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

Septic Shock Clinical Trial

— EXCHANGE-2  

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05726825
• Other study ID #: EXCHANGE-2
• Status: Not yet recruiting
• Phase: N/A
• Start date: November 28, 2023
• Est. completion date: January 31, 2027

Study information

• Verified date: September 2023
• Source: Hannover Medical School
• Contact: Sascha David, Prof. Dr.
• Phone: +41 44 255 8653
• Email: sascha.david[@]usz.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 274
• Est. completion date: January 31, 2027
• Est. primary completion date: August 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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)

Related Conditions & MeSH terms

• Septic Shock
• Shock
• Shock, Septic

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.

Locations

Country	Name	City	State
Austria	University Hospital Innsbruck	Innsbruck
Austria	University Hospital Vienna	Vienna
Germany	St. Joseph Hospital	Berlin
Germany	University Hospital Berlin Charite	Berlin
Germany	University Hospital Bonn	Bonn
Germany	Hospital Braunschweig	Braunschweig
Germany	Hospital Bremerhaven	Bremerhaven
Germany	Hospital Cologne Meerheim	Cologne
Germany	University Hospital Cologne	Cologne
Germany	University Hospital Erlangen	Erlangen
Germany	University Hospital Essen	Essen
Germany	University Hospital Halle	Halle
Germany	University Hospital Hamburg (UKE)	Hamburg
Germany	Hannover Medical School Anesthesiology	Hannover
Germany	Hannover Medical School Internal Medicine	Hannover
Germany	University Hospital Heidelberg	Heidelberg
Germany	University Hospital Jena	Jena
Germany	University Hospital Kiel	Kiel
Germany	Hospital Magdeburg	Magdeburg
Germany	University Hospital Muenster Anesthesiology	Muenster
Germany	University Hospital Munich (TUM) Anesthesiology	Munich
Germany	University Hospital Munich (TUM) Internal Medicine	Munich
Germany	University Hospital Rostock	Rostock
Switzerland	University Hospital Bern	Bern
Switzerland	University Hospital Zurich	Zurich

Sponsors (1)

Lead Sponsor	Collaborator
Hannover Medical School

Countries where clinical trial is conducted

Austria,  Germany,  Switzerland, 

References & Publications (6)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Primary	28-day mortality		from randomization up to 28 days following randomization
Secondary	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
Secondary	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
Secondary	90-day mortality		from randomization up to 90 days following randomization
Secondary	Intensive Care unit (ICU) length of stay	total days in ICU	from randomization until ICU discharge
Secondary	Hospital length of stay	total days in hospital	from randomization until hospital discharge
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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	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