Extracorporal Cytokin Removal in Septic Shock: a Prospective, Randomized, Multicenter Clinical Trial

Study Overview
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Brief Summary
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Sepsis and septic shock have mortality rates between 20-50%. When standard therapeutic measures fail to improve patients' condition, additional therapeutic alternatives are applied to reduce morbidity and mortality. One of the most recent alternatives is extracorporeal cytokine hemoadsorption. One of the most tested devices is CytoSorb, however, there are a lot of open questions, such timing, dosing and of course its overall efficacy. This study aims to compare the efficacy of standard medical therapy (Group A, SMT) and continuous extracorporeal cytokine removal with CytoSorb therapy in patients with early refractory septic shock. Furthermore, we compare the dosing of CytoSorb adsorber device - as the cartridge will be changed in every (12 Group B) or 24 hours (Group C).

Official Title
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Dosing of Extracorporeal Cytokine Removal In Septic Shock (DECRISS): a Prospective, Randomized, Multicenter Clinical Trial

Conditions
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Septic Shock

Intervention / Treatment
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* Combination Product: Standard medical therapy
* Device: Standard medical therapy plus cytokine removal treatment using Cytosorb, with the adsorber changed in every 12 hours
* Device: Standard medical therapy plus cytokine removal treatment using Cytosorb, with the adsorber changed in every 24 hours


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Septic shock as defined by the Sepsis-3 criteria Septic shock both medical or surgical ethiology (except for re-operation) APACHE > 25 Mechanical ventilation Norepinephrine requirement ≥0.4 µg/kg/min for at least 30 minutes, when hypovolemia is highly unlikely as indicated by invasive hemodynamic measurements assessed by the attending physician Invasive hemodynamic monitoring to determine cardiac output and derived variables Procalcitonin level ≥ 10 ng/ml Inclusion within 6 - 24 hours after the onset of vasopressor need and after all standard therapeutic measures have been implemented without clinical improvement (i.e.: the shock is considered refractory) Exclusion Criteria: Patients under 18 years and over 80 Lack of health insurance Pregnancy Standard guideline-based medical treatment not exhausted (detailed below at 3.6) standard medical therapy) End stage organ failure New York Heart Association Class IV. Chronic renal failure with eGFR < 15 ml/min/1,73 m2 End-stage liver disease (MELD score >30, Child-Pugh score Class C Unlikely survival for 24 hours according to the attending physician Acute onset of hemato-oncological illness Post cardiopulmonary resuscitation care Re-operation in context with the septic insult Immunosuppression systemic steroid therapy (>10 mg prednisolon/day) immunosuppressive agents (i.e.: methotrexate, azathioprine, cyclosporin, tacrolimus, cyclophosphamide) Human immunodeficiency virus infection (active AIDS): HIV-VL > 50 copies/mL Patients with transplanted vital organs Thrombocytopenia (<20.000/ml) More than 10%-of body surface area with a third-degree burn Acute coronary syndrome

