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

NCT ID: NCT01349699

Last Updated: 2015-11-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-02-28
• Study Completion Date: 2010-09-30

Brief Summary

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.

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.

Conditions

Systemic Inflammatory Process; Anemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

Iron loading

Subjects will receive 1.25 mg/kg iron sucrose intravenously 1 hour before endoxin administration 2ng/kg.

Group Type: ACTIVE_COMPARATOR

iron sucrose

Intervention Type: DRUG

1.25 mg/kg iron sucrose is administered intravenously 1 hr before endotoxin administration

endotoxin

Intervention Type: DRUG

at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously

Iron chelation

Subjects will receive 30mg/kg deferasirox orally 2 hours before endotoxin administration 2ng/kg.

Group Type: ACTIVE_COMPARATOR

Deferasirox

Intervention Type: DRUG

30 mg/kg deferasirox is administered orally 2 hrs before endotoxin administration.

endotoxin

Intervention Type: DRUG

at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously

Placebo

Subjects will receive placebo instead of iron chelation or iron loading before endotoxin administration

Group Type: PLACEBO_COMPARATOR

endotoxin

Intervention Type: DRUG

at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously

Placebo

Intervention Type: DRUG

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.

Interventions

iron sucrose

1.25 mg/kg iron sucrose is administered intravenously 1 hr before endotoxin administration

Intervention Type: DRUG

Deferasirox

30 mg/kg deferasirox is administered orally 2 hrs before endotoxin administration.

Intervention Type: DRUG

endotoxin

at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Venofer; Exjade; LPS

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

ZonMw: The Netherlands Organisation for Health Research and Development

OTHER

Sponsor Role: collaborator

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Peter Pickkers

MD. PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Peter Pickkers, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Radboud University Medical Center

Other Identifiers

2009/189

Identifier Type: -

Identifier Source: org_study_id