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Cytokine Adsorption in Patients With Severe COVID-19 Pneumonia Requiring Extracorporeal Membrane Oxygenation (CYCOV-II)

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ClinicalTrials.gov Identifier: NCT04385771
Recruitment Status : Recruiting
First Posted : May 13, 2020
Last Update Posted : November 4, 2020
Sponsor:
Collaborators:
Klinikum Ibbenbüren
Ludwig-Maximilians - University of Munich
University Hospital, Saarland
Klinikum Ludwigsburg
University of Ulm
SLK-Kliniken Heilbronn
Martin-Luther-Universität Halle-Wittenberg
Information provided by (Responsible Party):
Dr. Alexander Supady, University Hospital Freiburg

Tracking Information
First Submitted Date  ICMJE April 19, 2020
First Posted Date  ICMJE May 13, 2020
Last Update Posted Date November 4, 2020
Actual Study Start Date  ICMJE September 1, 2020
Estimated Primary Completion Date May 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 11, 2020)
  • IL-6 reduction by 75% or more after 72 hours as compared to the baseline measurement [ Time Frame: 72 hours ]
    measurement of IL-6 levels in patient blood after 72 hours of cytokine adsorption (in relation to level before initiation of cytokine adsorption)
  • time to successful ECMO-explantation [ Time Frame: 30 days ]
    time to successful ECMO-explantation within 30 days after randomization
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 12, 2020)
  • Ventilator free days (VFD) [ Time Frame: 30 days ]
    Ventilator free days (VFD) in the first 30 days after randomization, where invasive mechanical ventilation (IMV), non-invasive ventilation (NIV) and ECMO are defined as ventilator days. VFD=0, if the patient dies in the first 30 days after randomization
  • Time to extubation from ventilation and explantation from ECMO [ Time Frame: 30 days ]
    Time to extubation from ventilation and explantation from ECMO. Death under ventilation and/or ECMO will be analyzed as a competing event. The time will be censored at the time of last visit for surviving patients under ventilation and/or ECMO.
  • Overall survival time [ Time Frame: 30 days ]
    Overall survival time, defined as time from randomization to death. The time will be censored at the time of last visit for surviving patients.
  • Days on intensive care unit (ICU) [ Time Frame: 30 days ]
    Days on intensive care unit (ICU)
  • Vasopressor dosage [ Time Frame: 24, 48, 72 hours ]
    Vasopressor dosage of adrenaline, noradrenaline, vasopressin, and dobutamine at 24, 48,72 h
  • Fluid substitution and fluid balance [ Time Frame: 24, 48, 72 hours ]
    Total fluid[ml] substitution and fluid balance [ml] at 24, 48, 72 h
  • Serum lactate [ Time Frame: 24, 48, 72 hours ]
    Serum lactate at 24, 48, 72 h
  • Urine output [ Time Frame: 24, 48, 72 hours ]
    Urine output at 24, 48, 72 h
  • Willebrand factor [ Time Frame: 24, 48, 72 hours ]
    Willebrand factor at 24, 48, 72 h
  • d-dimers [ Time Frame: 24, 48, 72 hours ]
    d-dimers at 24, 48, 72 h
  • interleukin-6 levels [ Time Frame: 24, 48, 72 hours ]
    interleukin-6 levels at 24, 48, 72 h
  • SOFA-Score [ Time Frame: 24, 48, 72 hours ]
    Sequential Organ Failure Assessment Score at 24, 48, 72 h (values from 6 to 24, where the higher values explain higher disease severity)
  • serious adverse device effects [ Time Frame: 30 days ]
    serious complications or malfunctions related to the CytoSorb device
  • adverse event of special interest: air in the ECMO system [ Time Frame: 30 days ]
    unintended air in the ECMO system during operation of the device
  • adverse event of special interest: blood-clotting in the ECMO system [ Time Frame: 30 days ]
    unintended blood-clotting in the ECMO system during operation of the device
  • adverse event of special interest: bleeding complications [ Time Frame: 30 days ]
    major bleeding events
Original Secondary Outcome Measures  ICMJE
 (submitted: May 11, 2020)
  • Ventilator free days (VFD) [ Time Frame: 30 days ]
    Ventilator free days (VFD) in the first 30 days after randomization, where invasive mechanical ventilation (IMV), non-invasive ventilation (NIV) and ECMO are defined as ventilator days. VFD=0, if the patient dies in the first 30 days after randomization
  • Time to extubation from ventilation and explantation from ECMO [ Time Frame: 30 days ]
    Time to extubation from ventilation and explantation from ECMO. Death under ventilation and/or ECMO will be analyzed as a competing event. The time will be censored at the time of last visit for surviving patients under ventilation and/or ECMO.
  • Overall survival time [ Time Frame: 30 days ]
    Overall survival time, defined as time from randomization to death. The time will be censored at the time of last visit for surviving patients.
  • Days on intensive care unit (ICU) [ Time Frame: 30 days ]
    Days on intensive care unit (ICU)
  • Vasopressor dosage [ Time Frame: 72 hours ]
    Vasopressor dosage of adrenaline, noradrenaline, vasopressin, and dobutamine at 24, 48,72 h
  • Fluid substitution and fluid balance [ Time Frame: 72 hours ]
    Total fluid[ml] substitution and fluid balance [ml] at 24, 48, 72 h
  • Serum lactate [ Time Frame: 72 hours ]
    Serum lactate at 24, 48, 72 h
  • Urine output [ Time Frame: 72 hours ]
    Urine output at 24, 48, 72 h
  • Willebrand factor [ Time Frame: 72 hours ]
    Willebrand factor at 24, 48, 72 h
  • d-dimers [ Time Frame: 72 hours ]
    d-dimers at 24, 48, 72 h
  • interleukin-6 levels [ Time Frame: 72 hours ]
    interleukin-6 levels at 24, 48, 72 h
  • SOFA-Score [ Time Frame: 72 hours ]
    Sequential Organ Failure Assessment Score at 24, 48, 72 h (values from 6 to 24, where the higher values explain higher disease severity)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Cytokine Adsorption in Patients With Severe COVID-19 Pneumonia Requiring Extracorporeal Membrane Oxygenation
Official Title  ICMJE Cytokine Adsorption in Patients With Severe COVID-19 Pneumonia Requiring Extracorporeal Membrane Oxygenation - Randomized, Controlled, Open-label Intervention, Multi-center Trial (CYCOV-II-study)
Brief Summary