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Interventional Model Description: Prospective, randomized, controlled, three-arm, open-label, international, multi-centre, phase III study
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A<br>Patients randomized to standard medical therapy. | Combination Product: Standard medical therapy<br>* Standard medical therapy (according to the Surviving Sepsis Campaign) will include standard monitoring (pulseoximetry, 5-lead ECG, continuous invasive blood pressure monitoring, central venous cannulation and 24 with PiCCO-technology. Norepinephrine as a vasopressor and dobutamine - if needed - as an inotrope will be administered by the attending physician.<br>|
| Active Comparator: Group B<br>Patients randomized to cytokine removal therapy with Cytosorb, with the adsorber device changed in every 12 hours. | Device: Standard medical therapy plus cytokine removal treatment using Cytosorb, with the adsorber changed in every 12 hours<br>* Standard medical therapy, as discussed above will be applied. Furthermore, Cytosorb will be administered as soon as it is possible after randomization but not later than 2 hour (start of the treatment, T0). In a blood pump circuit in pre-haemofilter position, using a kidney replacement device of Fresenius Multifiltrate as a solo therapy or in combination with renal replacement therapy. It will be run in CVVHD, CVVHDF or CVVH mode with a 150 and 200 ml/min blood flow. Anticoagulation will be applied intravenously with heparin, low molecular weight heparin or citrate. The aim of the pump flow rate will be 100-400 mL/min, and the flow rate will be recorded. Possible shock reversal will be assessed by the physician attending. Adsorber cartridges will be changed in every 12 hours. End of the study period (Te): 12 hours after shock reversal, death of the patient, or maximum of five days, whichever happens first.<br>|
| Active Comparator: Group C<br>Patients randomized to cytokine removal therapy with Cytosorb, with the adsorber device changed in every 24 hours. | Device: Standard medical therapy plus cytokine removal treatment using Cytosorb, with the adsorber changed in every 24 hours<br>* The standard medical therapy and method of Cytosorb treatment as detailed above will be applied. Adsorber cartridges will be changed in every 24 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Shock reversal | Proportion of patients achieving shock reversal, defined as follows: no need (or minimal need, meaning max. the 10% of the maximum dose) of vasopressore for 3 hours, with haemodynamic measurements, and arterial, central venous blood gas analysis, arterial lactate level measurement, venous and arterial pCO2-gap and O2 saturation measurements to confirm cardiorespiratory stability | At the time of shock reversal assessed up to 5 days | 
| Time to shock reversal | The time from the start of the treatment (T0) until shock reversal | From the start of the treatment until shock reversal assessed up to 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Procalcitonine level | Absolute level of procalcitonine | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Change in procalcitonine level | Change in procalcitonine level from the start of the treatment until the end of the study period | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Interleukin-6 level | Absolute level of interleukin-6 | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Change in interleukin-6 level | Change in interleukin-6 level from the start of the treatment until the end of the study period | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| C-reactive protein level | Absolute level of C-reactive protein | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Change in C-reactive protein level | Change in C-reactive protein level from the start of the treatment until the end of the study period | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Interleukin-1 level | Absolute level of interleukin-1 | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Change in interleukin-1 level | Change in interleukin-1 level from the start of the treatment until the end of the study period | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Interleukin-1ra level | Absolute level of interleukin-1ra | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Change in interleukin-1ra level | Change in interleukin-1ra level from the start of the treatment until the end of the study period | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Interleukin-8 level | Absolute level of interleukin-8 | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Change in interleukin-8 level | Change in interleukin-8 level from the start of the treatment until the end of the study period | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Interleukin-10 level | Absolute level of interleukin-10 | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Change in interleukin-10 level | Change in interleukin-10 level from the start of the treatment until the end of the study period | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Tumor necrosis factor alpha level | Absolute level of tumor necrosis factor alpha | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Change in tumor necrosis factor alpha level | Change in tumor necrosis factor alpha level from the start of the treatment until the end of the study period | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Syndecan-1 level | Absolute level of syndecan-1 | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Change in syndecan-1 level | Change in syndecan-1 level from the start of the treatment until the end of the study period | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Heparan sulphate level | Absolute level of heparan sulphate | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Change in heparan sulphate level | Change in heparan sulphate level from the start of the treatment until the end of the study period | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Arterial lactate levels | Absolute level of arterial lactate levels | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Change in arterial lactate levels level | Change in arterial lactate level from the start of the treatment until the end of the study period | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | 
| Change in SOFA score | Change in SOFA score from the start of the treatment until the end of the study period | From the start of the treatment until the end of the treatment assessed up to 5 days | 
| Change in extravascular lung water (EVLW) | Change in extravascular lung water (EVLW) from the start of the treatment until the end of the study period | From the start of the treatment until the end of the treatment assessed up to 5 days | 
| Duration of mechanical ventilation | Duration of mechanical ventilation given in days | From the start of the treatment until the end of the treatment assessed up to 5 days | 
| Duration of catecholamine requirement | Duration of catecholamine requirement given in days | From the start of the catecholamine requirement until the end of the catecholamine requirement assessed up to 5 days | 
| Duration of renal replacement therapy | Duration of renal replacement therapy given in days | From the start of the renal replacement therapy requirement until the end of the renal replacement therapy requirement assessed up to 90+/-7 days at the second follow-up visit | 
| Need for dialysis | Rate of patients, who require dialysis | day 28±7, day 90±7 | 
| Length of internsive care unit stay | Length of intensive care unit stay given in days | From admission to intensive care unit until the end of intensive care unit assessed at study completion an avarage of 90 days | 
| Length of hospital stay | Length of hospital stay given in days | From admission to the hospital until the end of hospital stay assessed at study completion an avarage of 90 days | 
| Survival | Rate of surviving patients | Rate if surviving patients assessed at death, or study completion which ever happens first, up to 90 +/-7 days | 
| Adverse events | Rate of patients experiencing adverse events, or device deficiencies | Recorded at the occurrance of adverse events, and study completion up to 90 +/- 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, septic shock, cytosorb, cytokine removal