Sickness Behavior Clinical Trial
Official title:
Endotoxin-induced Inflammatory and Behavioral Responses and Predictors of Individual Differences: A Randomized, Double-blind Placebo Controlled Study on Healthy Human Volunteers
The objective of the present study is to specifically assess the effect of lipopolysaccharide
(LPS) administration on the development of behavioral symptoms and the underlying
contribution of inflammatory processes. In particular, the investigators will assess the
development of subjective and objective behavioral symptoms. In addition, the investigators
will determine whether some psychological trait or state can predict and/or modulate the
LPS-induced inflammatory and behavioral responses.
Twenty-five healthy subjects will be included. A placebo-controlled, double-blinded and
cross-over design will be used. Subjects will receive an intravenous injection of endotoxin
at 2 nanogram/kilogram (ng/kg) of body weight and an intravenous injection of sodium chloride
as placebo of endotoxin injection at two different occasions.
Prior to inclusion and randomization, subjects will come at the hospital and will receive a
medical examination. Psychological variables that could affect the behavioral (or immune)
response to LPS will be assessed at that time, using several self-assessment questionnaires.
On the trial days, injection of endotoxin or sodium chloride will be performed and blood
samples will be taken just before the endotoxin or sodium chloride injection and 1, 1.5, 2,
3, 4, 5, 6 and 7.5 hours after the injection. Blood samples will be used to measure several
inflammatory and immune markers. Urine samples will be taken before the endotoxin or sodium
chloride injection and as late as possible after the injection. Subjects will wear T-shirt
all day. Urine and T-shirt samples will be used for behavioral assessment and analysis of
body odor compound.
Self-assessment questionnaires assessing behavioral and psychological variables will be
completed by participants just before the endotoxin or sodium chloride injection, three hours
and 7.5 hours after the injection. A short questionnaire assessing sickness behavior
(SicknessQ) will be repeatedly completed by participants from just before to 7.5 hours after
the endotoxin or sodium chloride injection.
Several behavioral tests will be used, including a motivation task, a test assessing
behavioral response to negative and sickness stimuli. Analysis of gait and motion, as well as
of social interactions, will be performed. Photographs will be taken for the further rating
of the faces.
Study design
Twenty-five subjects will be included in the present study, which will follow a prospective,
placebo-controlled and cross-over design. Participants will be blinded, as well as research
personnel in charge of the participants and the laboratory.
Subjects will be randomly assigned in the cross-over design with two trials, with about four
weeks wash-out between LPS stimulations:
1. Trial 1: endotoxin. Subjects will receive an intravenous injection of endotoxin at 2
ng/kg of body weight.
2. Trial 2: placebo. Subjects will receive an intravenous injection of sodium chloride as
placebo of endotoxin injection.
Ten other healthy volunteers will be recruited in a pilot study prior the beginning of the
main study, in order to test the behavioral tasks that will be used. These subjects will be
recruited among the university staff or among university students. They will perform four
specific behavioral tasks and will complete the questionnaires assessing psychological and
behavioral variables in order to associate outcomes from the behavioral tasks to
psychological and subjective behavioral assessments. No biological samples (blood, urine or
tee-shirt samples) will be taken in subjects recruited in the pilot study.
Treatment
The LPS is provided by LGC Promochem AB, Albanoliden 5, 4tr, 506 30 Borås, Sweden. The USP
(United States Pharmacopeial Convention) Endotoxin (Cat. No. 1235503) does come as a
lyophilized (freeze-dried) powder and each vial contains 10,000 USP Endotoxin Units. Each
vial contains very approximately 1 microgram of Endotoxin and is mixed with 5 milliliter (mL)
of sterile water.
Study procedure
The study will be conducted at Department of Clinical Sciences, Danderyd Hospital.
Prior to inclusion and randomization, subjects will come at the hospital in order to be
subjected to a medical examination, including an electrocardiogram and blood laboratory
analyses. Socio-demographic data and medical history will be assessed at this occasion, as
well as body variables (weight, height, body composition) and physical activity using the
Swedish version of the IPAQ (International Physical Activity Questionnaire). History of major
depression will be assessed using the Mini-International Neuropsychiatric Interview
(M.I.N.I.) for major depression. Psychological variables that could affect the behavioral (or
immune) response to LPS, and which are not believed to change between the screening day and
the trial days, will be also assessed at that time, using several web-based self-assessment
questionnaires. These measures will include the subjects' perception of the body and health
risk (e.g., interoceptive awareness, perceived vulnerability to disease, health anxiety and
disgust reactivity, somatosensory amplification, fear of anxiety-related sensations) and
psychological well-being (e.g., perceived stress, optimism, social support, cognitive
well-being). The overall time for the medical examination will be of 30-45 minutes. The time
to complete questionnaires is estimated to approximately 45 minutes but can be done from
home. The participants will also receive a kit with a T-shirt (with sewn-in cotton pads) and
a scent-free soap. Participants will be asked to wear the T-shirt in the morning (after
washing armpits) on each trial day, and take it off after their arrival. This will allow
collecting pre-treatment (baseline) samples of body odor.
Participants will then be subjected to the two trials performed in a randomized order, with
at least six weeks of wash-out: endotoxin versus placebo.
The participants will be asked to restrain from strenuous exercise and alcohol taking 48
hours before the trial day, to avoid strong spices 24 hours before the trial day, and to take
a light breakfast the morning of the trial day. Participants will arrive on the morning (at
7.30AM). They will turn in their morning T-shirt (see above) and change to a new T-shirt
(with sewn-in cotton pads in the armpit) to wear during all day. The T-shirts will be used
for behavioral assessment and analysis of body odor compound. Shortly after their arrival,
two intravenous catheters will be placed: one for blood sampling at one arm and one at one
hand for the injection of endotoxin or sodium chloride that will be removed after the
injection. An anesthetic cream will be provided to spread on their arm in order to minimize
the pain of venipuncture. Subjects will then rest for at least 30 minutes.
Injection of endotoxin or sodium chloride will be performed when the rest is completed
(around 8.30AM). Blood samples (10 mL in EDTA (Ethylenediaminetetraacetic acid) tubes and 10
mL in sodium citrate tubes) will be taken just before the endotoxin or sodium chloride
injection and 1, 1.5, 2, 3, 4, 5, 6 and 7.5 hours after the injection. In addition, 2.5 mL in
PAXGene™ tubes will be taken before and 2, 4 and 7.5 hours after the injection. Two
additional samples in EDTA tubes (8 mL of blood) will be taken before the injection and 3 and
7.5 hours after the injection. The total quantity of blood taken will be of about 200 mL,
corresponding to a third of the amount given at a blood donation. Blood samples will be used
to measure concentrations of pro- and anti-inflammatory cytokines and other inflammatory
markers (e.g., C-Reactive protein - CRP) using Enzyme-Linked Immunosorbent Assay (ELISA),
immune cell subpopulations and concentrations of microparticles using flow cytometry, genetic
markers using Cap analysis gene expression (CAGE) analyses and white blood cell count and
differential.
Urine samples will be taken before the endotoxin or sodium chloride injection (i.e., before
the catheters are placed) and as late as possible after the injection (classically around
four hours after the injection).
Participants will be monitored with continuous electrocardiogram. Oxygen saturation (SO2),
blood pressure and body temperature will be monitored every 30 minutes. Nitrogen dioxide
(NO2) will be monitored continuously, methemoglobin checked at the same time than each blood
sample.
Self-assessment questionnaires assessing behavioral and psychological variables will be
completed by participants just before the endotoxin or sodium chloride injection (during the
rest period), three hours and 7.5 hours after the injection. A short questionnaire assessing
sickness behavior (SicknessQ) will be repeatedly completed by participants from just before
to 7.5 hours after the endotoxin or sodium chloride injection. Subjects will be filmed when
in bed and will wear a sociometric badge, in order to analyze participants' behavioral
response to a standardized situation of social interaction.
Photographs will be taken before (i.e., before the catheters are placed), two hours after and
7.5 hours after the injection, for the further rating of the faces (e.g., health,
attractiveness, tiredness). In parallel, skin color will be measured at the same time than
blood samples (except T1.5) in order to assess a potential mediating effect of faces' health
ratings. Analysis of subjects' gait and motion will be performed two and half hours after the
injection. Short computerized cognitive tests will be performed after these tests, just
before three hours after the injection. Subjects will perform a motivation task after
completing the questionnaires three hours after the injection. In addition, two tests
assessing behavior in response to positive/negative and healthy/sickness stimuli (an
approach-avoidance behavior test and a regulation of emotion test) will be executed three
hours and half after the injection.
Participants will be allowed to take a light meal (snack and juice drink) around lunch time
(12.30) and will hand in their T-shirt just before five and half hours after the injection.
The last blood samples will be taken 7.5 hours after the injection and participants will be
discharged.
Monitoring of the experiment will be done by a medical doctor, supervised by a specialist in
anesthesia and intensive care.
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