In Vivo Effects of C1-esterase Inhibitor on the Innate Immune Response During Human Endotoxemia
Condition: Endotoxemia; Inflammation; Multi Organ Dysfunction Syndrome
MeSH terms: Endotoxemia; Inflammation
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): C1-esterase inhibitor; Endotoxin administration
Intervention type(s): Drug; Drug
Intervention description(s): C1-esterase inhibitor 100 U/kg infusion over 30 minutes.; 2 ng/kg E. coli reference endotoxin 11:H 10:K negative intravenously
Intervention MeSH terms: Complement C1s; Complement C1 Inhibitor Protein; Complement C1 Inactivator Proteins
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Basic Science
Keywords: Endotoxin; C1-inhibitor; Inflammation; Sepsis; Multi organ dysfunction syndrome; Complement activation