Safety and Efficacy of HA380 Hemoadsorption in Patients With Septic Shock

Study Overview
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Brief Summary
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Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Intensive care unit (ICU) mortality in patients with septic shock and acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) remains high and approximates 50-60%. Sepsis is the leading etiology for AKI and CRRT requirement in ICU patients. In septic shock, the dysregulated host response to infectious pathogens leads to a cytokine storm with uncontrolled production and release of humoral pro-inflammatory mediators. These pro-inflammatory mediators and cytokines exert cellular toxicity and promote the development of organ dysfunction and increased mortality. In addition to treating AKI, CRRT techniques can be employed for adsorption of inflammatory mediators extracorporally using specially developed adsorption membranes, hemoperfusion sorbent cartridges or columns. Several methods and devices, such as Oxiris®-AN69 membrane, CytoSorb® cytokine hemoadsorption and polymyxin B (Toraymyxin) endotoxin adsorption and plasmapheresis have been evaluated in small study series but to date the data on outcome benefits remains controversial. HA380 (Jafron Biomedical Co , Ltd, Zhuhai, China) is a CE-labeled hemoadsorption cartridge developed to treat patients with septic shock. It contains hemo-compatible, porous polymeric beads that adsorp cytokines and mid-molecular weight toxins on their surface. The cytokines absorved using this cartridge are IL-1, IL-6, IL-8, IL-10 in addition to TNF-α8. Therefore, this study aims to examine the potential effects of cytokine adsorption using HA380 in addition to hemodiafiltration with the Oxiris®-AN69 membrane on ICU- and 90-day mortality in patients with septic shock and AKI.

Detailed Description
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Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection and carries a risk for lethality, considerably exceeding that of a mere infection. Intensive care unit (ICU) mortality in patients with septic shock and acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) remains high and approximates 50-60% despite recent technical advancements in patient care. Sepsis is the leading etiology for AKI and CRRT requirement in ICU patients and almost half of the critically ill patients with sepsis develop AKI. In septic shock, the dysregulated host response to infectious pathogens leads to a cytokine storm with uncontrolled production and release of humoral pro-inflammatory mediators. These pro-inflammatory mediators and cytokines exert cellular toxicity and promote the development of organ dysfunction and increased mortality. Septic shock is defined according to the Sepsis-3 consensus criteria as sepsis with a vasopressor requirement to maintain a mean blood pressure (MAP) ≥65 mm Hg, despite adequate fluid resuscitation, and a serum lactate level >2 mmol/L. In addition to treating AKI, CRRT techniques can be employed for adsorption of inflammatory mediators extracorporally using specially developed adsorption membranes, hemoperfusion sorbent cartridges or columns. The aim of these techniques is to decrease the early deleterious effects of the cytokine storm and high endotoxin levels during the first hours and days of treatment of septic shock to benefit the patient. Several methods and devices, such as Oxiris®-AN69 membrane, CytoSorb® cytokine hemoadsorption and polymyxin B (Toraymyxin) endotoxin adsorption and plasmapheresis have been evaluated in small study series or are under evaluation for improving patient outcomes in septic shock. However, to date the data on outcome benefits remains controversial. Previous study series have shown a decrease in cytokine levels, improved hemodynamics and diminished need for vasopressor in patients treated using these methods. However, mortality benefit remains unclear. HA380 (Jafron Biomedical Co , Ltd, Zhuhai, China) is a CE-labeled hemoadsorption cartridge developed to treat patients with septic shock. It contains hemo-compatible, porous polymeric beads that adsorp cytokines and mid-molecular weight toxins on their surface. The cytokines absorved using this cartridge are IL-1, IL-6, IL-8, IL-10 in addition to TNF-α8. Therefore, this study aims to examine the potential effects of cytokine adsorption using HA380 in addition to hemodiafiltration with the Oxiris®-AN69 membrane on ICU- and 90-day mortality in patients with septic shock. To study patients with the highest degree of morbidity the study will recruit only septic shock patients with a high vasopressor requirement before CRRT initiation.

