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Assessing the Effects of CytoSorb Hemoperfusion on the Development on Immunoparalysis (EndoSorb)

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ClinicalTrials.gov Identifier: NCT04643639
Recruitment Status : Recruiting
First Posted : November 25, 2020
Last Update Posted : March 12, 2021
Sponsor:
Collaborator:
CytoSorbents Europe GmbH
Information provided by (Responsible Party):
Radboud University Medical Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Sepsis Immune Deficiency Hemoperfusion Blood Purification Device: CytoSorb hemoperfusion Phase 3

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label Randomized Controlled Experimental Endotoxemia Study on the Effects of the Cytokine-adsorber CytoSorb on the Development of Immunoparalysis in Humans
Actual Study Start Date : September 16, 2020
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : August 31, 2021

Arm Intervention/treatment
Experimental: Active Device: CytoSorb hemoperfusion
Subjects will be treated with CytoSorb hemoperfusion (in stand-alone setup) for 6 hours at a flow rate of 250 ml/min during endotoxemia.

No Intervention: Control



Primary Outcome Measures :
  1. Between group differences in plasma interleukin (IL)-6 levels during the second endotoxin challenge. [ Time Frame: Samples will be obtained starting 1 hour prior until 8 hours after endotoxin administration ]
    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.


Secondary Outcome Measures :
  1. Between group differences in plasma levels of other inflammatory cytokines during the second endotoxin challenge. [ Time Frame: Samples will be obtained starting 1 hour prior until 8 hours after endotoxin administration ]
    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)

  2. Between group differences in mHLA-DR expression [ Time Frame: 1 hour before, 3 hours after and 6 hours after endotoxin administration ]
    Differences in Human Leukocyte Antigen (HLA)-DR expression on monocytes will be assessed using flowcytometry.

  3. Between group differences in norepinephrine sensitivity [ Time Frame: One hour before and 4 hours after endotoxin administration during the first endotoxin challenge ]
    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.

  4. Cytokine clearance by the adsorber [ Time Frame: Every 30 minutes until cessation of hemoperfusion (six hours after endotoxin administration) ]
    Blood samples will be obtained from the afferent and efferent tubing of the CytoSorb adsorber to calculate clearance of cytokines by the adsorber

  5. Between group differences in endotoxemia-induced metabolic activity of platelets [ Time Frame: 1 hour prior until 8 hours after endotoxin administration ]
    Blood samples will be collected in citrated tubes to allow assessment of ATP production by platelets.

  6. Between group differences in endotoxemia-induced clinical symptoms [ Time Frame: Every 30 minutes from 1 hour prior until 8 hours after endotoxin administration ]
    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.

  7. Between group differences in body temperature [ Time Frame: Every 30 minutes from 1 hour prior until 8 hours after endotoxin administration ]
    Body temperature will be assessed using tympanic temperature measurements

  8. Between group differences in blood pressure [ Time Frame: From 1 hour prior until 8 hours after endotoxin administration ]
    Systolic, diastolic and mean arterial pressure will be measured continuously using a radial artery catheter.

  9. Between group differences in heart rate [ Time Frame: From 1 hour prior until 8 hours after endotoxin administration ]
    Heart rate will be recorded continuously using a 3-lead ECG.

  10. Between group differences in markers of endothelial injury [ Time Frame: Samples will be obtained starting 1 hour prior until 8 hours after endotoxin administration ]
    Vascular cell adhesion protein (VCAM)-1 and Intercellular Adhesion Molecule (ICAM)-1



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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04643639


Contacts
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Contact: Aron Jansen, MD +31243616735 aron.jansen@radboudumc.nl
Contact: Matthijs Kox, PhD matthijs.kox@radboudumc.nl

Locations
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Netherlands
Radboud University Medical Center Recruiting
Nijmegen, Gelderland, Netherlands, 6500HB
Contact: Aron Jansen, MD    +31243616735    aron.jansen@radboudumc.nl   
Sub-Investigator: Aron Jansen, MD         
Sponsors and Collaborators
Radboud University Medical Center
CytoSorbents Europe GmbH
Investigators
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Principal Investigator: Peter Pickkers, MD, PhD Radboud University Medical Center
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Responsible Party: Radboud University Medical Center
ClinicalTrials.gov Identifier: NCT04643639    
Other Study ID Numbers: The EndoSorb Study
First Posted: November 25, 2020    Key Record Dates
Last Update Posted: March 12, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Immunologic Deficiency Syndromes
Immune System Diseases