Systemic Inflammatory ProcessNCT01349699
Effects of Iron Loading and Iron Chelation Therapy on Innate Immunity During Human Endotoxemia
A study testing iron sucrose, Deferasirox and endotoxin in people with Systemic Inflammatory Process and Anemia, run by Radboud University Medical Center.
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. Read more about this study
- Who is it for?
- Ages 18 to 35 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Systemic Inflammatory Process, Anemia
- What is being tested?
- iron sucrose, Deferasirox and endotoxin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 30 participants
- Where
- No sites listed yet
- Study dates
- Feb 2010to Sep 2010
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 35 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- male
- healthy
- between 18 and 35 years of age
Who cannot join
- 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
About this study
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.
Read the 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
- Being tested
- iron sucrose, Deferasirox, endotoxin, Placebo
- Keywords
- endotoxemia, inflammation, iron, iron chelation, cytokines
- Medical subject headings
- Anemia, Endotoxemia, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
iron sucroseDrug
Also called Venofer
1.25 mg/kg iron sucrose is administered intravenously 1 hr before endotoxin administration
DeferasiroxDrug
Also called Exjade
30 mg/kg deferasirox is administered orally 2 hrs before endotoxin administration.
endotoxinDrug
Also called LPS
at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously
PlaceboDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Iron loading | Active comparator | Subjects will receive 1.25 mg/kg iron sucrose intravenously 1 hour before endoxin administration 2ng/kg. Receives: Drug: iron sucrose; Drug: endotoxin |
| Iron chelation | Active comparator | Subjects will receive 30mg/kg deferasirox orally 2 hours before endotoxin administration 2ng/kg. Receives: Drug: Deferasirox; Drug: endotoxin |
| Placebo | Placebo comparator | Subjects will receive placebo instead of iron chelation or iron loading before endotoxin administration Receives: Drug: endotoxin; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
TNF-alfa
Level of TNF-alfa 90 minutes after endotoxin administration
Measured: Level of TNF-alfa 90 minutes after endotoxin administration
Secondary outcomes (3)
Cytokines
Levels of TNF-alfa, IL-6, IL-10 IL-1RA, ICAM and VCAM.
Measured: 24 hrs after the administration of endotoxin
Oxidative stress
Several parameters of oxidative stress are measured:
TBARS,carbonyls,oxidative radical production of neutrophils, ferric reducing ability of plasma.
Measured: 24 hrs after the administration of iron / iron chelator / placebo
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.
Measured: 24 hours after the administration of endotoxin
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 May 2011 (estimated)
- Study startFeb 2010
- Primary completionMay 2010
- Study completionSep 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Systemic Inflammatory ProcessStudies of the same condition, open and under way.
- More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development
- Responsible party
- Principal investigator, Peter Pickkers, Radboud University Medical Center
- Investigators
- Peter Pickkers, MD, PhD, Principal investigator, Radboud University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01349699
- Sponsor's protocol ID
- 2009/189
- Status last verified
- Nov 2015
- First submitted
- 5 May 2011
- Last updated
- 17 Nov 2015
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 17 Nov 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of Iron Loading and Iron Chelation Therapy on Innate Immunity During Human Endotoxemia
- ClinicalTrials.gov ID
- NCT01349699
- Acronym / sponsor ID
- 2009/189
- Conditions
- Systemic Inflammatory Process, Anemia
- Keywords
- endotoxemia, inflammation, iron, iron chelation, cytokines
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development
- Study start
- Feb 2010
- Primary completion
- May 2010 (actual)
- Study completion
- Sep 2010 (actual)
- First posted
- 6 May 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Iron loading | Active comparator | Drug: iron sucrose, Drug: endotoxinSubjects will receive 1.25 mg/kg iron sucrose intravenously 1 hour before endoxin administration 2ng/kg. |
| Iron chelation | Active comparator | Drug: Deferasirox, Drug: endotoxinSubjects will receive 30mg/kg deferasirox orally 2 hours before endotoxin administration 2ng/kg. |
| Placebo | Placebo comparator | Drug: endotoxin, Drug: PlaceboSubjects will receive placebo instead of iron chelation or iron loading before endotoxin administration |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- male
- healthy
- between 18 and 35 years of age
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| iron sucroseAlso: Venofer1.25 mg/kg iron sucrose is administered intravenously 1 hr before endotoxin administration | Drug | Iron loading |
| DeferasiroxAlso: Exjade30 mg/kg deferasirox is administered orally 2 hrs before endotoxin administration. | Drug | Iron chelation |
| endotoxinAlso: LPSat t=0 2ng/kg purified E.Coli endotoxin is administered intravenously | Drug | Iron chelation, Iron loading, Placebo |
| PlaceboAt 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. | Drug | Placebo |
Primary outcome
TNF-alfa
Time frame: Level of TNF-alfa 90 minutes after endotoxin administration
Level of TNF-alfa 90 minutes after endotoxin administration
3 secondary outcomes
Cytokines
Time frame: 24 hrs after the administration of endotoxin
Oxidative stress
Time frame: 24 hrs after the administration of iron / iron chelator / placebo
Hemodynamic response
Time frame: 24 hours after the administration of endotoxin
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Nov 2015.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Peter Pickkers, MD, PhD principal investigator
Radboud University Medical Center
Questions about this trial
What is this clinical trial studying?
A study testing iron sucrose, Deferasirox and endotoxin in people with Systemic Inflammatory Process and Anemia, run by Radboud University Medical Center.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Nov 2015. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
TNF-alfa (time frame: Level of TNF-alfa 90 minutes after endotoxin administration). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Nov 2015.