Clinical trial NCT04643639: Assessing the Effects of CytoSorb Hemoperfusion on the Development on Immunoparalysis
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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Sepsis
Immune Deficiency
Hemoperfusion
Blood Purification
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: CytoSorbents Europe GmbH
First posted: 2020-11-25
Enrollment: 24
Sex: MALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Between group differences in plasma interleukin (IL)-6 levels during the second endotoxin challenge.
timeFrame: Samples will be obtained starting 1 hour prior until 8 hours after endotoxin administration
Secondary outcomes:
measure: Between group differences in plasma levels of other inflammatory cytokines during the second endotoxin challenge.
timeFrame: Samples will be obtained starting 1 hour prior until 8 hours after endotoxin administration
measure: Between group differences in mHLA-DR expression
timeFrame: 1 hour before, 3 hours after and 6 hours after endotoxin administration
measure: Between group differences in norepinephrine sensitivity
timeFrame: One hour before and 4 hours after endotoxin administration during the first endotoxin challenge
measure: Cytokine clearance by the adsorber
timeFrame: Every 30 minutes until cessation of hemoperfusion (six hours after endotoxin administration)
measure: Between group differences in endotoxemia-induced metabolic activity of platelets
timeFrame: 1 hour prior until 8 hours after endotoxin administration
measure: Between group differences in endotoxemia-induced clinical symptoms
timeFrame: Every 30 minutes from 1 hour prior until 8 hours after endotoxin administration
measure: Between group differences in body temperature
timeFrame: Every 30 minutes from 1 hour prior until 8 hours after endotoxin administration
measure: Between group differences in blood pressure
timeFrame: From 1 hour prior until 8 hours after endotoxin administration
measure: Between group differences in heart rate
timeFrame: From 1 hour prior until 8 hours after endotoxin administration
measure: Between group differences in markers of endothelial injury
timeFrame: Samples will be obtained starting 1 hour prior until 8 hours after endotoxin administration
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
state: Gelderland
Study officials:
affiliation: Radboud University Medical Center
name: Peter Pickkers, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: