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

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

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.

Study Overview

• Status: Completed
• Conditions: Sepsis; Immune Deficiency; Hemoperfusion; Blood Purification
• Intervention / Treatment: Device: CytoSorb hemoperfusion

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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6500HB
      • Radboud University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control
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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: CytoSorbents Europe GmbH
• Investigators: Principal Investigator: Peter Pickkers, MD, PhD, Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2020
• Primary Completion (Actual): October 19, 2022
• Study Completion (Actual): October 19, 2022

Study Registration Dates

• First Submitted: September 15, 2020
• First Submitted That Met QC Criteria: November 19, 2020
• First Posted (Actual): November 25, 2020

Study Record Updates

• Last Update Posted (Actual): December 22, 2022
• Last Update Submitted That Met QC Criteria: December 20, 2022
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Immunologic Deficiency Syndromes
• Other Study ID Numbers: The EndoSorb Study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• 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