Efficacy of add-on Plasma Exchange as an Adjunctive Strategy Against Septic Shock

Study Overview
=================
Brief Summary
-----------------
Randomized, prospective, multicenter, open-label, controlled, parallel-group interventional trial to test the adjunctive effect of therapeutic plasma exchange in patients with early septic shock.

Detailed Description
-----------------
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection; in septic shock profound circulatory, cellular and metabolic abnormalities are associated with an even higher mortality. Sepsis is a major healthcare problem, affecting millions of individuals around the world each year. Its incidence appears to be rising, and the mortality caused by septic shock in Germany in 2015 remains extraordinarily high (58.8%). It is well known - from the pathophysiological point of view - that these patients do not die from their infection per se but rather from multiple organ failure caused by their own overwhelming host response. This fact is so fundamental that it has been implemented as a key part of the 2016 sepsis definition (SEPSIS-3). Despite tremendous efforts during the last decades, innovative approaches targeting this fundamental hallmark of the disease, thereby reducing organ dysfunction, are lacking. Undoubtedly, there is an unmet need to expand the current standard of care for these patients by a more specific intervention. The investigators hypothesize that early Therapeutic Plasma Exchange (TPE) in the most severely ill individuals will dampen the injurious maladaptive host response by removing injurious mediators thereby limiting organ dysfunction. The potential impact of this trial is of immense clinical relevance as it evaluates a promising adjunctive treatment option for a patient cohort suffering from an extraordinary high mortality. A positive trial result could truly change the current standard of care (SOC) - that is mostly supportive - of septic shock patients. Of note, there is neither a patent nor a direct commercial interest in such a trial.

Official Title
-----------------
Randomized, Prospective, Multicenter, Open-label, Controlled, Parallel-group Trial Investigating the Efficacy of add-on Plasma Exchange as an Adjunctive Strategy Against Septic Shock - 2

