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

November 16, 2015 updated by: Peter Pickkers, Radboud University Medical Center
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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
30

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 35 years (Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Male

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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 Names:
  • Venofer
Drug: endotoxin
at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously
Other Names:
  • LPS
Active Comparator: Iron chelation
Subjects will receive 30mg/kg deferasirox orally 2 hours before endotoxin administration 2ng/kg.
Drug: endotoxin
at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously
Other Names:
  • LPS
Drug: Deferasirox
30 mg/kg deferasirox is administered orally 2 hrs before endotoxin administration.
Other Names:
  • Exjade
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 Names:
  • 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.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
TNF-alfa
Time Frame: Level of TNF-alfa 90 minutes after endotoxin administration
Level of TNF-alfa 90 minutes after endotoxin administration
Level of TNF-alfa 90 minutes after endotoxin administration

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Cytokines
Time Frame: 24 hrs after the administration of endotoxin
Levels of TNF-alfa, IL-6, IL-10 IL-1RA, ICAM and VCAM.
24 hrs after the administration of endotoxin
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.
24 hrs after the administration of iron / iron chelator / placebo
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.
24 hours after the administration of endotoxin

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Radboud University Medical Center

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
ZonMw: The Netherlands Organisation for Health Research and Development

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Peter Pickkers, MD, PhD, Radboud University Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
February 1, 2010

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
May 1, 2010

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 1, 2010

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 5, 2011

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 5, 2011

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 6, 2011

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
November 17, 2015

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 16, 2015

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
November 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2009/189

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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