Assessing the Effects of CytoSorb Hemoperfusion on the Development on Immunoparalysis

Study Overview
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Brief Summary
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In this randomized, open-label study, the investigators will assess whether CytoSorb hemoperfusion will prevent or attenuate the development of immunoparalysis in healthy volunteers undergoing repeated experimental endotoxemia.

Detailed Description
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Sepsis is an inflammatory syndrome with high mortality rates and increasing incidence. Sepsis-induced immunoparalysis, increasingly recognized as the overriding immune disorder in sepsis patients, attributes significantly to late mortality in sepsis patients. The investigators hypothesize that 'blood purification' techniques targeted at the removal of excess circulating cytokines, such as the CytoSorb hemoperfusion device, might prevent or attenuate the development of immunoparalysis. The objective of this trial is to determine the effects of CytoSorb hemoperfusion on the development of immunoparalysis in a repeated experimental endotoxemia model in healthy male volunteers. To this end, 24 healthy male volunteers subjects will be randomized in a 1:1 fashion into one of two treatment groups (active or control). Both study groups will undergo two endotoxin challenges, separated by seven days. To this end, endotoxin (LPS) will be administered as a bolus of 1 ng/kg, followed by continuous infusion of 0.5 ng/kg/hr for three hours. The active group will be treated with CytoSorb hemoperfusion during the first endotoxin challenge, whereas the control group will receive no additional treatment. During both endotoxin challenges, blood samples will be obtained serially to measure levels of circulating cytokines and other inflammatory mediators.

Official Title
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An Open-label Randomized Controlled Experimental Endotoxemia Study on the Effects of the Cytokine-adsorber CytoSorb on the Development of Immunoparalysis in Humans

Conditions
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Sepsis, Immune Deficiency, Hemoperfusion, Blood Purification

Intervention / Treatment
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* Device: CytoSorb hemoperfusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent Male Age ≥ 18 and ≤ 35 years Healthy (as determined by medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG) and routine clinical laboratory parameters) Exclusion Criteria: Use of any medication Smoking Known anaphylaxis or hypersensitivity to any (non-)investigational products or their excipients. History or signs of atopic syndrome (asthma, rhinitis with medication and/or eczema) History or signs of hematological disease History or signs of thromboembolic disorders History of (intracranial) aneurysmal or hemorrhagic diseases History of heparin-induced thrombocytopenia (HIT) Thrombocytopenia (<150*109/ml) or anemia (hemoglobin < 8.0 mmol/L) History, signs or symptoms of cardiovascular disease, in particular: Previous spontaneous vagal collapse History of atrial or ventricular arrhythmia Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrio-ventricular block or a complete left bundle branch block Hypertension (defined as RR systolic > 160 or RR diastolic > 90 mmHg) Hypotension (defined as RR systolic < 100 or RR diastolic < 50 mmHg) Renal impairment (defined as plasma creatinine >120 μmol/l) Liver enzyme abnormalities (above 2x the upper limit of normal) Medical history of any disease associated with immune deficiency Signs of infection (CRP > 20 mg/L, WBC > 12x109/L or < 4x109/L) Clinically significant acute illness, including infections or trauma, within 1 month of the first endotoxin challenge Previous (participation in a study with) endotoxin (LPS) administration Any vaccination within 3 months within of the first endotoxin challenge Participation in a drug trial or donation of blood within 3 months prior to first endotoxin challenge Recent hospital admission or surgery with general anesthesia within 3 months prior to first endotoxin challenge Use of recreational drugs within 1 month of the first endotoxin challenge Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active<br> | Device: CytoSorb hemoperfusion<br>* Subjects will be treated with CytoSorb hemoperfusion (in stand-alone setup) for 6 hours at a flow rate of 250 ml/min during endotoxemia.<br>|
| No Intervention: Control<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Between group differences in plasma interleukin (IL)-6 levels during the second endotoxin challenge. | Blood samples will be obtained at predefined time points before, during and after endotoxin administration to assess plasma levels (in pg/mL) of circulating inflammatory mediatiors. To assess between group differences, the area under the curve (AUC) of the time concentration curve (expressed in arbitrary units) of each inflammatory mediator will be calculated. | Samples will be obtained starting 1 hour prior until 8 hours after endotoxin administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Between group differences in plasma levels of other inflammatory cytokines during the second endotoxin challenge. | Interleukin (IL)-6, IL-8, IL-10, Monocyte Chemoattractant Protein (MCP)-1, C-X-C motif chemokine ligand (CXCL)-10, Macrophage Inflammatory Protein (MIP)-1α, MIP-1β, and Granulocyte Colony-Stimulating Factor (G-CSF) | Samples will be obtained starting 1 hour prior until 8 hours after endotoxin administration | 
| Between group differences in mHLA-DR expression | Differences in Human Leukocyte Antigen (HLA)-DR expression on monocytes will be assessed using flowcytometry. | 1 hour before, 3 hours after and 6 hours after endotoxin administration | 
| Between group differences in norepinephrine sensitivity | To assess the effects of CytoSorb hemoperfusion on norepinephrine sensitivity, norepinephrine will be administered in increasing dosages (0.025; 0.05 and 0.1 γ) for 5 minutes per dose. Blood pressure will be recorded continuously with an arterial catheter. | One hour before and 4 hours after endotoxin administration during the first endotoxin challenge | 
| Cytokine clearance by the adsorber | Blood samples will be obtained from the afferent and efferent tubing of the CytoSorb adsorber to calculate clearance of cytokines by the adsorber | Every 30 minutes until cessation of hemoperfusion (six hours after endotoxin administration) | 
| Between group differences in endotoxemia-induced metabolic activity of platelets | Blood samples will be collected in citrated tubes to allow assessment of ATP production by platelets. | 1 hour prior until 8 hours after endotoxin administration | 
| Between group differences in endotoxemia-induced clinical symptoms | Clinical symptoms will be scored on a Likert scale (ranging from 0 to 5) in a composite endpoint consisting of headache, nausea, shivering, muscle soreness and lower back pain. Higher numbers indicate more severe symptoms. | Every 30 minutes from 1 hour prior until 8 hours after endotoxin administration | 
| Between group differences in body temperature | Body temperature will be assessed using tympanic temperature measurements | Every 30 minutes from 1 hour prior until 8 hours after endotoxin administration | 
| Between group differences in blood pressure | Systolic, diastolic and mean arterial pressure will be measured continuously using a radial artery catheter. | From 1 hour prior until 8 hours after endotoxin administration | 
| Between group differences in heart rate | Heart rate will be recorded continuously using a 3-lead ECG. | From 1 hour prior until 8 hours after endotoxin administration | 
| Between group differences in markers of endothelial injury | Vascular cell adhesion protein (VCAM)-1 and Intercellular Adhesion Molecule (ICAM)-1 | Samples will be obtained starting 1 hour prior until 8 hours after endotoxin administration |