In December 2019 in the city of Wuhan in China, a series of patients with unclear pneumonia was noticed, some of whom have died of it. In virological analyses of samples from the patients' deep respiratory tract, a novel coronavirus was isolated (SARS-CoV-2). The disease spread rapidly in the city of Wuhan at the beginning of 2020 and soon beyond in China and, in the coming weeks, around the world.

Initial studies described numerous severe courses, particularly those associated with increased patient age and previous cardiovascular, metabolic and respiratory diseases. A small number of the particularly severely ill patients required not only highly invasive ventilation therapy but also extracorporeal membrane oxygenation (vv-ECMO) to supply the patient's blood with sufficient oxygen.

Even under maximum intensive care treatment, a very high mortality rate of approximately 80-100% was observed in this patient group. In addition, high levels of interleukin-6 (IL-6) could be detected in the blood of these severely ill patients, which in turn were associated with poor outcome.

From experience in the therapy of severely ill patients with severe infections and respiratory failure, we know that treatment with a CytoSorb® adsorber can lead to a reduction of the circulating pro- and anti-inflammatory cytokines and thus improve the course of the disease and the outcome of the patients.

The aim of the study is to investigate the influence of extracorporeal cytokine adsorption on interleukin-6-levels and time to successful ECMO explantation under controlled conditions in patients with particularly severe COVID-19 disease requiring extracorporeal membrane oxygenation.

Detailed Description

In December 2019, a series of unexplained cases of pneumonia in the city of Wuhan in China has come to light. In virologic analyses of samples from the patients' deep respiratory tract, a novel coronavirus was isolated (first named 2019-nCoV, then SARS-CoV-2). The disease spread rapidly in the city of Wuhan in early 2020 and soon beyond. On 30 January 2020, the Director-General of the World Health Organization (WHO) declared the outbreak a public health emergency of international concern, and on 11 March 2020, the World Health Organization declared the virus a pandemic.

