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Cytokine Adsorption in Severe, Refractory Septic Shock

Primary Purpose

Septic Shock, Cytokine Storm

Status
Completed
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
Cytokine Adsorption
Standard of Care
Sponsored by
University of Zurich
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Septic Shock focused on measuring Septic Shock, Cytokine Adsorption, Hemadsorption, extracorporeal removal

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients diagnosed septic shock in the 24 hours ensuing diagnosis:

(I) severe, refractory septic shock defined as:

  1. an acute SOFA score increase ≥2 points consequent to a presumed or proven infection
  2. volume resuscitation of at least 30ml/kg in the last 24 hours
  3. a Vasopressor Dependency Index11 (VPI) above or equal to 3
  4. a persistently elevated serum lactate level >2mmol/l (II) Interleukin-6 levels equal or above 1000 ng/l (III) were above 18 years of age.

Exclusion Criteria:

  1. Contraindication on ethical grounds
  2. child bearing or breastfeeding women
  3. terminal patients
  4. human immunodeficiency virus with a CD4 cell count <0.2 106/l
  5. allergy to Polystyrene/ Divinylbenzene, Polycarbonate, Polypropylene, Silicon or Polyester
  6. need for extra-corporeal membrane oxygenation
  7. no given consent.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Other

    Arm Label

    Cytokine Adsorption Arm

    Historical Comparison

    Arm Description

    Intervention with CytoSorb

    Patients extracted from a septic shock population treated at the same institution between 2010 and 2018 and matched to the intervention group.

    Outcomes

    Primary Outcome Measures

    Change in circulating Interleukin-6 levels over time
    Change in circulating Interleukin-6 levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Change in Vasopressor requirements over time
    Change in the Vasopressor Dependency Index, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Cumulative intensive care mortality at 30 days
    Intensive care mortality assessment at day 30 between groups

    Secondary Outcome Measures

    Change in C-reactive protein levels over time
    Change in C-reactive protein levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Change in Procalcitonin levels over time
    Change in Procalcitonin levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Change in SOFA Score over time
    Change in SOFA Score, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Change in arterial lactate levels over time
    Change in arterial lactate levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Change in cardiac index over time
    Change in cardiac index, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Change in Extra Vascular Lung Water Index over time
    Change in Extra Vascular Lung Water Index, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Change in daily Infused Volume over time
    Change in daily Infused Volume, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Change in PaO2/ FiO2 Ratio over time
    Change in PaO2/ FiO2 Ratio, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Change in Serum Albumin levels over time
    Change in Serum Albumin levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Change in Bilirubin levels over time
    Change in Bilirubin levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria

    Full Information

    First Posted
    May 27, 2021
    Last Updated
    June 7, 2021
    Sponsor
    University of Zurich
    Collaborators
    CytoSorbents Europe GmbH
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    1. Study Identification

    Unique Protocol Identification Number
    NCT04910893
    Brief Title
    Cytokine Adsorption in Severe, Refractory Septic Shock
    Official Title
    Cytokine Adsorption in Severe, Refractory Septic Shock
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    June 2021
    Overall Recruitment Status
    Completed
    Study Start Date
    November 27, 2014 (Actual)
    Primary Completion Date
    August 24, 2018 (Actual)
    Study Completion Date
    December 31, 2018 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    University of Zurich
    Collaborators
    CytoSorbents Europe GmbH

