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

Anemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01349699
• Other study ID #: 2009/189
• Status: Completed
• Phase: N/A
• First received: May 5, 2011
• Last updated: November 16, 2015
• Start date: February 2010
• Est. completion date: September 2010

Study information

• Verified date: November 2015
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: September 2010
• Est. primary completion date: May 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 35 Years

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Anemia
• Endotoxemia
• Systemic Inflammatory Process

Intervention

Drug:
• iron sucrose
1.25 mg/kg iron sucrose is administered intravenously 1 hr before endotoxin administration
• Deferasirox
30 mg/kg deferasirox is administered orally 2 hrs before endotoxin administration.
• endotoxin
at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously
• 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.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Radboud University	ZonMw: The Netherlands Organisation for Health Research and Development

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	TNF-alfa	Level of TNF-alfa 90 minutes after endotoxin administration	Level of TNF-alfa 90 minutes after endotoxin administration	No
Secondary	Cytokines	Levels of TNF-alfa, IL-6, IL-10 IL-1RA, ICAM and VCAM.	24 hrs after the administration of endotoxin	No
Secondary	Oxidative stress	Several parameters of oxidative stress are measured: TBARS,carbonyls,oxidative radical production of neutrophils, ferric reducing ability of plasma.	24 hrs after the administration of iron / iron chelator / placebo	No
Secondary	Hemodynamic response	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.	24 hours after the administration of endotoxin	Yes