Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT04310423 |
Other study ID # |
19-001561 |
Secondary ID |
|
Status |
Completed |
Phase |
Phase 2
|
First received |
|
Last updated |
|
Start date |
October 19, 2021 |
Est. completion date |
November 14, 2023 |
Study information
Verified date |
March 2024 |
Source |
University of California, Los Angeles |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial 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.
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.