    4. Oversight

    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
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    Septic shock and the underlying dysregulated inflammatory host-response remain a major contributor to mortality in critically ill patients. Cytokine adsorption represents an attractive approach to the treatment of septic shock. Nevertheless, its effect on circulating cytokine levels, as well as on the course of disease remains largely unassessed.
    Detailed Description
    Cytokine-release plays an important role in the physiology of immune response to pathologic influences by recruiting immune cells to the pathogenic loci, be they of infectious or of non-infectious nature. Once at the focus, the activated immune cells can in turn release more cytokines if a more extensive immune response is needed. This extremely important mechanism for the organism, can however become pathological if the positive feedback loop between immune cells and cytokines, for any reason, overshoots in form of a so called cytokine storm and substantial amounts of released cytokines gain a systemic influence. The acute complication of this immune over-reaction is a SIRS, which can critically escalate into a potentially lethal multiple organ dysfunction syndrome, thus requiring immediate intensive care treatment. It is, having this framework in mind, the reason why the CytoSorb-Adsorber has been developed as a new therapeutic milestone. Essentially a haemoperfusion-filter, which through its layering with polymer beads (Divinylbenzene/ Polyvinylpyrrolidone) can adsorb cytokines as well as multiple inflammatory mediators and thus effectively remove them from the bloodstream, reducing their possible systemic influence and hence improving the outcome for patients being treated with it. The CytoSorb-Adsorber is an already CE-approved product, which has demonstrated its capacity to significantly reduce cytokine-levels such as IL-6, IL-8, IL-10, TNFα, HMGB-1, IL-1ra in a variety of pre-clinical studies. As well as in a clinical randomised multicentre study, which tested the CytoSorb-Adsorber on a cohort of ALI/ ARDS and severely septic/ septically shocked patients. The results of the later study can be very positively assessed, first of all and most importantly showing, that no security concerns had to be had in regard to the haemoperfusion-filter, as no adverse-effects attributable to the device were found. And further, by proving an effect on systemic cytokine-levels in form of a significant reduction in IL-6, IL-8, MCP-1 and IL-1ra, as well as a reduction in mortality of those patients with high initial cytokine levels, effectively reducing the 60 day mortality rate from 60% to 17% in a pool of 14 patients. With the intention to further elucidate the usefulness and clinical importance of this device this study proposes a prospective recruitment of patients in severe refractory septic shock to test the efficiency of this device.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Septic Shock, Cytokine Storm
    Keywords
    Septic Shock, Cytokine Adsorption, Hemadsorption, extracorporeal removal

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Not Applicable
    Interventional Study Model
    Parallel Assignment
    Model Description
    Prospective interventional study with comparative matched septic shock cohort
    Masking
    ParticipantOutcomes Assessor
    Allocation
    Non-Randomized
    Enrollment
    48 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Cytokine Adsorption Arm
    Arm Type
    Experimental
    Arm Description
    Intervention with CytoSorb
    Arm Title
    Historical Comparison
    Arm Type
    Other
    Arm Description
    Patients extracted from a septic shock population treated at the same institution between 2010 and 2018 and matched to the intervention group.
    Intervention Type
    Device
    Intervention Name(s)
    Cytokine Adsorption
    Other Intervention Name(s)
    CytoSorb
    Intervention Description
    Cytokine adsorption therapy will be provided continuously for 72 hours by means of the CytoSorb® (CytoSorbents Corporation, Monmouth Junction, USA) column, run in series to a veno-venous continuous hemodialysis system, which will be exchanged every 24 hours.
    Intervention Type
    Other
    Intervention Name(s)
    Standard of Care
    Intervention Description
    Standard intensive care of patients suffering septic shock
    Primary Outcome Measure Information:
    Title
    Change in circulating Interleukin-6 levels over time
    Description
    Change in circulating Interleukin-6 levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Time Frame
    Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
    Title
    Change in Vasopressor requirements over time
    Description
    Change in the Vasopressor Dependency Index, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Time Frame
    Mixed Model Assessment at timepoints 0, 2, 4, 8, 12 , 24, 48, 72 hours
    Title
    Cumulative intensive care mortality at 30 days
    Description
    Intensive care mortality assessment at day 30 between groups
    Time Frame
    30 days post fulfillment of inclusion criteria
    Secondary Outcome Measure Information:
    Title
    Change in C-reactive protein levels over time
    Description
    Change in C-reactive protein levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Time Frame
    Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
    Title
    Change in Procalcitonin levels over time
    Description
    Change in Procalcitonin levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Time Frame
    Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
    Title
    Change in SOFA Score over time
    Description
    Change in SOFA Score, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Time Frame
    Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
    Title
    Change in arterial lactate levels over time
    Description
    Change in arterial lactate levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Time Frame
    Mixed Model Assessment at timepoints 0, 2, 4, 8, 12 , 24, 48, 72 hours
    Title
    Change in cardiac index over time
    Description
    Change in cardiac index, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Time Frame
    Mixed Model Assessment at timepoints 0, 2, 4, 8, 12 , 24, 48, 72 hours
    Title
    Change in Extra Vascular Lung Water Index over time
    Description
    Change in Extra Vascular Lung Water Index, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Time Frame
    Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
    Title
    Change in daily Infused Volume over time
    Description
    Change in daily Infused Volume, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Time Frame
    Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
    Title
    Change in PaO2/ FiO2 Ratio over time
    Description
    Change in PaO2/ FiO2 Ratio, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Time Frame
    Mixed Model Assessment at timepoints 0, 2, 4, 8, 12 , 24, 48, 72 hours
    Title
    Change in Serum Albumin levels over time
    Description
    Change in Serum Albumin levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Time Frame
    Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
    Title
    Change in Bilirubin levels over time
    Description
    Change in Bilirubin levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
    Time Frame
    Mixed Model Assessment at timepoints 0, 24, 48, 72 hours

