EndotoxemiaNCT01374711
The Effects of Immunostimulation With GM-CSF or IFN-y on Immunoparalysis Following Human Endotoxemia
A study testing GM-CSF, IFN-Y and E.coli endotoxin in people with Endotoxemia and Inflammation, run by Radboud University Medical Center at 1 site in Netherlands.
Trial summary
The human body knows a biphasic immunological reaction to sepsis. First, the pro-inflammatory reaction takes place, marked by the release of pro-inflammatory cytokines like TNF-α, as a reaction to the bacterial toxins. Secondly, the counter regulatory anti-inflammatory reaction arises. 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
- Endotoxemia, Inflammation, Multi Organ Dysfunction Syndrome
- What is being tested?
- GM-CSF, IFN-Y and E.coli endotoxin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 18 participants
- Where
- 1 siteNetherlands
- Study dates
- May 2011to Nov 2011
- 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
- Healthy male volunteers
Who cannot join
- seropositivity for markers of hepatitis B or HIV infection or medical history of any other obvious disease associated with immune deficiency
- Use of any medication or drugs
- a history of adverse reaction or hypersensitivity to GM-CSF/ IFN-γ
- Smoking.
- Previous spontaneous vagal collapse.
- History, signs or symptoms of cardiovascular disease.
Show all 20Show fewer
- (Family) history of myocardial infarction or stroke under the age of 65 years.
- Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex bundle branch block.
- Hypertension (defined as RR systolic > 160 or RR diastolic > 90) or hypotension (defined as RR systolic < 100 or RR diastolic < 50).
- Renal impairment (defined as plasma creatinin >120 μmol/l).
- Liver enzyme abnormalities or positive hepatitis serology.
- Febrile illness during the week before the LPS challenge
- Participation in a drug trial or donation of blood 3 months prior to the LPS challenge.
- Chronic hiccups (defined as hiccups longer than 15 minutes in the past 6 months)
- Pre-existent muscle disease (congenital or acquired) or diseases / disorders know to be associated with myopathy including diabetes and auto-immune diseases.
- Pre-existent lung disease
- Upper airway / esophageal pathology
- Recent (< 1 month) nasal bleeding
- Phrenic nerve lesions
- Any metals in body (pacemaker, splinters, metal stitches)
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Radboud University Nijmegen Medical Centre
Nijmegen, Gelderland, 6500 HB
About this study
Official title: The Effects of Immunostimulation With GM-CSF or IFN-y on Immunoparalysis Following Human Endotoxemia. A Parallel Randomized Double-blind Placebo-controlled Study
The human body knows a biphasic immunological reaction to sepsis. First, the pro-inflammatory reaction takes place, marked by the release of pro-inflammatory cytokines like TNF-α, as a reaction to the bacterial toxins. Secondly, the counter regulatory anti-inflammatory reaction arises. This phase is acting as negative feedback on the inflammation by inhibition of the pro-inflammatory cytokines. This is called "immunoparalysis", a pronounced immunosuppressive state, which renders patients vulnerable to opportunistic infections. Most of the septic patients survive the initial pro-inflammatory phase, but die during this second stage.Research in the past has shown that immunostimulatory therapy with GM-CSF or IFN-γ has promising effects on the pro-inflammatory reaction during immunoparalysis ex vivo. Both drugs are known for their immunostimulatory effects. Recent pilot studies have showed in septic patients, that long-lasting monocyte deactivation in sepsis ex vivo can be reversed by these two immunostimulants. However, the mechanism and extent of immunoparalysis recovery may be different between the two compounds. Previously it has been shown that human endotoxemia (induced by LPS), leads to marked immunosuppression in healthy individuals, characterized by a transient refractory state to a subsequent LPS challenge (endotoxin tolerance). Consequently, human endotoxemia can serve as a standardized, controlled model for sepsis-induced immunoparalysis. Until now, all studies have focused on the ex vivo tolerance. However, we have recently proved, that the ex vivo condition is not completely representative for the in vivo situation. Ex vivo, leukocyte tolerance to LPS resolves within one day, while the in vivo immunoparalysis persists for two weeks. In this project, we will investigate the effects of both GM-CSF and IFN-γ in a parallel double-blind placebo controlled randomized manner on the immunoparalysis following human endotoxemia, both in-vitro and in vivo. As a result, we hope to get more insight in the pathophysiology of sepsis-induced immunoparalysis and thereby develop new immunostimulatory therapies that improve patient outcome
- Conditions
- Endotoxemia, Inflammation, Multi Organ Dysfunction Syndrome, Sepsis
- Being tested
- GM-CSF, IFN-Y, E.coli endotoxin
- Keywords
- Endotoxin, Inflammation, Sepsis, GM-CSF, IFN-y
- Medical subject headings
- Endotoxemia, Inflammation, Sepsis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GM-CSFDrug
GM-CSF (4microgram/kg/day subcutaneously) on days 2, 4 and 6.
IFN-YDrug
IFN-Y (100 microgram/day, subcutaneously) on days 2, 4 and 6.
E.coli endotoxinOther
2 ng/kg E.coli reference endotoxin 11:H 10:K negative intravenously
| Study group | Role | What they receive |
|---|---|---|
| placebo | Placebo comparator | LPS will be administered twice on days 1 and 7. In between placebo will be administered on days 2, 4 and 6 subcutaneously. Receives: Other: E.coli endotoxin |
| GM-CSF | Active comparator | LPS will be administered twice on days 1 and 7. In between GM-CSF will be administered on days 2, 4 and 6 subcutaneously. Receives: Drug: GM-CSF; Other: E.coli endotoxin |
| IFN-y | Active comparator | LPS will be administered twice on days 1 and 7. In between IFN-Y will be administered on days 2, 4 and 6 subcutaneously. Receives: Drug: IFN-Y; Other: E.coli endotoxin |
What is being measured
The primary outcome is the main question the study is designed to answer.
the effects of GM-CSF/IFN-γ on the development of in vivo immunoparalysis induced by experimental human endotoxemia
This will be determined by measuring plasma levels of various pro and anti-inflammatory cytokines and assessing the difference in the LPS-induced cytokine response between day 1 and 7
Measured: 1 week (day 1- day 8)
Secondary outcomes (11)
The effects of GM-CSF/IFN-γ on the ex-vivo responsiveness of leukocytes to various inflammatory stimuli
Measured: 1 week (day 1- day 8)
the effects of GM-CSF/IFN-γ on monocyte HLA-DR expression
Measured: 1 week (day 1- day 8)
the effects of GM-CSF/IFN-γ on transcriptional pathways of leukocytes (qPCR and microarray)
Measured: 1 week (day 1- day 8)
the effects of GM-CSF/IFN-γ on urine markers of tubular injury
Measured: 1 week (day 1- day 8)
The effect of LPS on twitch transdiaphragmatic pressure
Measured: 1 day
the effects of GM-CSF/IFN-γ on clinical symptoms (illness score, mean arterial pressure, heart rate and temperature)
Measured: 1 week (day 1- day 8)
the effects of GM-CSF/IFN-γ on changes in phenotype and gene expression caused by mechanisms other than changes in the underlying DNA sequence
Measured: 1 week (day 1- day 8)
Beta 2 Glycoprotein and platelet-monocyte interactions post-LPS
Measured: 1 day
Macrophage differentiation
Measured: 1 day
Immunosuppressive neutrophil populations
Measured: 1 week (day 1- day 8)
Blood viscosity
Measured: 1 day
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jun 2011 (estimated)
- Study startMay 2011
- Primary completionNov 2011
- Study completionNov 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for EndotoxemiaStudies 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
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Peter Pickkers, Radboud University Medical Center
- Investigators
- Peter Pickkers, Prof, MD, PhD, Principal investigator, Radboud University Nijmegen Medical Centre, The Netherlands
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01374711
- Sponsor's protocol ID
- NL36068.091.11 BI
- Status last verified
- Jun 2013
- First submitted
- 19 May 2011
- Last updated
- 27 Jun 2013
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Leentjens J, Kox M, Koch RM, Preijers F, Joosten LA, van der Hoeven JG, Netea MG, Pickkers P. Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am J Respir Crit Care Med. 2012 Nov 1;186(9):838-45. doi: 10.1164/rccm.201204-0645OC. Epub 2012 Jul 19.
PubMed 22822024
Study at a glance
From the registry record, last updated by the sponsor on 27 Jun 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects of Immunostimulation With GM-CSF or IFN-y on Immunoparalysis Following Human Endotoxemia. A Parallel Randomized Double-blind Placebo-controlled Study
- ClinicalTrials.gov ID
- NCT01374711
- Acronym / sponsor ID
- NL36068.091.11 BI
- Conditions
- Endotoxemia, Inflammation, Multi Organ Dysfunction Syndrome, Sepsis
- Keywords
- Endotoxin, Inflammation, Sepsis, GM-CSF, IFN-y
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Study start
- May 2011
- Primary completion
- Nov 2011 (actual)
- Study completion
- Nov 2011 (actual)
- First posted
- 16 Jun 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.
The human body knows a biphasic immunological reaction to sepsis. First, the pro-inflammatory reaction takes place, marked by the release of pro-inflammatory cytokines like TNF-α, as a reaction to the bacterial toxins. Secondly, the counter regulatory anti-inflammatory reaction arises. This phase is acting as negative feedback on the inflammation by inhibition of the pro-inflammatory cytokines. This is called "immunoparalysis", a pronounced immunosuppressive state, which renders patients vulnerable to opportunistic infections. Most of the septic patients survive the initial pro-inflammatory phase, but die during this second stage.Research in the past has shown that immunostimulatory therapy with GM-CSF or IFN-γ has promising effects on the pro-inflammatory reaction during immunoparalysis ex vivo. Both drugs are known for their immunostimulatory effects. Recent pilot studies have showed in septic patients, that long-lasting monocyte deactivation in sepsis ex vivo can be reversed by these two immunostimulants. However, the mechanism and extent of immunoparalysis recovery may be different between the two compounds. Previously it has been shown that human endotoxemia (induced by LPS), leads to marked immunosuppression in healthy individuals, characterized by a transient refractory state to a subsequent LPS challenge (endotoxin tolerance). Consequently, human endotoxemia can serve as a standardized, controlled model for sepsis-induced immunoparalysis. Until now, all studies have focused on the ex vivo tolerance. However, we have recently proved, that the ex vivo condition is not completely representative for the in vivo situation. Ex vivo, leukocyte tolerance to LPS resolves within one day, while the in vivo immunoparalysis persists for two weeks. In this project, we will investigate the effects of both GM-CSF and IFN-γ in a parallel double-blind placebo controlled randomized manner on the immunoparalysis following human endotoxemia, both in-vitro and in vivo. As a result, we hope to get more insight in the pathophysiology of sepsis-induced immunoparalysis and thereby develop new immunostimulatory therapies that improve patient outcome
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| placebo | Placebo comparator | Other: E.coli endotoxinLPS will be administered twice on days 1 and 7. In between placebo will be administered on days 2, 4 and 6 subcutaneously. |
| GM-CSF | Active comparator | Drug: GM-CSF, Other: E.coli endotoxinLPS will be administered twice on days 1 and 7. In between GM-CSF will be administered on days 2, 4 and 6 subcutaneously. |
| IFN-y | Active comparator | Drug: IFN-Y, Other: E.coli endotoxinLPS will be administered twice on days 1 and 7. In between IFN-Y will be administered on days 2, 4 and 6 subcutaneously. |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- Healthy male volunteers
Key exclusion criteria (20 listed)
- seropositivity for markers of hepatitis B or HIV infection or medical history of any other obvious disease associated with immune deficiency
- Use of any medication or drugs
- a history of adverse reaction or hypersensitivity to GM-CSF/ IFN-γ
- Smoking.
- Previous spontaneous vagal collapse.
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 |
|---|---|---|
| GM-CSFGM-CSF (4microgram/kg/day subcutaneously) on days 2, 4 and 6. | Drug | GM-CSF |
| IFN-YIFN-Y (100 microgram/day, subcutaneously) on days 2, 4 and 6. | Drug | IFN-y |
| E.coli endotoxin2 ng/kg E.coli reference endotoxin 11:H 10:K negative intravenously | Other | GM-CSF, IFN-y, placebo |
Primary outcome
the effects of GM-CSF/IFN-γ on the development of in vivo immunoparalysis induced by experimental human endotoxemia
Time frame: 1 week (day 1- day 8)
This will be determined by measuring plasma levels of various pro and anti-inflammatory cytokines and assessing the difference in the LPS-induced cytokine response between day 1 and 7
11 secondary outcomes
The effects of GM-CSF/IFN-γ on the ex-vivo responsiveness of leukocytes to various inflammatory stimuli
Time frame: 1 week (day 1- day 8)
the effects of GM-CSF/IFN-γ on monocyte HLA-DR expression
Time frame: 1 week (day 1- day 8)
the effects of GM-CSF/IFN-γ on transcriptional pathways of leukocytes (qPCR and microarray)
Time frame: 1 week (day 1- day 8)
the effects of GM-CSF/IFN-γ on urine markers of tubular injury
Time frame: 1 week (day 1- day 8)
The effect of LPS on twitch transdiaphragmatic pressure
Time frame: 1 day
the effects of GM-CSF/IFN-γ on clinical symptoms (illness score, mean arterial pressure, heart rate and temperature)
Time frame: 1 week (day 1- day 8)
the effects of GM-CSF/IFN-γ on changes in phenotype and gene expression caused by mechanisms other than changes in the underlying DNA sequence
Time frame: 1 week (day 1- day 8)
Beta 2 Glycoprotein and platelet-monocyte interactions post-LPS
Time frame: 1 day
Macrophage differentiation
Time frame: 1 day
Immunosuppressive neutrophil populations
Time frame: 1 week (day 1- day 8)
Blood viscosity
Time frame: 1 day
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 27 Jun 2013.
- Derived from this study: PubMed 22822024Leentjens J, Kox M, Koch RM, Preijers F, Joosten LA, van der Hoeven JG, Netea MG, Pickkers P. Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am J Respir Crit Care Med. 2012 Nov 1;186(9):838-45. doi: 10.1164/rccm.201204-0645OC. Epub 2012 Jul 19.
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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, Prof, MD, PhD principal investigator
Radboud University Nijmegen Medical Centre, The Netherlands
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing GM-CSF, IFN-Y and E.coli endotoxin in people with Endotoxemia and Inflammation, run by Radboud University Medical Center at 1 site in Netherlands.
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 1 inclusion and 20 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 27 Jun 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
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?
the effects of GM-CSF/IFN-γ on the development of in vivo immunoparalysis induced by experimental human endotoxemia (time frame: 1 week (day 1- day 8)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01374711, which also lists 1 linked publication.
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 27 Jun 2013.