotoxin (0.8 ng/kg)

Biological: Endotoxin

Interventions

Placebo DRUG

Matched to endotoxin

Also known as: Saline (0.9%)

Placebo

Endotoxin BIOLOGICAL

Bolus dose of 0.8 ng/kg

Also known as: Escherichia coli

Endotoxin

Eligibility Criteria

• Age: 21 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Be between the ages of 21 and 45
• Be non-treatment seeking for AUD
• Have had at least one alcoholic beverage in the last 30 days
• FOR HEAVY DRINKERS: Alcohol Use Disorder Identification Test (AUDIT) score between 8 - 15; FOR LIGHT DRINKERS: AUDIT score \< 4
• 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

You may not qualify if:

• Have a current (last 12 months) DSM-5 diagnosis of substance use disorder for any psychoactive substances other than alcohol and nicotine
• Have a lifetime DSM-5 diagnosis of schizophrenia, bipolar disorder, or any psychotic disorder
• Have current moderate to severe depression as indicated by a score of ≥ 21 on the Beck Depression Inventory - II (BDI-II)
• Have current suicidal ideation or lifetime history of suicide attempt as reported on the Columbia-Suicide Severity Rating Scale (C-SSRS)
• Have a positive urine screen for drugs other than cannabis;
• Have clinically significant alcohol withdrawal symptoms as indicated by a score ≥ 8 on the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-R)
• Have an intense fear of needles or have had any adverse reactions to needle puncture
• 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

Sponsors & Collaborators

• University of California, Los Angeles: lead

Study Sites (1)

UCLA Addictions Laboratory

Los Angeles, California, 90095, United States

Location

MeSH Terms

Conditions

Alcoholism; Consciousness Disorders

Interventions

Sodium Chloride; Endotoxins

Condition Hierarchy (Ancestors)

Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurocognitive Disorders

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Bacterial Toxins; Toxins, Biological; Biological Factors

Limitations and Caveats

Due to COVID-19 pandemic-related research delays in 2020, as well as a FDA clinical hold on Endotoxin product testing and release, the original target of 38 heavy drinking participants and 38 light-drinking controls was not met. The study team was able to randomize a total of 20 heavy drinking participants and leveraged 20 light-drinking matched control participants from sub-investigator Dr. Naomi Eisenberger's previously completed Endotoxin study.

Results Point of Contact

• Title: Dr. Lara Ray
• Organization: University of California, Los Angeles

lararay@psych.ucla.edu

310-794-5383

Study Officials

• Lara Ray, PhD

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: The study team, medical personnel, and participants will be blind to drug condition.
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Randomized, triple-blind, placebo-controlled, parallel-group study of low dose endotoxin (0.8 ng/kg)

Study Record Dates

• First Submitted: March 11, 2020
• First Posted: March 17, 2020
• Study Start: October 19, 2021
• Primary Completion: November 14, 2023
• Study Completion: November 14, 2023
• Last Updated: May 1, 2025
• Results First Posted: May 1, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)