Endotoxins and Cytokines Removal During Continuous Hemofiltration With oXiris™

Study Overview
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Brief Summary
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Sepsis is a major cause of death in Intensive Care Units and therefore finding new therapies to improve survival rates and limit morbidity is a major goal. Over the past decades, blood purification has been proposed as an adjuvant therapy for sepsis. The goal of blood purification is to restore the immune homeostasis and efficiency through the removal of bacterial products including endotoxins, broad-spectrum cytokines and other inflammatory mediators. Indeed, the large and overwhelmed release of these mediators in the early phase of sepsis may induce multiple organ failure syndrome. In 2017, different techniques are proposed for blood purification. Among them, the highly adsorptive membrane, oXiris™, seems promising. This membrane can be used in case of Acute Kidney Injury associated with sepsis and exhibits enhanced blood purification capacities. Previous studies on animals have already proven that this membrane can remove broad-spectrum cytokines but also endotoxins from the blood. This ability to remove endotoxins is particularly interesting since endotoxins are believed to be the trigger of the immune cascade at the initiation of sepsis. The lack of clinical evidence is the main limit to a wider use of this membrane. Therefore, the aim of the present clinical trial is to characterize the blood purification properties of the membrane in a human clinical setting. The oXiris™ membrane is specifically designed to improve the adsorptive capacities of the polyacrylonitrile-based AN69 membrane. Its extremely rich coating of polyethyleneimine (PEI) gives the membrane the ability to bind and remove not only cytokines but also endotoxins due to the positive charges of PEI at the surface of the membrane. The tested hypothesis is that the oXiris™ filter allows for a greater endotoxin and cytokine removal compared to a standard polysulfone (PrismafleX HF1400) filter in patients with septic shock.

Official Title
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Endotoxins and Cytokines Removal During Continuous Hemofiltration With oXiris™

Conditions
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Peritonitis, Septic Shock

Intervention / Treatment
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* Biological: Arterial blood sampling
* Biological: Ultrafiltrate sampling
* Device: CVVH using oXiris™ filter
* Device: CVVH using PrismafleX HF1400 filter


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged ≥ 18 years old, Early septic shock (in the first 12 hours after Intensive Care Unit (ICU) admission or readmission in the ICU after surgery), with lactatemia > 2 mmol/L and norepinephrine needs > 0.2 µg/kg/min 2 hours after the end of the initial surgery (to ensure that a potential anesthesia effect as disappeared), Secondary to a community-acquired or a nosocomial peritonitis (secondary or tertiary but not primary peritonitis), AKI KDIGO ≥ stage 2 or another indication for renal replacement therapy, according to the clinician in charge (if baseline creatinine is unknown, KDIGO ≥ stage 2 can be defined by a serum creatinine ≥ 2-fold the normal creatinine for age, gender, and ethnicity). Exclusion Criteria: Inability to obtain informed consent from the patient or next of kin, Actual participation in another interventional study, Contraindications to citrate, Allergy to heparin, Pregnant or breastfeeding woman, Neutropenia < 0.5 G/L resulting from chemotherapy or other iatrogenic causes Patient receiving immunosuppressive therapy, long-term corticosteroids, therapeutic antibodies, chemotherapy in the last 6 months (whatever the dose), Patient with innate or acquired immune deficiency (for example severe combined immunodeficiency, HIV or AIDS) Onco-hematological disease (lymphoma, leukemia, myeloma) treated within the last 5 years (but inclusion of a patient with solid cancer who did not receive chemotherapy during the past 6 months is possible), Patient with expected ICU length of stay < 48 hours, Patient for whom a limitation of active care was pronounced at the time of enrollment, Patient with no social security insurance, with restricted liberty, or under legal protection.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CVVH using oXiris™ filter<br>Patients included in this arm will have renal replacement therapy by performing Continuous Veno-Venous Hemofiltration (CVVH) using oXiris™ membrane. They will also have arterial blood sampling and ultrafiltrate sampling during the CVVH. | Biological: Arterial blood sampling<br>* All patients will have arterial blood sampling to assess pre-filter and post-filter plasma endotoxin mass and activity and plasma cytokine levels<br>Biological: Ultrafiltrate sampling<br>* All patients will have ultrafiltrate sampling to assess cytokine levels<br>Device: CVVH using oXiris™ filter<br>* Patients included in the experimental arm will have renal replacement therapy by performing CVVH using oXiris™ filter<br>|
| Active Comparator: CVVH using PrismafleX HF1400 filter<br>Patients included in this arm will have renal replacement therapy by performing CVVH using a standard polysulfone filter (PrismafleX HF1400). They will also have arterial blood sampling and ultrafiltrate sampling during the CVVH. | Biological: Arterial blood sampling<br>* All patients will have arterial blood sampling to assess pre-filter and post-filter plasma endotoxin mass and activity and plasma cytokine levels<br>Biological: Ultrafiltrate sampling<br>* All patients will have ultrafiltrate sampling to assess cytokine levels<br>Device: CVVH using PrismafleX HF1400 filter<br>* Patients included in the experimental arm will have renal replacement therapy by performing CVVH using PrismafleX HF1400 filter<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interleukin 6 (IL-6) plasmatic concentration |  | 24 hours after the initiation of CVVH | 
| Endotoxin plasmatic mass concentration |  | 24 hours after the initiation of CVVH | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre-filter plasma endotoxin mass |  | At initiation of CCVH (H0) then 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Pre-filter plasma endotoxin activity |  | At initiation of CCVH (H0) then 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Post-filter plasma endotoxin mass |  | 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Post-filter plasma endotoxin activity |  | 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Pre-filter plasma cytokine level |  | At initiation of CCVH (H0) then 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Post-filter plasma cytokine level |  | 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Ultrafiltrate cytokine level |  | 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Pre-filter plasma lipids level |  | At initiation of CCVH (H0) then 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Post-filter plasma lipids level |  | 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Pre-filter plasma Procalcitonin level |  | At initiation of CCVH (H0) then 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Post-filter plasma Procalcitonin level |  | 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Pre-filter plasma Phospholipid Transfer Protein level |  | At initiation of CCVH (H0) then 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Post-filter plasma Phospholipid Transfer Protein level |  | 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Pre-filter plasma Cholesteryl Ester Transfer Protein level |  | At initiation of CCVH (H0) then 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Post-filter plasma Cholesteryl Ester Transfer Protein level |  | 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Pre-filter plasma lipopolysaccharide (LPS) Binding Protein level |  | At initiation of CCVH (H0) then 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Post-filter plasma LPS-Binding Protein level |  | 1, 4, 12 and 24 hours after the initiation of CVVH | 
| Norepinephrine requirements |  | 4, 12 and 24 hours after the initiation of CVVH | 
| Fluids infused |  | 4, 12 and 24 hours after the initiation of CVVH | 
| Patient survival |  | At day 7 | 
| Patient survival |  | At day 30 | 
| Patient survival |  | At day 90 | 
| Comparison of the results obtained on the above-mentioned parameters, according to the type of bacteria identified from standard care microbiological exams. |  | At day 7 |