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An Inflammatory Challenge Using Endotoxin

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ClinicalTrials.gov Identifier: NCT04310423
Recruitment Status : Recruiting
First Posted : March 17, 2020
Last Update Posted : October 21, 2021
Information provided by (Responsible Party):
Lara Ray, PhD, University of California, Los Angeles

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.

Condition or disease Intervention/treatment Phase
Alcohol Use Disorder Inflammatory Response Craving Depressed Mood Drug: Placebo Biological: Endotoxin Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 76 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, triple-blind, placebo-controlled, parallel-group study of low dose endotoxin (0.8 ng/kg)
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: The study team, medical personnel, and participants will be blind to drug condition.
Primary Purpose: Diagnostic
Official Title: An Inflammatory Challenge Using Endotoxin
Actual Study Start Date : October 19, 2021
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Placebo Comparator: Placebo
Matched to endotoxin
Drug: Placebo
Matched to endotoxin
Other Name: Saline (0.9%)

Experimental: Endotoxin
Bolus dose of endotoxin (0.8 ng/kg)
Biological: Endotoxin
Bolus dose of 0.8 ng/kg
Other Name: Escherichia coli

Primary Outcome Measures :
  1. Cue-induced craving [ Time Frame: The cue-reactivity paradigm is conducted 2 hours post-infusion of placebo or low dose endotoxin during the experimental visit. ]
    Alcohol Urge Questionnaire score (alcohol minus water) is the primary outcome for the cue-reactivity paradigm. The Alcohol Urge Questionnaire (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. 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 and compared to light drinking controls.

  2. Change in depressed mood [ Time Frame: The POMS will be completed at 5 timepoints during the experimental visit. Specifically, depressed 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. ]
    The Profile of Mood States (POMS) measures dimensions of mood and will be completed electronically. The investigators are interested in whether low dose endotoxin will increase depressed mood as compared to placebo.

Secondary Outcome Measures :
  1. Change in reward responsiveness [ Time Frame: The PRT and 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. ]
    The Probabilistic Reward Task (PRT) measures reward-based behavioral modulation, and the Reward Responsiveness Scale (RRS) measures self-report reward responsiveness. Both measures will be completed electronically. The investigators are interested in whether low dose endotoxin will decrease reward responsiveness as compared to placebo.

  2. Effect on neural alcohol cue-reactivity [ Time Frame: 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. ]
    The fMRI scan will include a cue-reactivity paradigm in which participants will view images of alcoholic beverages, non-alcoholic beverages, negative images, and fixation cross. Participants will be asked to rate their alcohol craving before the scan and after each cue block. The investigators are interested in determining the effects of endotoxin on neural alcohol cue-reactivity.

Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04310423

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Contact: Jessica Jenkins, MS 310-206-6756 jenkinsj@ucla.edu
Contact: Lara Ray, PhD (310) 794-5383 lararay@psych.ucla.edu

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United States, California
UCLA Addictions Laboratory Recruiting
Los Angeles, California, United States, 90095
Contact: Jessica Jenkins, MS    310-206-6756    jenkinsj@ucla.edu   
Principal Investigator: Lara Ray, PhD         
Sub-Investigator: Karen Miotto, MD         
Sub-Investigator: Michael Irwin, MD         
Sponsors and Collaborators
University of California, Los Angeles
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Principal Investigator: Lara Ray, PhD University of California, Los Angeles
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Responsible Party: Lara Ray, PhD, Professor, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT04310423    
Other Study ID Numbers: 19-001561
First Posted: March 17, 2020    Key Record Dates
Last Update Posted: October 21, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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.: No
Additional relevant MeSH terms:
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Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders