sepsis induced immunoparalysis MedDRA version: 16.1 Level: PT Classification code 10040047 Term: Sepsis System Organ Class: 10021881 - Infections and infestations
Conditions
Interventions
Trade Name: ?-Irradiated BCG vaccine (BCG-Vaccin SSI [Nederlands Vaccin Instituut]) Danish strain 1331
Product Name: ?-Irradiated BCG vaccine
Product Code: Not applicable
Pharmaceutical Form:
Pharma
Sponsors
Radboud University Nijmegen Medical Centre
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: - Written informed consent - Age =18 and =35 yrs - Male - Healthy Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 36 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: - Use of any medication - History of BCG-vaccination - Vaccination other than BCG, within 3 months prior to study or within study period - Smoking - Previous spontaneous vagal collapse - History of atrial or ventricular arrhythmia - (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) - Hypotension (defined as RR systolic 120 µmol/l) - Liver enzyme abnormalities or positive hepatitis serology - Medical history of any disease associated with immune deficiency - CRP > 20 mg/L, WBC > 12x109/L, or clinically significant acute illness, including infections, within 4 weeks before endotoxin administration - Participation in a drug trial or donation of blood 3 months prior to the LPS challenge - Use of recreational drugs within 21 days prior to experiment day - Recent hospital admission or surgery with general anaesthesia (<3 months)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. Single endotoxemia To determine the effects of ?-irradiated BCG-vaccination on the in vivo innate immune responses induced by human endotoxemia. This will be determined by measuring plasma levels of various pro- and anti-inflammatory cytokines and assessing the difference in the Lipopolysacharide (LPS)-induced cytokine response between ?-irradiated BCG-vaccined subjects and placebo-treated control subjects. 2. Repeated endotoxemia To determine the effects of ?-irradiated BCG-vaccination on endotoxin tolerance induced by 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 following the first and second endotoxemia, between ?-irradiated BCG-vaccined and placebo-treated control subjects. ;Secondary Objective: 1. To determine the effects of ?-irradiated BCG-vaccination on ex vivo responsiveness of leukocytes to various inflammatory stimuli. 2. To determine the effects of ?-irradiated BCG-vaccination on the phenotype of circulating monocytes (e.g. expression pattern of cell-surface receptors by use of flow cytometry). 3. To determine the effects of ?-irradiated BCG-vaccination on inflammatory transcriptional pathways (by use of qPCR/microarrays). 4. To determine the effects of ?-irradiated BCG-vaccination on epigenetic changes, including H3K4 trimethylation, in circulating immune cells. 5. To determine the effects of ?-irradiated BCG-vaccination on LPS-induced clinical symptoms (illness score) and hemodynamic/temperature changes. ;Primary end point(s): Single endotoxemia: the primary study endpoint is the differences in LPS-induced plasma concentration of TNF-a following endotoxemia, between ?-irradiated BCG-vaccined subjects and placebo-treated controls. Repeated endotoxemia: the primary study endpoint is the difference in the LPS-induced TNF-a concentration following the first and second endotoxemia, between ?-irr | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary study parameters include various other inflammatory cytokines, including IL-6 and IL-10, the ex vivo production of inflammatory mediators by stimulated leukocytes, the phenotype of circulating monocytes, inflammatory transcriptional pathways (by use of qPCR/microarrays), epigenetic changes in leukocytes including H3K4 trimethylation, illness score, mean arterial pressure, heart rate and temperature;Timepoint(s) of evaluation of this end point: Single endotoxemia: 0, 60, 90, 120, 180, 240, 360 and 480 minutes after endotoxin administration Repeated endotoxemia: 0, 60, 90, 120, 180, 240, 360 and 480 minutes after both endotoxin administrations | — |
Countries
Netherlands
Contacts
Public ContactJenneke Leentjens
Radboud University Nijmegen Medical Centre
Outcome results
None listed