Conditions
-----------------
Septic Shock

Intervention / Treatment
-----------------
* Device: Therapeutic Plasma Exchange (TPE)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: New onset of septic shock (< 24 hrs), (SEPSIS-3 definition) Norepinephrine (NE) dose ≥ 0.4 μg/kg/min ≥ 30 min OR NE ≥ 0.3 μg/kg/min + vasopressin (any dose) Established vascular access suitable for plasma exchange independent of study inclusion (due to established indication of RRT, expected need for RRT within the next 48 hours or other medical reasons as assessed by treating physician team) Exclusion Criteria: Age < 18 or > 80 years Urogenital focus of infection Pregnancy Heparin-induced thrombocytopenia Known reaction against fresh frozen plasma (FFP)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Therapeutic Plasma Exchange (TPE)<br>1 x TPE with donor Fresh Frozen Plasma (FFPs) (1.2 x individual plasma volume) within the first 6 hrs after randomization. A second TPE can be performed if the patient remains vasopressor dependent ≥ 0.4 ug/kg/min within 24 hours after the first intervention. | Device: Therapeutic Plasma Exchange (TPE)<br>* The TPE treatment will be initiated within 6 hrs after randomization. Duration of TPE treatment is approximately 120-180 minutes. An additional second TPE can be performed if the patient remains vasopressor dependent ≥ 0.4 ug/kg/min after 24 hours following the first TPE procedure. Both unfractionated heparin (UFH) and citrate may be used as anticoagulant medication. To ensure treatment comparability between different patients, we will replace plasma in a fixed ratio of 1.2 x the individual patient's total plasma fluid.<br>|
| No Intervention: Standard of Care (SOC)<br>Non-interventional standard of care | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28-day mortality |  | from randomization up to 28 days following randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean daily Sequential Organ Failure Score (SOFA) score over the first 7 days (KEY secondary outcome) | Per-patient mean daily SOFA score over the first 7 days, ranging from 0-24 points with higher scores indicating more severe organ dysfunction | from randomization up to 7 days following randomization | 
| Organ support free days until day 28 (KEY secondary outcome) | total days free of invasive ventilation, vasopressors/inotrops and renal replacement therapy (RRT) until day 28 | from randomization up to 28 days following randomization | 
| 90-day mortality |  | from randomization up to 90 days following randomization | 
| Intensive Care unit (ICU) length of stay | total days in ICU | from randomization until ICU discharge | 
| Hospital length of stay | total days in hospital | from randomization until hospital discharge | 
| Basic Hemodynamics | includes: Norepinephrine- [µg/kg/min], Dobutamine [µg/kg/min], Epinephrine- [µg/kg/min] and Vasopressin-dose [U/kg/min], Vasocative-inotropic (VIS) Score with higher scores indicating higher vasopressor/inotropic support, Mean arterial pressure (MAP, [mmHg]), Heart Rate (HR, [1/min]), Central venous pressure (CVP, [mmHg]) and Central-Venous Oxygen Saturation (ScvO2, [%]) at 0 and 12 hrs, d1-7 | at days 1-7 following randomization | 
| Extended Hemodynamics | includes: Cardiac Index (CI, [l/min/m2]), Global End-Diastolic Volume Index (GEDI, [ml/m2]), Sytemic Vascular Resistance Index (SVRI, [dyn*s*cm-5*m2]), Stroke Volume Variation (SVV, [%] ), Extravascular Lung Water Index (ELWI, [ml/kg]) and Pulmonar Vascular Permeability Index (PVPI) at at 0 and 12 hrs, d1-7 | at days 1-7 following randomization | 
| Arterial blood gas analysis | includes: pH, PCO2 [mmHg], HCO3- [mmol], PO2 [mmHg], Lactate [mmol/l] at 0 and 12 hrs, d1-7 | at days 1-7 following randomization | 
| Respiratory function | includes: pO2/FiO2, Tidal Volume (VT, [ml]), Positive End-Exspiratory Pressure (PEEP, [cmH2O]), Peak-Pressure (Ppeak, [cmH2O]), Plateau-Pressure (Pplat, [cmH2O]), Respiratory Rate (RR, [1/min]), Inspiratory Time (Tinsp, [s]), Inspiratory-Flow and End-tidal-CO2 (etCO2, [mmHg]) at 0 and 12 hrs, d1-7 | at days 1-7 following randomization | 
| Renal function | includes: Presence of Acute kindey injury (AKI), AKI stage (KDIGO definition) stage 1-3 with higher stage indicating worse renal function, Need for Renal Replacement Therapy (RRT), Estimated Glomerular Filtration Rate (eGFR following CKD-EPI equation) [ml/min], Fluid intake [ml/d], Urine output [ml/d], Ultrafiltration and Net daily fluid balance [ml/d] at 0 and 12 hrs, d1-7 and at ICU discharge | at days 1-7 following randomization and at ICU discharge | 
| Liver Function | includes: Bilirubin, Aspartate aminotransferase (AST, [U/l]), Alanine aminotransferase (ALT, [U/l]), Alkaline phosphatase (AP, [U/l]), Gamma-glutamyl transferase (GGT, [U/l]), Cholinesterase (CHE, [kU/l]) and Albumin [g/l] at 0 and 12 hrs, d1-7 and at ICU discharge | at days 1-7 following randomization and at ICU discharge | 
| Sepsis associated coagulopathy | includes: Differential blood count including schistocytes [%], Fibrinogen [g/l] , D-Dimer [mg/l], International Normalized Ratio (INR), Lactate dehydrogenase (LDH, [U/l]), Antithrombin-III (AT-III, [%]), Protein C [%] and International Society on Thrombosis and Hemostasis- Disseminated Intravscular Coagulation Score (ISTH-DIC, [U/l]) ranging from 0-8 points with higher values indication more severe DIC at 0 and 12 hrs, d1-7, A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13, [%]) and von-Willebrand-Factor Antigen (vWF:Ag,[IU/l]) at 0 and 24 hrs | at days 1-7 following randomization | 
| Inflammatory response | includes: C-reactive protein (CRP, [mg/l]), Procalcitonin (PCT, [ug/l]), Interleukin-6 (IL-6, [ng/ml]), Ferritin [ug/l] and Neutrophil/Lymphocyte ratio at 0 and 12 hrs, d1-7 | at days 1-7 following randomization | 
| Cardiac function | includes: Creatine kinase (CK, [U/l]), Myoglobin [ug/l], Troponin T [ng/l], NT-proBNP [ng/l] at 0 and 12 hrs, d1-7 and at ICU discharge | at days 1-7 following randomization and at ICU discharge | 
| Secondary infections | includes: incidence and type of secondary infections until ICU and hospital discharge, incidence of viral (HSV, EBV, CMV) reactivation at d7 and d14 | from randomization until hospital discharge | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Septic Shock, Sepsis, Multi-organ failure, Extracorporeal therapy, Plasmapheresis