Inflammation Clinical Trial
Official title:
In Vivo Effects of C1-esterase Inhibitor on the Innate Immune Response During Human Endotoxemia
Excessive inflammation is associated with tissue damage caused by over-activation of the
innate immune system. This can range from mild disease to extreme conditions such as
multiple organ failure (MOF). In marked contrast to adaptive immunity which is very
sensitive to immune modulators such as steroids, the innate immune system cannot be
sufficiently targeted by currently available anti-inflammatory drugs.
We hypothesize that C1-esterase inhibitor can modulate the innate immune response.
In this study, human endotoxemia will be used as a model for inflammation. Subjects will,
additionally to endotoxin, receive C1 esterase inhibitor or placebo. Blood will be sampled
to determine the levels of markers of the innate immune response.
Rationale:
There is an unmet need for novel therapeutic agents focused on the complications caused by
acute and excessive activation of the innate immune response after injury. As this
activation responds poorly to currently used therapy including inhaled steroids novel agents
need to be tested, developed or applied. C1INH comprises a potential important target drug
for antagonism of the excessive activation of the innate immune response during acute
inflammation seen after injury. This might be achieved by inhibiting the redistribution and
homing of cells to inflammatory tissues.
Before going to a clinical trial in injured human subjects we want to perform a pilot study
in healthy volunteers to exploit the "human endotoxemia model". The human endotoxemia model
permits elucidation of key players in this pro-inflammatory response in humans in vivo,
therefore serving as a useful tool to investigate potential novel therapeutic strategies in
a standardized setting. The model bears striking resemblance to LPS models in animals. These
latter studies have shown that C1INH protects from neutrophil mediated disease [1-4].
Together with the finding that C1INH has been shown to be safe in the treatment of humans,
we propose to use this protein in the treatment of neutrophil driven acute inflammation such
as seen after injury.
Objectives:
Primary objective: The primary objective of the study is to determine the effect of C1INH on
systemic activation of the innate immune response induced by LPS challenge. This response
will be objectivised by measurement of enhanced TNF-α levels 90 min after LPS challenge.
Secondary Objective(s): The secondary objective of the study is to determine the effect of
C1INH on redistribution of neutrophils in the human endotoxemia model.
Study design: Double-blind placebo-controlled randomized intervention study in healthy human
volunteers during experimental endotoxemia.
Study population: Non-smoking healthy male volunteers, age 18-35 yrs Intervention: Subjects
will receive C1INH in a dose of 100 U/kg (n=10) or placebo (n=10) 30 min after LPS
administration. Pre-hydration will be performed by infusion of 1.5 L 2.5% glucose/0.45%
saline solution in 1 hour before LPS administration. LPS derived from E coli O:113 will be
injected (2 ng/kg iv., infusion rate 1 minute).
Main study parameters/endpoints: The main study parameter is the concentration of
circulating cytokines after LPS in the absence or presence of C1INH. Secondary study
parameters include the influence of C1INH on the redistribution pattern of neutrophils and
neutrophil phenotypes.
;
Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Basic Science
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