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

Primary Purpose

Sepsis, Immune Deficiency, Hemoperfusion

Status

Completed

Phase

Phase 3

Locations

Netherlands

Study Type

Interventional

Intervention

CytoSorb hemoperfusion

About this trial

This is an interventional treatment trial for Sepsis

Eligibility Criteria

18 Years - 35 Years (Adult)MaleAccepts Healthy Volunteers

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.

Sites / Locations

Radboud University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Active

Control

Arm Description

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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)

Between group differences in mHLA-DR expression

Differences in Human Leukocyte Antigen (HLA)-DR expression on monocytes will be assessed using flowcytometry.

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.

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

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.

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.

Between group differences in body temperature

Body temperature will be assessed using tympanic temperature measurements

Between group differences in blood pressure

Systolic, diastolic and mean arterial pressure will be measured continuously using a radial artery catheter.

Between group differences in heart rate

Heart rate will be recorded continuously using a 3-lead ECG.

Between group differences in markers of endothelial injury

Vascular cell adhesion protein (VCAM)-1 and Intercellular Adhesion Molecule (ICAM)-1

Full Information

NCT ID

NCT04643639

First Posted

September 15, 2020

Last Updated

December 20, 2022

Sponsor

Radboud University Medical Center

Collaborators

CytoSorbents Europe GmbH

1. Study Identification

Unique Protocol Identification Number

NCT04643639

Brief Title

Assessing the Effects of CytoSorb Hemoperfusion on the Development on Immunoparalysis

Acronym

EndoSorb

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2021

Overall Recruitment Status

Completed

Study Start Date

September 16, 2020 (Actual)

Primary Completion Date

October 19, 2022 (Actual)

Study Completion Date

October 19, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Radboud University Medical Center

Collaborators

CytoSorbents Europe GmbH

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Sepsis, Immune Deficiency, Hemoperfusion, Blood Purification

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

24 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Active

Arm Type

Experimental

Arm Title

Control

Arm Type

No Intervention

Intervention Type

Device

Intervention Name(s)

CytoSorb hemoperfusion

Intervention Description

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

Primary Outcome Measure Information:

Title

Between group differences in plasma interleukin (IL)-6 levels during the second endotoxin challenge.

Description

Time Frame

Samples will be obtained starting 1 hour prior until 8 hours after endotoxin administration

Secondary Outcome Measure Information:

Title

Between group differences in plasma levels of other inflammatory cytokines during the second endotoxin challenge.

Description

Time Frame

Samples will be obtained starting 1 hour prior until 8 hours after endotoxin administration

Title

Between group differences in mHLA-DR expression

Description

Differences in Human Leukocyte Antigen (HLA)-DR expression on monocytes will be assessed using flowcytometry.

Time Frame

1 hour before, 3 hours after and 6 hours after endotoxin administration

Title

Between group differences in norepinephrine sensitivity

Description

Time Frame

One hour before and 4 hours after endotoxin administration during the first endotoxin challenge

Title

Cytokine clearance by the adsorber

Description

Blood samples will be obtained from the afferent and efferent tubing of the CytoSorb adsorber to calculate clearance of cytokines by the adsorber

Time Frame

Every 30 minutes until cessation of hemoperfusion (six hours after endotoxin administration)

Title

Between group differences in endotoxemia-induced metabolic activity of platelets

Description

Blood samples will be collected in citrated tubes to allow assessment of ATP production by platelets.

Time Frame

1 hour prior until 8 hours after endotoxin administration

Title

Between group differences in endotoxemia-induced clinical symptoms

Description

Time Frame

Every 30 minutes from 1 hour prior until 8 hours after endotoxin administration

Title

Between group differences in body temperature

Description

Body temperature will be assessed using tympanic temperature measurements

Time Frame

Every 30 minutes from 1 hour prior until 8 hours after endotoxin administration

Title

Between group differences in blood pressure

Description

Systolic, diastolic and mean arterial pressure will be measured continuously using a radial artery catheter.

Time Frame

From 1 hour prior until 8 hours after endotoxin administration

Title

Between group differences in heart rate

Description

Heart rate will be recorded continuously using a 3-lead ECG.

Time Frame

From 1 hour prior until 8 hours after endotoxin administration

Title

Between group differences in markers of endothelial injury

Description

Vascular cell adhesion protein (VCAM)-1 and Intercellular Adhesion Molecule (ICAM)-1

Time Frame

Samples will be obtained starting 1 hour prior until 8 hours after endotoxin administration

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

35 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Peter Pickkers, MD, PhD

Organizational Affiliation

Radboud University Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Radboud University Medical Center

City

Nijmegen

State/Province

Gelderland

ZIP/Postal Code

6500HB

Country

Netherlands

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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Assessing the Effects of CytoSorb Hemoperfusion on the Development on Immunoparalysis

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