Clinical Trial: In Vivo Effects of C1-esterase Inhibitor on the Innate Immune Response During Human Endotoxemia

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: In Vivo Effects of C1-esterase Inhibitor on the Innate Immune Response During Human Endotoxemia

Brief 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 Summary:

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 d
Sponsor: Radboud University

Current Primary Outcome:

  • Cytokines and other markers of Inflammation [ Time Frame: 24 hrs after LPS administration ]
  • Neutrophil redistribution and phenotype [ Time Frame: 24 hours after LPS administration ]
  • C1-inhibitor and complement concentration and activity [ Time Frame: 24 hours after LPS administration ]
  • Hemodynamic response [ Time Frame: 24 hours after LPS administration ]
  • Markers of Renal Injury [ Time Frame: 24 hours after LPS administration ]


Original Primary Outcome: Same as current

Current Secondary Outcome:

Original Secondary Outcome:

Information By: Radboud University

Dates:
Date Received: November 4, 2008
Date Started: November 2008
Date Completion:
Last Updated: April 21, 2011
Last Verified: May 2009