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
|First Submitted Date ICMJE||March 11, 2020|
|First Posted Date ICMJE||March 17, 2020|
|Last Update Posted Date||October 21, 2021|
|Actual Study Start Date ICMJE||October 19, 2021|
|Estimated Primary Completion Date||December 2022 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||An Inflammatory Challenge Using Endotoxin|
|Official Title ICMJE||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.|
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):
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 ICMJE||Interventional|
|Study Phase ICMJE||Phase 2|
|Study Design ICMJE||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)
The study team, medical personnel, and participants will be blind to drug condition.Primary Purpose: Diagnostic
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Estimated Study Completion Date ICMJE||December 2022|
|Estimated Primary Completion Date||December 2022 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Exclusionary Criteria for Inflammatory Challenge Visits:
|Ages ICMJE||21 Years to 45 Years (Adult)|
|Accepts Healthy Volunteers ICMJE||Yes|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT04310423|
|Other Study ID Numbers ICMJE||19-001561|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Current Responsible Party||Lara Ray, PhD, University of California, Los Angeles|
|Original Responsible Party||Same as current|
|Current Study Sponsor ICMJE||University of California, Los Angeles|
|Original Study Sponsor ICMJE||Same as current|
|Collaborators ICMJE||Not Provided|
|PRS Account||University of California, Los Angeles|
|Verification Date||October 2021|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP