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

NCT ID: NCT01374711

Last Updated: 2013-06-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-05-31
• Study Completion Date: 2011-11-30

Brief 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. 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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

placebo

LPS will be administered twice on days 1 and 7. In between placebo will be administered on days 2, 4 and 6 subcutaneously.

Group Type: PLACEBO_COMPARATOR

E.coli endotoxin

Intervention Type: OTHER

2 ng/kg E.coli reference endotoxin 11:H 10:K negative intravenously

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.

Group Type: ACTIVE_COMPARATOR

GM-CSF

Intervention Type: DRUG

GM-CSF (4microgram/kg/day subcutaneously) on days 2, 4 and 6.

E.coli endotoxin

Intervention Type: OTHER

2 ng/kg E.coli reference endotoxin 11:H 10:K negative intravenously

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.

Group Type: ACTIVE_COMPARATOR

IFN-Y

Intervention Type: DRUG

IFN-Y (100 microgram/day, subcutaneously) on days 2, 4 and 6.

E.coli endotoxin

Intervention Type: OTHER

2 ng/kg E.coli reference endotoxin 11:H 10:K negative intravenously

Interventions

GM-CSF

GM-CSF (4microgram/kg/day subcutaneously) on days 2, 4 and 6.

Intervention Type: DRUG

IFN-Y

IFN-Y (100 microgram/day, subcutaneously) on days 2, 4 and 6.

Intervention Type: DRUG

E.coli endotoxin

2 ng/kg E.coli reference endotoxin 11:H 10:K negative intravenously

Intervention Type: OTHER

Eligibility 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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Peter Pickkers

MD, PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Peter Pickkers, Prof, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Radboud University Nijmegen Medical Centre, The Netherlands

Locations

Radboud University Nijmegen Medical Centre

Nijmegen, Gelderland, Netherlands

Countries

Netherlands

References

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.

Reference Type: DERIVED

PMID: 22822024 (View on PubMed)

Other Identifiers

NL36068.091.11 BI

Identifier Type: -

Identifier Source: org_study_id