An Inflammatory Challenge Using Endotoxin

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

Tracking Information

• First Submitted Date: March 11, 2020
• First Posted Date: March 17, 2020
• Last Update Posted Date: October 21, 2021
• Actual Study Start Date: October 19, 2021
• Estimated Primary Completion Date: December 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 19, 2020)

• 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.
• 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.

Original Primary Outcome Measures (submitted: March 12, 2020)

• 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 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..
• 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.

Current Secondary Outcome Measures (submitted: May 13, 2021)

• 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.
• 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.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: An Inflammatory Challenge Using Endotoxin
• Official Title: An Inflammatory Challenge Using Endotoxin
• 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.

Detailed Description

RECRUITMENT: Participants will be recruited from the community through online and newspaper advertisements. Campaigns in local buses and print publications (e.g., LA Weekly) will also be implemented. Targeted recruitment will also take place through a lab database of previous study participants who agreed to be contacted for future studies.

TELEPHONE SCREEN: Individuals who call the lab (in response to flyers and advertisements) expressing interest in the study will receive detailed information about the study procedures, and if they remain interested they will complete a telephone screen performed by a trained research assistant for self-reported inclusion and exclusion criteria. Those who appear eligible will be invited to the laboratory for an initial in-person screening session.

INITIAL SCREENING: Prior to conducting any research related procedures, research staff will conduct the informed consent process, which details the procedures to take place during the screening visit. Informed consent will be a three part process. First, participants will be asked to read and provide verbal consent for breathalyzer. If the breathalyzer is above 0.000, the visit will be stopped and the participant will not be compensated. The participant will be given an opportunity to reschedule the visit for another day. If the breathalyzer test is negative, the written informed consent form will be reviewed and signed by the participant and study staff outlining procedures for the initial screening visit. A second written consent form will be reviewed and signed in the presence of the study physician at the medical screening visit if the participant is found eligible to continue to that visit. At the initial screening visit, subjects will be asked to provide a urine sample to test for drugs of abuse and pregnancy (if female), and will complete a series of individual differences measures (described in detail below). This visit should take approximately 2 hours. Following the initial in-person screening, the study coordinator will meet with the PI to determine if the participant is eligible to continue to the medical screening based on study inclusion/exclusion criteria.

MEDICAL SCREENING: Those participants who appear to be eligible after the initial screening visit, will then be scheduled for a second screening visit. This visit will be conducted by the study physician and will start with a breathalyzer test. If the breathalyzer is above 0.000, the visit will be stopped and the participant will not be compensated. The participant will be given an opportunity to reschedule the visit for another day. If the breathalyzer test is negative, the physician will conduct the second written (experimental) consent; medical history interview and physical exam. In addition, a urine drug screen test will be repeated. The participant will then be accompanied by research personnel to the CTRC for blood specimen collection including Comprehensive Metabolic Panel and Complete Blood Count to evaluate overall health; and EKG to screen for medical conditions that could make study participation medically unsafe. The study physician will review each participant's medical history, vital signs, weight, review of systems, and laboratory tests, including liver function tests (LFTs), drug screen, chemistry screen, and urine pregnancy screen to determine if it is medically safe for the participant to take the study medication. Any subject who is excluded from the study will be compensated for their time in the screening session and will be offered referrals for alcohol treatment in the community.

RANDOMIZATION/INFLAMMATORY CHALLENGE: Upon arrival to the CTRC, eligibility for the inflammatory challenge will be reviewed to ensure that none of the exclusion criteria have been met as described above. A nurse, who will be blind to the condition, will insert a catheter with a heparin lock into the non-dominant forearm for drug administration and hourly blood draws. Each participant will be randomly assigned to receive either low-dose endotoxin (0.8 ng/kg of body weight administered) or placebo (same volume of 0.9% saline), which will be administered by the nurse as an intravenous bolus. The endotoxin will be derived from Escherichia coli (E. Coli group O:113: BB-IND 12948 to M.R.I) and will be provided by the National Institutes of Health Clinical Center as a reference endotoxin for studies of experimental inflammation in humans. Participants will complete assessments as outlined below at baseline and every hour for 4 hours post-infusion. One standard meal and one snack will be provided by the CTRC to each participant during the experimental visit. At the end of the experimental period, participants will have the catheter removed and will be discharged with instructions to abstain from consuming alcohol for 24 hours after discharge. A follow-up phone call by the study physician will be conducted the day after the inflammatory challenge and again 1-2 weeks later to assess for any adverse events.

