In Vivo Effects of C1-esterase Inhibitor on the Innate Immune Response During Human Endotoxemia (VECTOR)

This study has been completed.
Sponsor:
Information provided by:
Radboud University
ClinicalTrials.gov Identifier:
NCT00785018
First received: November 4, 2008
Last updated: April 21, 2011
Last verified: May 2009
  Purpose

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.


Condition Intervention
Endotoxemia
Inflammation
Multi Organ Dysfunction Syndrome
Drug: C1-esterase inhibitor
Drug: Endotoxin administration

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Basic Science
Official Title: In Vivo Effects of C1-esterase Inhibitor on the Innate Immune Response During Human Endotoxemia

Resource links provided by NLM:


Further study details as provided by Radboud University:

Primary Outcome Measures:
  • Cytokines and other markers of Inflammation [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
  • Neutrophil redistribution and phenotype [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
  • C1-inhibitor and complement concentration and activity [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
  • Hemodynamic response [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
  • Markers of Renal Injury [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]

Enrollment: 20
Study Start Date: November 2008
Study Completion Date: August 2009
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: C1-esterase inhibitor
Endotoxin 2ng/kg followed by C1- esterase inhibitor 100 U/kg infusion
Drug: C1-esterase inhibitor
C1-esterase inhibitor 100 U/kg infusion over 30 minutes.
Drug: Endotoxin administration
2 ng/kg E. coli reference endotoxin 11:H 10:K negative intravenously
Placebo Comparator: Placebo
Endotoxin 2ng/kg followed by saline 0.9%(placebo) infusion
Drug: Endotoxin administration
2 ng/kg E. coli reference endotoxin 11:H 10:K negative intravenously

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.

  Eligibility

Ages Eligible for Study:   18 Years to 35 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy male volunteers (18-35 years old)

Exclusion Criteria:

  • Relevant medical history
  • Drug-, nicotine-, alcohol abuses
  • Tendency towards fainting
  • Hyper- or hypotension
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00785018

Locations
Netherlands
Radboud University Nijmegen Medical Centre
Nijmegen, Netherlands, 6500HB
Sponsors and Collaborators
Radboud University
Investigators
Principal Investigator: Peter Pickkers, MD, PhD Radboud University Nijmegen Medical Centre, The Netherlands
  More Information

No publications provided

Responsible Party: P. Pickkers, MD, PhD, Radboud University Nijmegen Medical Centre
ClinicalTrials.gov Identifier: NCT00785018     History of Changes
Other Study ID Numbers: VECTOR study 2008/197
Study First Received: November 4, 2008
Last Updated: April 21, 2011
Health Authority: Netherlands: Medical Ethics Review Committee (METC)

Keywords provided by Radboud University:
Endotoxin
C1-inhibitor
Inflammation
Sepsis
Multi organ dysfunction syndrome
Complement activation

Additional relevant MeSH terms:
Inflammation
Syndrome
Endotoxemia
Pathologic Processes
Disease
Bacteremia
Sepsis
Infection
Toxemia
Systemic Inflammatory Response Syndrome
Complement C1s
Complement C1 Inactivator Proteins
Complement C1 Inhibitor Protein
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Complement Inactivating Agents
Immunosuppressive Agents

ClinicalTrials.gov processed this record on September 18, 2014