To assess the relationship between administration of low doses of LPS (0.5, 1 and 2 ng/kg bodyweight) and the inflammatory response (cytokine levels and hs-CRP) in healthy male volunteers;To assess the duration of tolerance/paralysis of the immune…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
-Relationship LPS dose - inflammatory response:
Hs-CRP, cytokine panel (TNF-alpha among others, t.b.d.).
-Relationship with other systemic responses:
Coagulation: aPTT, PT.
-Tolerance/paralysis of the immune system after in vivo LPS administration:
TNF-alpha release after ex vivo whole blood LPS challenge.
-Renal damage:
KIM-1, NAG, alpha-GST, beta 2 microglobulin, creatinine.
Secondary outcome
Not applicable
Background summary
Human models of systemic inflammation have been developed with the purpose to
explore the molecular mechanisms and physiological significance of the systemic
inflammatory response encountered in acute as well as chronic inflammatory
disease, such as sepsis, trauma, type 2 diabetes, atherosclerosis, and
Alzheimer*s disease, in a controlled, standardized experimental setting. A
better understanding of the underlying molecular and pathophysiological
mechanisms in acute as well as in chronic inflammation, could lead to optimized
prevention and treatment of these disorders, associated with morbidity and
mortality. In addition, human models of systemic inflammation can be applied in
clinical pharmacology studies to assess the effects of specific interventions
(medicinal or non-medicinal) on the inflammatory response in non-diseased
populations.
Study objective
To assess the relationship between administration of low doses of LPS (0.5, 1
and 2 ng/kg bodyweight) and the inflammatory response (cytokine levels and
hs-CRP) in healthy male volunteers;
To assess the duration of tolerance/paralysis of the immune system after in
vivo LPS administration, as determined by ex vivo LPS challenges;
To assess the quantitative and temporal relationship between LPS-induced
inflammation and other systemic responses (e.g. coagulation);
To assess whether in vivo LPS administration results in a (temporary)
alteration of renal function, by measurement of renal damage markers.
Study design
A randomized, double-blind, placebo-controlled study of ascending single low
doses of LPS administered intravenously to healthy male volunteers.
Study burden and risks
Intravenous administration of LPS can lead to influenza-like symptoms (e.g.
chills, headache, eye sensitivity to light, nausea, myalgia and arthralgia),
increase in core temperature and pulse rate, and decline in mean arterial
pressure. Most symptoms are dose-related and resolve within 2-6 hours. As with
any study involving administration of exogenous substance, rare side effects
cannot be excluded beforehand. Reports of a decrease in cardiac contractility
have been made following administration of 4 ng/kg bodyweight
Zernikedreef 10
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Zernikedreef 10
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Listed location countries
Age
Inclusion criteria
-Healthy male volunteers aged 18 to 40 years, inclusive, on study day 1;
-Body Mass Index (BMI) in the range of 18 to 25 kg/m2;
-No history of alcohol or elicit drug abuse;
-No history of trauma and/or surgery to spleen;
-Free from any clinically relevant febrile illness 30 days preceding study day 1;
-No use of any prescription drugs, aspirin or other non-steroid anti-inflammatory drugs, either topical or systemic;
Exclusion criteria
-Previous participation in a LPS challenge trial or prior exposure to endotoxin in an experimental setting within 4 weeks of the anticipate exposure;
-Recent antibiotic use, operation or intervention by surgeon/dentist;
-Any active inflammatory or infectious disease (e.g. periodontitis);
-Hypertension (defined as systolic blood pressure RR > 160 mmHg or diastolic blood pressure RR > 90 mmHg, repeatedly measured after 5 minutes in resting supine position);
-Hypotension (defined as systolic blood pressure RR < 100 mmHg or diastolic blood pressure RR < 50 mmHg);
-Clinically significant abnormalities on the 12-lead ECG (QRS complex > 120 ms, PR interval > 200 ms, QTc interval > 430 ms).
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL40751.018.12 |