The study physician (Dr. Miotto) will be on-call and will manage any adverse events during the inflammatory challenge. She will consult with Dr. Irwin, Co-I, as needed to manage adverse events. In the event that significant medical problems are encountered, the blind will be broken and appropriate medical treatment will be provided. Individuals who meet the following stopping criteria will discontinue study-related data collection procedures (cytokine assays and cue exposure paradigm):

1. >1 SAE at least possibly related to endotoxin administration
2. >2 Grade 3 (severe) adverse events at least possibly related to endotoxin administration, based on the FDA Guidance Document "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials" ALCOHOL CUE REACTIVITY SESSION (CR): Approximately 2 hours after receiving intravenous endotoxin (or matched placebo), participants will complete the cue-exposure paradigm. Alcohol cue exposure will follow well-established experimental procedures. Sessions will begin with a 3-minute relaxation period. Participants will then hold and smell a glass of water for 3 minutes to control for the effects of simple exposure to any potable liquid. Next, participants will hold and smell a glass of their preferred alcoholic beverage for 3 minutes. Order is not counterbalanced because of carryover effects that are known to occur. Participants (who are smokers) will be allowed a smoke break immediately prior to and immediately after the CR assessment. After every 3 minute period, participants will rate their urge to drink on the Alcohol Urge Questionnaire.

REWARD RESPONSIVENESS: Approximately 2 hours after receiving intravenous endotoxin (or matched placebo), participants will complete the reward responsiveness paradigm, including the Probabilistic Reward Task (PRT) and Reward Responsiveness Scale (RRS). The PRT is a 25-minute task that will be administered at baseline and hour 2. The task assesses behavioral modulation as a function of reward-based reinforcement (i.e. reward seeking) by asking participants to respond to stimuli, eliciting a response bias by introducing an asymmetric reinforcer ratio. The RRS is a self-report questionnaire that measures reward responsiveness by asking subjects to rate their agreement with various statements on a 4-point Likert scale.

NEUROIMAGING CUE-REACTIVITY (fMRI): Approximately 3 hours after receiving intravenous endotoxin (or matched placebo), participants will complete a functional magnetic resonance imaging (fMRI) scan. This scan will include an fMRI visual alcohol cue-reactivity paradigm, which will follow well-established procedures. The alcohol cues task consists of viewing visual alcohol, negative, and neutral cues, presented in six 120-s epochs (total scan duration: 12 minutes), with each epoch consisting of four 24-s blocks (one block of alcohol cues, one block of neutral cues, one block of negative images, and one block of fixation). Alcohol blocks will be specific to beverage type (beer, wine, or liquor), with two blocks of each beverage type. Prior to scanning, participants will rate their craving on a four-point scale and will also provide ratings of their craving immediately following each cue block.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

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

Condition

• Alcohol Use Disorder
• Inflammatory Response
• Craving
• Depressed Mood

Intervention

• Drug: Placebo
  Matched to endotoxin
  Other Name: Saline (0.9%)
• Biological: Endotoxin
  Bolus dose of 0.8 ng/kg
  Other Name: Escherichia coli

Study Arms

• Placebo Comparator: Placebo
  Matched to endotoxin
  Intervention: Drug: Placebo
• Experimental: Endotoxin
  Bolus dose of endotoxin (0.8 ng/kg)
  Intervention: Biological: Endotoxin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 13, 2021): 76
• Original Estimated Enrollment (submitted: March 12, 2020): 40
• Estimated Study Completion Date: December 2022
• Estimated Primary Completion Date: December 2022 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 21 Years to 45 Years (Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Jessica Jenkins, MS; 310-206-6756; jenkinsj@ucla.edu

Contact: Lara Ray, PhD; (310) 794-5383; lararay@psych.ucla.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04310423
• Other Study ID Numbers: 19-001561
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Lara Ray, PhD, University of California, Los Angeles
• Original Responsible Party: Same as current
• Current Study Sponsor: University of California, Los Angeles
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Lara Ray, PhD; University of California, Los Angeles

• PRS Account: University of California, Los Angeles
• Verification Date: October 2021