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Effects of Iron Loading and Iron Chelation Therapy on Innate Immunity During Human Endotoxemia

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01349699
First Posted: May 6, 2011
Last Update Posted: November 17, 2015
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
Peter Pickkers, Radboud University
  Purpose
Iron affects immunity. However, the exact effect of iron on the innate immune response is not known. Animal data suggest that iron administration induced oxidative stress which enhances the innate immune response, whereas iron chelation has the opposite effect. The investigators tested the hypothesis that administration of iron sucrose 1.25 mg/kg augments the innate immune response, and iron chelation by deferasirox 30 mg/kg attenuates the innate immune response during human experimental endotoxemia.

Condition Intervention
Systemic Inflammatory Process Anemia Drug: iron sucrose Drug: Deferasirox Drug: endotoxin Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Effects of Iron Loading and Iron Chelation Therapy on Innate Immunity During Human Endotoxemia

Resource links provided by NLM:


Further study details as provided by Peter Pickkers, Radboud University:

Primary Outcome Measures:
  • TNF-alfa [ Time Frame: Level of TNF-alfa 90 minutes after endotoxin administration ]
    Level of TNF-alfa 90 minutes after endotoxin administration


Secondary Outcome Measures:
  • Cytokines [ Time Frame: 24 hrs after the administration of endotoxin ]
    Levels of TNF-alfa, IL-6, IL-10 IL-1RA, ICAM and VCAM.

  • Oxidative stress [ Time Frame: 24 hrs after the administration of iron / iron chelator / placebo ]

    Several parameters of oxidative stress are measured:

    TBARS,carbonyls,oxidative radical production of neutrophils, ferric reducing ability of plasma.


  • Hemodynamic response [ Time Frame: 24 hours after the administration of endotoxin ]
    Hemodynamic sequelae of endotoxin administration are monitored (heart rate, blood pressure) and the response of fore arm vessels to the infusion of vasoactive medication (norepinephrine, acetycholine, and nitroglycerine) is measured.


Enrollment: 30
Study Start Date: February 2010
Study Completion Date: September 2010
Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Iron loading
Subjects will receive 1.25 mg/kg iron sucrose intravenously 1 hour before endoxin administration 2ng/kg.
Drug: iron sucrose
1.25 mg/kg iron sucrose is administered intravenously 1 hr before endotoxin administration
Other Name: Venofer
Drug: endotoxin
at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously
Other Name: LPS
Active Comparator: Iron chelation
Subjects will receive 30mg/kg deferasirox orally 2 hours before endotoxin administration 2ng/kg.
Drug: Deferasirox
30 mg/kg deferasirox is administered orally 2 hrs before endotoxin administration.
Other Name: Exjade
Drug: endotoxin
at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously
Other Name: LPS
Placebo Comparator: Placebo
Subjects will receive placebo instead of iron chelation or iron loading before endotoxin administration
Drug: endotoxin
at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously
Other Name: LPS
Drug: Placebo

At t=-2 hrs starch is dissolved in water to serve as a placebo for exjade. It is prepared and administered orally by a research nurse that is unblinded to the protocol.

At t=-1 hrs 0.9% NaCl is administered intravenously serving as a placebo for iron sucrose. The infused volume is identical, and the syringes en tubes are blinded by aluminum foil. The administration is carried out by a research nurse that is unblinded to the protocol.


Detailed Description:

Systemic inflammation is accompanied by profound changes in iron distribution, mainly under the influence of hepcidin, leading to sequestration of iron in macrophages of the reticuloendothelial system, and ultimately anemia of inflammation. This redistribution of iron may represent an effective defense mechanism against a variety of pathogens, that need iron for replication and growth. The fact that iron withholding strategy is such a highly conserved part of the innate immune response illustrates that iron homeostasis and immunity are closely related. Concordantly, several studies in animal models have revealed immune modulatory effects of both iron and iron chelation: Iron sucrose has been shown to potentiate the inflammatory response and associated mortality, while iron chelation appears to attenuate inflammation and improve outcome in murine models of inflammation and sepsis. The immune modulatory effects of iron supplements and chelators are mainly attributed to their ability to potentiate or reduce the formation of reactive oxygen species (ROS). A subfraction of non-transferrin bound catalytically active iron, labile plasma iron, is thought to be responsible as this free iron is able to easily donate or accept electrons, thereby fueling redox reactions. Oxidative stress is associated with propagation of the immune response, endothelial dysfunction, and contributes to the organ damage that occurs during systemic inflammation. In accordance, anti-oxidants exert anti-inflammatory effects. As such, iron chelation has been suggested to be a valuable adjuvant therapy during infection for two distinct reasons: inhibition of bacterial growth and protection of organs against inflammation induced oxidative stress.

Effects of iron status on the immune response has up till now mainly been investigated in in vitro and in animal models, often using supra-therapeutic dosages of iron donors or iron chelators. Data on the effect of iron loading and iron chelation during systemic inflammation in humans are lacking. The objectives of the present study were to investigate the acute effect of therapeutic dosages of iron loading and iron chelation therapy on iron homeostasis, oxidative stress, the innate immune response, and subclinical organ injury during systemic inflammation induced by experimental endotoxemia in humans in vivo.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • male
  • healthy
  • between 18 and 35 years of age

Exclusion Criteria:

  • smoking
  • use of prescription drugs
  • febrile illness < 2 weeks before the study date
  • abnormalities found at screening
  • participation in another trial in the preceding 6 months
  • iron disorders in the family
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01349699


Sponsors and Collaborators
Radboud University
ZonMw: The Netherlands Organisation for Health Research and Development
Investigators
Principal Investigator: Peter Pickkers, MD, PhD Radboud University
  More Information

Responsible Party: Peter Pickkers, MD. PhD, Radboud University
ClinicalTrials.gov Identifier: NCT01349699     History of Changes
Other Study ID Numbers: 2009/189
First Submitted: May 5, 2011
First Posted: May 6, 2011
Last Update Posted: November 17, 2015
Last Verified: November 2015

Keywords provided by Peter Pickkers, Radboud University:
endotoxemia
inflammation
iron
iron chelation
cytokines

Additional relevant MeSH terms:
Endotoxemia
Bacteremia
Sepsis
Infection
Toxemia
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Iron
Deferasirox
Ferric oxide, saccharated
Ferric Compounds
Trace Elements
Micronutrients
Growth Substances
Physiological Effects of Drugs
Iron Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Hematinics