Official Title
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Safety and Efficacy of HA380 HEMoadsorption in Combination With OXiris Membrane for Continuous HemoDiaFiltration in Patients With Septic Shock - HEMOX-HDF Trial

Conditions
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Septic Shock, Acute Kidney Injury

Intervention / Treatment
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* Device: Combined HA380 hemoadsorption and continuous veno-venous hemodiafiltration (CVVHDF) with Oxiris®-AN69 membranes
* Device: Continuous veno-venous hemodiafiltration (CVVHDF) with Oxiris®-AN69 membranes


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years, admitted to the ICU Septic shock according to the Sepsis-3 criteria and a norepinephrine requirement ≥0.2µg/kg/min despite adequate fluid resuscitation Acute kidney injury at or after ICU admission and the treating physician considers that initiation of CRRT is likely within 48 hours. Informed consent from the patient or family members is received Exclusion Criteria: Maintenance dialysis dependency or RRT during current hospital stay prior to ICU admission GFR less than 20ml/kg/1.73m2 prior to hospital admission (within 365 days) Neurosurgical patients Pregnant women Patient's lack of commitment to start RRT Chronic or acute clinical condition with a prognosis below 6 months History of heparin allergy or heparin induced thrombocytopenia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CVVHDF with Oxiris®-AN69 membrane<br>Control arm | Device: Continuous veno-venous hemodiafiltration (CVVHDF) with Oxiris®-AN69 membranes<br>* Continuous veno-venous hemodiafiltration (CVVHDF) with Oxiris®-AN69 membranes (control arm)<br>|
| Active Comparator: CVVHDF with Oxiris®-AN69 membrane + Hemoadsorption using HA380<br>Intervention arm | Device: Combined HA380 hemoadsorption and continuous veno-venous hemodiafiltration (CVVHDF) with Oxiris®-AN69 membranes<br>* Combined HA380 hemoadsorption and continuous veno-venous hemodiafiltration (CVVHDF) with Oxiris®-AN69 membranes (intervention arm)or mere CVVHDF using the Oxiris®-AN69 membrane (control arm).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intensive care mortality | Intensive care mortality | During ICU care, 1 year | 
| 90-day mortality | 90-day mortality | Within 90 days from ICU admission, 90 days | 
| Days alive at day 90 without vasoactives, invasive mechanical ventilation and renal replacement therapy. | Days alive at day 90 without vasoactives, invasive mechanical ventilation and renal replacement therapy. | 90 days following ICU admission, 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vasopressor support at 24 hours, 48 hours and 72 hours following CVVHDF initiation | Noradrenalin infusion rate (unit:µg/kg/min) at 24 hours, 48 hours and 72 hours following CVVHDF initiation | 24 hours, 48 hours and 72 hours following CVVHDF initiation | 
| Fluid balance at 24 hours, 48 hours and 72 hours following CVVHDF initiation | Cumulative fluid balance (unit: ml) at 24 hours, 48 hours and 72 hours following CVVHDF initiation | 24 hours, 48 hours and 72 hours following CVVHDF initiation | 
| Cytokine levels at 24 hours, 48 hours and 72 hours following CVVHDF initiation | Cytokine levels (unit: ng/l) at 24 hours, 48 hours and 72 hours following CVVHDF initiation | 24 hours, 48 hours and 72 hours following CVVHDF initiation | 
| C-reactive protein levels at 24 hours, 48 hours and 72 hours following CVVHDF initiation | C-reactive protein levels (unit: mg/l) at 24 hours, 48 hours and 72 hours following CVVHDF initiation | 24 hours, 48 hours and 72 hours following CVVHDF initiation | 
| Procalcitonin levels at 24 hours, 48 hours and 72 hours following CVVHDF initiation | Procalcitonin levels (unit: µg/l) at 24 hours, 48 hours and 72 hours following CVVHDF initiation | 24 hours, 48 hours and 72 hours following CVVHDF initiation | 
| Renal recovery at 90-days following randomization | Estimated glomerular filtration rate (unit: ml/min/1.73 m²) and dialysis dependency (yes/no) at 90-days following randomization | 90 days following randomization, 90 days |