Efficacy of Add-on Plasma Exchange As an Adjunctive Strategy Against Septic Shock (EXCHANGE-2)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Septic Shock
• Intervention / Treatment: Device: Therapeutic Plasma Exchange (TPE)

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.

• Study Type: Interventional
• Enrollment (Estimated): 274
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sascha David, Prof. Dr.; Phone Number: +41 44 255 8653; Email: sascha.david@usz.ch
• Study Contact Backup: Name: Klaus Stahl, PD Dr.; Phone Number: +49 (0)176 1532 8277; Email: stahl.klaus@mh-hannover.de

Study Locations

• Austria
  • Innsbruck, Austria
    • Not yet recruiting
    • University Hospital Innsbruck
    • Contact: Michael Joannidis, Prof. Dr.
  • Vienna, Austria
    • Not yet recruiting
    • University Hospital Vienna
    • Contact: Peter Schellongowski, Prof. Dr.
• Germany
  • Berlin, Germany
    • Not yet recruiting
    • St. Joseph Hospital
    • Contact: Christoph Buettner; Email: Christoph.Buettner@sjk.de
  • Berlin, Germany
    • Not yet recruiting
    • University Hospital Berlin Charite
    • Contact: Philipp Enghard, PD Dr.; Email: philipp.enghard@charite.de
  • Bonn, Germany, 53127
    • Recruiting
    • University Hospital Bonn
    • Contact: Christian Bode, PD Dr.; Phone Number: +49 (0)228 281 14119; Email: christian.bode@ukbonn.de
  • Braunschweig, Germany
    • Not yet recruiting
    • Hospital Braunschweig
    • Contact: Jan T. Kielstein, Prof. Dr.
  • Bremerhaven, Germany
    • Not yet recruiting
    • Hospital Bremerhaven
    • Contact: Joern Bramstedt, Dr.; Email: Joern.Bramstedt@klinikum-bremerhaven.de
  • Cologne, Germany
    • Not yet recruiting
    • University Hospital Cologne
    • Contact: Matthias Kochanek, Prof. Dr.; Email: matthias.kochanek@uk-koeln.de
  • Cologne, Germany
    • Not yet recruiting
    • Hospital Cologne Meerheim
    • Contact: Achim Joerres, Prof. Dr.; Email: joerresa@kliniken-koeln.de
  • Erlangen, Germany
    • Not yet recruiting
    • University Hospital Erlangen
    • Contact: Carsten Willam, Prof. Dr.; Email: Carsten.Willam@uk-erlangen.de
  • Essen, Germany
    • Not yet recruiting
    • University Hospital Essen
    • Contact: Thorsten Brenner, Prof. Dr.; Email: Thorsten.Brenner@uk-essen.de
  • Halle, Germany
    • Active, not recruiting
    • University Hospital Halle
  • Hamburg, Germany
    • Not yet recruiting
    • University Hospital Hamburg (UKE)
    • Contact: Stefan Kluge, Prof. Dr.
  • Hannover, Germany, 30625
    • Recruiting
    • Hannover Medical School Anesthesiology
    • Contact: Hans-Joerg Gillmann, Dr.; Email: gillmann.hans-joerg@mh-hannover.de
  • Hannover, Germany, 30625
    • Recruiting
    • Hannover Medical School Internal Medicine
    • Contact: Klaus Stahl, PD Dr.; Phone Number: +49 (0)176 1532 8277; Email: stahl.klaus@mh-hannover.de
  • Heidelberg, Germany, 69120
    • Not yet recruiting
    • University Hospital Heidelberg
    • Contact: Markus Weigand; Email: Markus.Weigand@med.uni-heidelberg.de
  • Jena, Germany
    • Not yet recruiting
    • University Hospital Jena
    • Contact: Michael Bauer, Prof. Dr.; Email: michael.bauer@med.uni-jena.de
  • Kiel, Germany
    • Not yet recruiting
    • University Hospital Kiel
    • Contact: Norbert Weiler, Prof. Dr.; Email: norbert.weiler@uksh.de
  • Magdeburg, Germany
    • Not yet recruiting
    • Hospital Magdeburg
    • Contact: Martin Sauer, Prof. Dr.; Email: Martin.Sauer@Klinikum-Magdeburg.de
  • Muenster, Germany
    • Not yet recruiting
    • University Hospital Muenster Anesthesiology
    • Contact: Alexander Zarbock, Prof. Dr.; Email: zarbock@uni-muenster.de
  • Munich, Germany
    • Not yet recruiting
    • University Hospital Munich (TUM) Anesthesiology
    • Contact: Markus Heim, Dr.; Email: m.heim@tum.de
  • Munich, Germany
    • Not yet recruiting
    • University Hospital Munich (TUM) Internal Medicine
    • Contact: Tobias Lahmer, PD Dr.
  • Rostock, Germany
    • Not yet recruiting
    • University Hospital Rostock
    • Contact: Steffen Mitzner, Prof. Dr.; Email: steffen.mitzner@med.uni-rostock.de
• Switzerland
  • Bern, Switzerland
    • Not yet recruiting
    • University Hospital Bern
    • Contact: Joerg C. Schefold
  • Zurich, Switzerland, 8091
    • Not yet recruiting
    • University Hospital Zurich
    • Contact: Sascha David, Prof. Dr.; Phone Number: +41 44 255 8653; Email: sascha.david@usz.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Therapeutic Plasma Exchange (TPE); 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); 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.
No Intervention: Standard of Care (SOC); Non-interventional standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Hannover Medical School
• Investigators: Principal Investigator: Sascha David, Prof. Dr., University of Zurich; Principal Investigator: Klaus Stahl, PD Dr., Hannover Medical School; Principal Investigator: Christian Bode, PD Dr., University Hospital, Bonn

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 19, 2025
• Primary Completion (Estimated): February 1, 2028
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: January 16, 2023
• First Submitted That Met QC Criteria: February 3, 2023
• First Posted (Actual): February 14, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 11, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Septic Shock; Sepsis; Plasmapheresis; Multi-organ failure; Extracorporeal therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Shock, Septic
• Other Study ID Numbers: EXCHANGE-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No