In humans, an infection with the virus can cause respiratory tract infections or even very severe pneumonia - these often end fatally, especially in old and pre-diseased patients. Due to the novelty of the virus, the data basis for therapy is very limited. To date, there are no clinical data for an effective specific therapy, nor is there a vaccination against the virus available, so that therapy, especially intensive care treatment for very severe courses, must concentrate only on supportive treatment of lung failure and other complications.

The virus is highly contagious and infection results in a relevant number of deaths. Due to very uncertain data on the spread of the virus in the population, it is difficult to estimate the mortality rate - the case fatality rate is about 4% based on the known case numbers.

In reports on the treatment of the first cases in Wuhan (Hubei Province, China) in January 2020, the need for intensive care treatment is described for about a quarter of the inpatient cases, 10-17% had to be ventilated invasively, and veno-venous extracorporeal membrane oxygenation (vv-ECMO) was necessary in 2-4% of the inpatient cases. Patients requiring ECMO have an extremely high mortality rate of 83-100% in the studies published, so far.

In severe cases a pronounced release of vasoactive cytokines was repeatedly observed. Excessive release of these vasoactive mediators ("cytokine storm") can result in severe vasodilatation and membrane leakage, which can ultimately lead to vasoplegic shock that is difficult to control. Ruan et al. and Zhou et al. have identified high interleukin 6 (IL-6) levels as a potential predictor of a fatal outcome when compared between survivors and patients who died of COVID-19 disease.

IL-6 is also an important factor in the pathophysiology of severe septic shock and excessive immune response in hemophagocytic lymphohistiocytosis (HLH) - for both indications has been shown, that the extracorporeal adsorption of IL-6 and other vasoactive substances in a CytoSorb® adsorber (CytoSorbents Corporation, Monmouth Junction, NJ, USA) leads to a significant reduction of these cytokines in the patient blood. Clinical experience and (previously unpublished) data from our monocentric registry study show that cytokine adsorption in a CytoSorb® Adsorber can also be safely integrated into a vv-ECMO system.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
randomized controlled trial examining COVID-patients requiring vv-ECMO therapy (+/- cytokine adsorption)
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Coronavirus Infection
  • COVID
  • SARS-CoV 2
  • Respiratory Failure
  • Cytokine Storm
  • Extracorporeal Membrane Oxygenation
Intervention  ICMJE
  • Device: vv-ECMO + cytokine adsorption (Cytosorb adsorber)
    in COVID-19-diseased vv-ECMO patients additional treatment with cytokine adsorption using a Cytosorb adsorber will be randomized (vs. control group)
  • Device: vv-ECMO only (no cytokine adsorption)
    COVID-19-diseased treated with vv-ECMO
Study Arms  ICMJE
  • Experimental: vv-ECMO + cytokine adsorption
    after indication of treatment with vv-ECMO in acute respiratory failure in COVID-19-disease, patients will additionally receive cytokine adsorption using a Cytosorb adsorber
    Intervention: Device: vv-ECMO + cytokine adsorption (Cytosorb adsorber)
  • vv-ECMO (no cytokine adsorption)
    treatment with vv-ECMO in acute respiratory failure in COVID-19-disease (standard treatment without additional cytokine adsorption)
    Intervention: Device: vv-ECMO only (no cytokine adsorption)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 11, 2020)
80
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 31, 2021
Estimated Primary Completion Date May 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • SARS-CoV-2-infection with COVID-pneumonia
  • vv-ECMO therapy

Exclusion Criteria:

  • known patient will against participation in the study or against the measures applied in the study
  • a decision (made prior to inclusion of the patient into this trial) to terminate the treatment within the next 24 hours
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Alexander Supady, Dr., MPH +49761270 ext 73790 alexander.supady@universitaets-herzzentrum.de
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04385771
Other Study ID Numbers  ICMJE CYCOV-II
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Dr. Alexander Supady, University Hospital Freiburg
Study Sponsor  ICMJE Dr. Alexander Supady
Collaborators  ICMJE
  • Klinikum Ibbenbüren
  • Ludwig-Maximilians - University of Munich
  • University Hospital, Saarland
  • Klinikum Ludwigsburg
  • University of Ulm
  • SLK-Kliniken Heilbronn
  • Martin-Luther-Universität Halle-Wittenberg
Investigators  ICMJE
Principal Investigator: Alexander Supady, Dr., MPH University Clinic Freiburg
PRS Account University Hospital Freiburg
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP