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Endotoxin-induced Inflammatory and Behavioral Responses and Predictors of Individual Differences

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ClinicalTrials.gov Identifier: NCT02529592
Recruitment Status : Completed
First Posted : August 20, 2015
Last Update Posted : August 20, 2015
Sponsor:
Collaborator:
Danderyd Hospital
Information provided by (Responsible Party):
Mats Lekander, Karolinska Institutet

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Sickness Behavior Biological: Endotoxin Biological: Placebo Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Endotoxin-induced Inflammatory and Behavioral Responses and Predictors of Individual Differences: A Randomized, Double-blind Placebo Controlled Study on Healthy Human Volunteers
Study Start Date : February 2015
Actual Primary Completion Date : April 2015
Actual Study Completion Date : April 2015

Arm Intervention/treatment
Experimental: Endotoxin
Endotoxin at 2ng/kg of body weight administered intravenously
Biological: Endotoxin
Other Names:
  • LPS
  • lipopolysaccharide

Placebo Comparator: Placebo
Placebo administered intravenously
Biological: Placebo
Other Names:
  • NaCl 0.9%
  • saline




Primary Outcome Measures :
  1. Change from baseline in sickness behavior as measured using the sicknessQ [ Time Frame: Before the administration and 1.5, 3, 5 and 7 hours after the administration ]
    Change in sickness behavior evaluated using the self-assessment questionnaire sicknessQ

  2. Change from baseline in anxiety state as measured using the STAI-State [ Time Frame: Before the administration and 3 and 7 hours after the administration ]
    Change in symptoms of anxiety evaluated using the self-assessment questionnaire State part of the State-Trait Anxiety Inventory (STAI)

  3. Change from baseline in psychological state as measured using the SCAS [ Time Frame: Before the administration and 3 and 7 hours after the administration ]
    Change in mood alterations evaluated using the self-assessment questionnaire Swedish Core Affect Scales (SCAS)

  4. Change from baseline in pain as measured using the short McGill questionnaire [ Time Frame: Before the administration and 3 and 7 hours after the administration ]
    Change in symptoms of pain evaluated using the self-assessment questionnaire Mc Gill questionnaire - short version

  5. Change from baseline in sleepiness as measured using the KSS [ Time Frame: Before the administration and 3 and 7 hours after the administration ]
    Change in sleepiness evaluated using the Karolinska Sleepiness Scale (KSS)

  6. Change from baseline in systemic IL-6 concentrations [ Time Frame: Before the administration and 1, 1.5, 2, 3, 4, 5, 7 hours after the administration ]
    Change in plasma concentration of the pro-inflammatory cytokine interleukin-6 (IL-6)

  7. Change from baseline in systemic TNF-a concentrations [ Time Frame: Before the administration and 1, 1.5, 2, 3, 4, 5, 7 hours after the administration ]
    Change in plasma concentration of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-a)

  8. Change from baseline in systemic IL-8 concentrations [ Time Frame: Before the administration and 1, 1.5, 2, 3, 4, 5, 7 hours after the administration ]
    Change in plasma concentration of the pro-inflammatory cytokine interleukin-8 (IL-8)

  9. Change from baseline in systemic HMGB1 concentrations [ Time Frame: Before the administration and 1, 1.5, 2, 3, 4, 5, 7 hours after the administration ]
    Change in plasma concentration of the pro-inflammatory cytokine high-mobility group box 1 (HMGB1)

  10. Change from baseline in systemic IL-1B concentrations [ Time Frame: Before the administration and 1, 1.5, 2, 3, 4, 5, 7 hours after the administration ]
    Change in plasma concentration of the pro-inflammatory cytokine interleukin-1 beta (IL-1B)

  11. Change from baseline in systemic IL-10 concentrations [ Time Frame: Before the administration and 1, 1.5, 2, 3, 4, 5, 7 hours after the administration ]
    Change in plasma concentration of the anti-inflammatory cytokine interleukin-10 (IL-10)

  12. Change from baseline in systemic IL-1ra concentrations [ Time Frame: Before the administration and 1, 1.5, 2, 3, 4, 5, 7 hours after the administration ]
    Change in plasma concentration of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra)

  13. Change from baseline in heart rate [ Time Frame: Before the administration and every half hour up to 7.5 hours after the administration ]
    Change in heart rate assessed using a cardiac monitoring

  14. Change from baseline in systolic blood pressure [ Time Frame: Before the administration and every half hour up to 7.5 hours after the administration ]
    Change in systolic blood pressure assessed using a cardiac monitoring

  15. Change from baseline in diastolic blood pressure [ Time Frame: Before the administration and every half hour up to 7.5 hours after the administration ]
    Change in diastolic blood pressure assessed using a cardiac monitoring

  16. Change from baseline in body temperature [ Time Frame: Before the administration and every half hour up to 7.5 hours after the administration ]
    Change in body temperature measured using an ear thermometer

  17. Change from baseline in headache scores as measured using a numerical scale [ Time Frame: Before the administration and every half hour up to 7.5 hours after the administration ]
    Change in headache scores measured using a numerical scale ranging from 0 (no headache) to 10 (most unbearable headache)

  18. Change from baseline in nausea scores as measured using a numerical scale [ Time Frame: Before the administration and every half hour up to 7.5 hours after the administration ]
    Change in nausea scores measured using a numerical scale ranging from 0 (no nausea) to 10 (most unbearable nausea)

  19. Change from baseline in back pain scores as measured using a numerical scale [ Time Frame: Before the administration and every half hour up to 7.5 hours after the administration ]
    Change in back pain scores measured using a numerical scale ranging from 0 (no back pain) to 10 (most unbearable back pain)


Secondary Outcome Measures :
  1. Change in cell expression of blood microparticles [ Time Frame: Before the administration and 1, 1.5, 2, 3, 4, 5, 7 hours after the administration ]
    Changes in concentrations of total microparticles (defined as particles less than 1μm in size and staining for lactadherin) and platelet-, monocytes- and endothelial-derived microparticles (co-staining of lactadherin and, respectively, cluster of differentiation (CD)42A, CD14 and CD62E).

  2. Modification in genetic markers [ Time Frame: Before the administration and 1, 2, 4, 7 hours after the administration ]
    Modification in genetic markers measured using CAGE analysis from PAXGene blood samples

  3. Change in expression of immune cell markers [ Time Frame: Before the administration and 1, 2, 3, 4, 7 hours after the administration ]
    Change in expression of immune cell subpopulations markers using flow cytometry from frozen whole blood in 10% Dimethylsulfoxid (DMSO)

  4. Change in odor compounds [ Time Frame: Before and after the administration ]
    Change in abundance of volatile odor compounds analyzed using gas chromatography mass spectrometry (GC-MS) from tee-shirt samples and urine samples

  5. Changes in social interaction [ Time Frame: During all day ]
    Modification in social interactions using movies of the study day and sociometric badges

  6. Gait [ Time Frame: 2 hours after the administration ]
    Gait analysis using the Kinect camera

  7. Approach-avoidance behavior [ Time Frame: 5 hours after the administration ]
    Whole-body approach-avoidance behavior to positive/negative stimuli

  8. Face expression of sickness [ Time Frame: Before the administration and 2 and 7.5 hours after ]
    Face expression of sickness measured using photos of the subject with a neutral face expression

  9. Change in skin color [ Time Frame: Before the administration and 1,2,3,4,5,7 hours after ]
    Change in skin color measurement using a spectrophotometer

  10. Motivation as measured using the Effort Expenditure for Rewards Task (EEfRT) [ Time Frame: 4 hours after the administration ]
    Choices of hard task (vs easy task) in the EEfRT



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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy subjects

Exclusion Criteria:

  • Diagnosed physiological or psychiatric disease
  • Needle anxiety or blood phobia
  • Regular medication (excluding contraceptive pill)
  • Infection in the last two weeks
  • Pregnancy or breastfeeding
  • Smoking
  • Excessive alcohol use
  • Body mass index in the range of obesity (>30 kg/m2) or underweight (<18.5 kg/m2)
  • Invisible veins in the antecubital area of the arms
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Mats Lekander, Professor, Karolinska Institutet
ClinicalTrials.gov Identifier: NCT02529592    
Other Study ID Numbers: LPS 2.0 - 2014/1946-31
First Posted: August 20, 2015    Key Record Dates
Last Update Posted: August 20, 2015
Last Verified: August 2015
Keywords provided by Mats Lekander, Karolinska Institutet:
Sickness behavior
Cytokines
Psychoneuroimmunology
Additional relevant MeSH terms:
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Illness Behavior