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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Therapeutic Plasma Exchange (TPE) | Experimental | 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. |
|
| Standard of Care (SOC) | No Intervention | Non-interventional standard of care |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Therapeutic Plasma Exchange (TPE) | Device | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 28-day mortality | from randomization up to 28 days following randomization |
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| Safety Endpoints | includes: Incidence of bleeding, allergic reactions, Transfusion associated lung injury (TRALI), severe thrombocytopenia (< 5000/µl) and (other) severe adverse events (SAEs) | from randomization until day 7 following randomization |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Sascha David, Prof. Dr. | Contact | +41 44 255 8653 | sascha.david@usz.ch | |
| Klaus Stahl, PD Dr. | Contact | +49 (0)176 1532 8277 | stahl.klaus@mh-hannover.de |
| Name | Affiliation | Role |
|---|---|---|
| Sascha David, Prof. Dr. | University of Zurich | Principal Investigator |
| Klaus Stahl, PD Dr. | Hannover Medical School | Principal Investigator |
| Christian Bode, PD Dr. |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Innsbruck | Not yet recruiting | Innsbruck | Austria |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30373638 | Background | Knaup H, Stahl K, Schmidt BMW, Idowu TO, Busch M, Wiesner O, Welte T, Haller H, Kielstein JT, Hoeper MM, David S. Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers. Crit Care. 2018 Oct 30;22(1):285. doi: 10.1186/s13054-018-2220-9. | |
| 32122366 |
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|
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 |
| University Hospital, Bonn |
| Principal Investigator |
| University Hospital Vienna | Not yet recruiting | Vienna | Austria |
|
| St. Joseph Hospital | Not yet recruiting | Berlin | Germany |
|
| University Hospital Berlin Charite | Not yet recruiting | Berlin | Germany |
|
| University Hospital Bonn | Recruiting | Bonn | 53127 | Germany |
|
| Hospital Braunschweig | Not yet recruiting | Braunschweig | Germany |
|
| Hospital Bremerhaven | Not yet recruiting | Bremerhaven | Germany |
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| Hospital Cologne Meerheim | Not yet recruiting | Cologne | Germany |
|
| University Hospital Cologne | Not yet recruiting | Cologne | Germany |
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| University Hospital Erlangen | Not yet recruiting | Erlangen | Germany |
|
| University Hospital Essen | Not yet recruiting | Essen | Germany |
|
| University Hospital Halle | Active, not recruiting | Halle | Germany |
| University Hospital Hamburg (UKE) | Not yet recruiting | Hamburg | Germany |
|
| Hannover Medical School Anesthesiology | Recruiting | Hanover | 30625 | Germany |
|
| Hannover Medical School Internal Medicine | Recruiting | Hanover | 30625 | Germany |
|
| University Hospital Heidelberg | Not yet recruiting | Heidelberg | 69120 | Germany |
|
| University Hospital Jena | Not yet recruiting | Jena | Germany |
|
| University Hospital Kiel | Not yet recruiting | Kiel | Germany |
|
| Hospital Magdeburg | Not yet recruiting | Magdeburg | Germany |
|
| University Hospital Munich (TUM) Anesthesiology | Not yet recruiting | Munich | Germany |
|
| University Hospital Munich (TUM) Internal Medicine | Not yet recruiting | Munich | Germany |
|
| University Hospital Muenster Anesthesiology | Not yet recruiting | Münster | Germany |
|
| University Hospital Rostock | Not yet recruiting | Rostock | Germany |
|
| University Hospital Bern | Not yet recruiting | Bern | Switzerland |
|
| University Hospital Zurich | Not yet recruiting | Zurich | 8091 | Switzerland |
|
| Stahl K, Schmidt JJ, Seeliger B, Schmidt BMW, Welte T, Haller H, Hoeper MM, Budde U, Bode C, David S. Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock. Crit Care. 2020 Mar 2;24(1):71. doi: 10.1186/s13054-020-2799-5. |
| 33063613 | Background | Stahl K, Bikker R, Seeliger B, Schmidt JJ, Schenk H, Schmidt BMW, Welte T, Haller H, Hoeper MM, Brand K, David S. Effect of Therapeutic Plasma Exchange on Immunoglobulin Deficiency in Early and Severe Septic Shock. J Intensive Care Med. 2021 Dec;36(12):1491-1497. doi: 10.1177/0885066620965169. Epub 2020 Oct 16. |
| 33471132 | Background | David S, Bode C, Putensen C, Welte T, Stahl K; EXCHANGE study group. Adjuvant therapeutic plasma exchange in septic shock. Intensive Care Med. 2021 Mar;47(3):352-354. doi: 10.1007/s00134-020-06339-1. Epub 2021 Jan 20. No abstract available. |
| 34817751 | Background | Stahl K, Hillebrand UC, Kiyan Y, Seeliger B, Schmidt JJ, Schenk H, Pape T, Schmidt BMW, Welte T, Hoeper MM, Sauer A, Wygrecka M, Bode C, Wedemeyer H, Haller H, David S. Effects of therapeutic plasma exchange on the endothelial glycocalyx in septic shock. Intensive Care Med Exp. 2021 Nov 24;9(1):57. doi: 10.1186/s40635-021-00417-4. |
| 35551628 | Background | Stahl K, Wand P, Seeliger B, Wendel-Garcia PD, Schmidt JJ, Schmidt BMW, Sauer A, Lehmann F, Budde U, Busch M, Wiesner O, Welte T, Haller H, Wedemeyer H, Putensen C, Hoeper MM, Bode C, David S. Clinical and biochemical endpoints and predictors of response to plasma exchange in septic shock: results from a randomized controlled trial. Crit Care. 2022 May 12;26(1):134. doi: 10.1186/s13054-022-04003-2. |
| 37061693 | Derived | David S, Bode C, Stahl K; EXCHANGE-2 Study group. EXCHANGE-2: investigating the efficacy of add-on plasma exchange as an adjunctive strategy against septic shock-a study protocol for a randomized, prospective, multicenter, open-label, controlled, parallel-group trial. Trials. 2023 Apr 15;24(1):277. doi: 10.1186/s13063-023-07300-5. |
| ID | Term |
|---|---|
| D012772 | Shock, Septic |
| D018805 | Sepsis |
| D009102 | Multiple Organ Failure |
| ID | Term |
|---|---|
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012769 | Shock |
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| ID | Term |
|---|---|
| D010951 | Plasma Exchange |
| ID | Term |
|---|---|
| D001803 | Blood Transfusion |
| D001691 | Biological Therapy |
| D013812 | Therapeutics |
| D010956 | Plasmapheresis |
| D001781 | Blood Component Removal |
| D016060 | Sorption Detoxification |
| D005112 | Extracorporeal Circulation |
| D013514 | Surgical Procedures, Operative |
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