- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04310423
An Inflammatory Challenge Using Endotoxin
Study Overview
Status
Intervention / Treatment
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 SAE at least possibly related to endotoxin administration
- >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
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Lara Ray, PhD
- Phone Number: (310) 794-5383
- Email: lararay@psych.ucla.edu
Study Contact Backup
- Name: Jessica Jenkins, MS
- Phone Number: 310-206-6756
- Email: jenkinsj@ucla.edu
Study Locations
-
-
California
-
Los Angeles, California, United States, 90095
- UCLA Addictions Laboratory
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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
- Complete abstinence from sexual intercourse
- Hormonal vaginal contraceptive ring
- 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)
- Have clinically significant abnormal EKG
- 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"
- Have any other circumstances that, in the opinion of the investigators, compromises participant safety
- Have non-removable ferromagnetic objects in body
- Have claustrophobia
- Have serious head injury or prolonged period of unconsciousness (>30 minutes)
Exclusionary Criteria for Inflammatory Challenge Visits:
- BrAC > 0.000 g/dl
- clinical withdrawal (CIWA-R) score ≥ 8
- blood pressure ≤ 90/60 or ≥ 160/120
- resting pulse ≤ 50 beats/minute or > 100 beats/minute
- temperature ≥ 99.5°F
- recent (past 2 weeks) acute illness or vaccination
- score of 10+ on Physical Sickness Symptoms Assessment
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Diagnostic
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: Placebo
Matched to endotoxin
|
Matched to endotoxin
Other Names:
|
Experimental: Endotoxin
Bolus dose of endotoxin (0.8 ng/kg)
|
Bolus dose of 0.8 ng/kg
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
The cue-reactivity paradigm is conducted 2 hours post-infusion of placebo or low dose endotoxin during the experimental visit.
|
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.
|
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.
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
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.
|
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.
|
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.
|
Collaborators and Investigators
Investigators
- Principal Investigator: Lara Ray, PhD, University of California, Los Angeles
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 19-001561
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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