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The Effects of Immunostimulation With GM-CSF or IFN-y on Immunoparalysis Following Human Endotoxemia

The recruitment status of this study is unknown because the information has not been verified recently.
Verified May 2011 by Radboud University.
Recruitment status was  Active, not recruiting
Sponsor:
Information provided by:
Radboud University
ClinicalTrials.gov Identifier:
NCT01374711
First received: May 19, 2011
Last updated: July 19, 2011
Last verified: May 2011
History of Changes
  Purpose

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


Condition Intervention
Endotoxemia
Inflammation
Multi Organ Dysfunction Syndrome
Sepsis
 Drug: GM-CSF
Drug: IFN-Y
Other: E.coli endotoxin

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:

MedlinePlus related topics: Sepsis
U.S. FDA Resources

Further study details as provided by Radboud University:

Primary Outcome Measures:
  • 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) ] [ Designated as safety issue: No ]
    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


Secondary Outcome Measures:
  • 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) ] [ Designated as safety issue: No ]
  • the effects of GM-CSF/IFN-γ on monocyte HLA-DR expression [ Time Frame: 1 week (day 1- day 8) ] [ Designated as safety issue: No ]
  • the effects of GM-CSF/IFN-γ on transcriptional pathways of leukocytes (qPCR and microarray) [ Time Frame: 1 week (day 1- day 8) ] [ Designated as safety issue: No ]
  • the effects of GM-CSF/IFN-γ on urine markers of tubular injury [ Time Frame: 1 week (day 1- day 8) ] [ Designated as safety issue: No ]
  • The effect of LPS on twitch transdiaphragmatic pressure [ Time Frame: 1 day ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • Beta 2 Glycoprotein and platelet-monocyte interactions post-LPS [ Time Frame: 1 day ] [ Designated as safety issue: No ]
  • Macrophage differentiation [ Time Frame: 1 day ] [ Designated as safety issue: No ]
  • Immunosuppressive neutrophil populations [ Time Frame: 1 week (day 1- day 8) ] [ Designated as safety issue: No ]
  • Blood viscosity [ Time Frame: 1 day ] [ Designated as safety issue: No ]

Estimated Enrollment: 18
Study Start Date: May 2011
Estimated Study Completion Date: November 2011
Estimated Primary Completion Date: November 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: placebo
LPS will be administered twice on days 1 and 7. In between placebo will be administered on days 2, 4 and 6 subcutaneously.
 Other: E.coli endotoxin
2 ng/kg E.coli reference endotoxin 11:H 10:K negative intravenously
Active Comparator: GM-CSF
LPS will be administered twice on days 1 and 7. In between GM-CSF will be administered on days 2, 4 and 6 subcutaneously.
 Drug: GM-CSF
GM-CSF (4microgram/kg/day subcutaneously) on days 2, 4 and 6.
Other: E.coli endotoxin
2 ng/kg E.coli reference endotoxin 11:H 10:K negative intravenously
Active Comparator: IFN-y
LPS will be administered twice on days 1 and 7. In between IFN-Y will be administered on days 2, 4 and 6 subcutaneously.
 Drug: IFN-Y
IFN-Y (100 microgram/day, subcutaneously) on days 2, 4 and 6.
Other: E.coli endotoxin
2 ng/kg E.coli reference endotoxin 11:H 10:K negative intravenously

  Eligibility

Ages Eligible for Study:   18 Years to 35 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy male volunteers

Exclusion Criteria:

  • 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.
  • (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)
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01374711

Locations
Netherlands
Radboud University Nijmegen Medical Centre
Nijmegen, Gelderland, Netherlands, 6500 HB
Sponsors and Collaborators
Radboud University
Investigators
Principal Investigator: Peter Pickkers, Prof, MD, PhD Radboud University Nijmegen Medical Centre, The Netherlands
  More Information

No publications provided

Responsible Party: P. Pickkers, MD, PhD, Radboud University Nijmegen Medical Centre
ClinicalTrials.gov Identifier: NCT01374711     History of Changes
Other Study ID Numbers: NL36068.091.11 BI
Study First Received: May 19, 2011
Last Updated: July 19, 2011
Health Authority: Netherlands: Medical Ethics Review Committee (METC)

Keywords provided by Radboud University:
Endotoxin
Inflammation
Sepsis
GM-CSF
IFN-y

Additional relevant MeSH terms:
Inflammation
Sepsis
Endotoxemia
Pathologic Processes
 Infection
Systemic Inflammatory Response Syndrome
Bacteremia
Toxemia

ClinicalTrials.gov processed this record on May 19, 2013