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Patients diagnosed septic shock in the 24 hours ensuing diagnosis: (I) severe, refractory septic shock defined as: an acute SOFA score increase ≥2 points consequent to a presumed or proven infection volume resuscitation of at least 30ml/kg in the last 24 hours a Vasopressor Dependency Index11 (VPI) above or equal to 3 a persistently elevated serum lactate level >2mmol/l (II) Interleukin-6 levels equal or above 1000 ng/l (III) were above 18 years of age. Exclusion Criteria: Contraindication on ethical grounds child bearing or breastfeeding women terminal patients human immunodeficiency virus with a CD4 cell count <0.2 106/l allergy to Polystyrene/ Divinylbenzene, Polycarbonate, Polypropylene, Silicon or Polyester need for extra-corporeal membrane oxygenation no given consent.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Marco Maggiorini, MD
    Organizational Affiliation
    Medizinische Intensivstation D-HOER 27, UniversitatsSpital Zürich
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    Citations:
    PubMed Identifier
    18606328
    Citation
    Wang H, Ma S. The cytokine storm and factors determining the sequence and severity of organ dysfunction in multiple organ dysfunction syndrome. Am J Emerg Med. 2008 Jul;26(6):711-5. doi: 10.1016/j.ajem.2007.10.031.
    Results Reference
    background
    PubMed Identifier
    20473001
    Citation
    Taniguchi T. Cytokine adsorbing columns. Contrib Nephrol. 2010;166:134-141. doi: 10.1159/000314863. Epub 2010 May 7.
    Results Reference
    background
    PubMed Identifier
    28979423
    Citation
    Morris C, Gray L, Giovannelli M. Early report: The use of Cytosorb haemabsorption column as an adjunct in managing severe sepsis: initial experiences, review and recommendations. J Intensive Care Soc. 2015 Aug;16(3):257-264. doi: 10.1177/1751143715574855. Epub 2015 Mar 18.
    Results Reference
    background
    PubMed Identifier
    21371356
    Citation
    Rimmele T, Kellum JA. Clinical review: blood purification for sepsis. Crit Care. 2011;15(1):205. doi: 10.1186/cc9411. Epub 2011 Feb 16.
    Results Reference
    background
    PubMed Identifier
    12169849
    Citation
    Reiter K, Bordoni V, Dall'Olio G, Ricatti MG, Soli M, Ruperti S, Soffiati G, Galloni E, D'Intini V, Bellomo R, Ronco C. In vitro removal of therapeutic drugs with a novel adsorbent system. Blood Purif. 2002;20(4):380-8. doi: 10.1159/000063108.
    Results Reference
    background
    PubMed Identifier
    15090965
    Citation
    Kellum JA, Song M, Venkataraman R. Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-kappaB DNA binding, and improves short-term survival in lethal endotoxemia. Crit Care Med. 2004 Mar;32(3):801-5. doi: 10.1097/01.ccm.0000114997.39857.69.
    Results Reference
    background
    PubMed Identifier
    18434884
    Citation
    Peng ZY, Carter MJ, Kellum JA. Effects of hemoadsorption on cytokine removal and short-term survival in septic rats. Crit Care Med. 2008 May;36(5):1573-7. doi: 10.1097/CCM.0b013e318170b9a7.
    Results Reference
    background
    Citation
    D Schädler, C Porzelius, A Jörres, G Marx, A Meier-Hellmann, C Putensen, M Quintel, C Spies, C Engel, NWeiler, M Kuhlmann. A multicenter randomized controlled study of an extracorporeal cytokine hemoadsorption device in septic patients. Critical Care 2013, 17(Suppl 2):P62 (19 March 2013).
    Results Reference
    background

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    Cytokine Adsorption in Severe, Refractory Septic Shock

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