Clinical trial NCT04385771: Cytokine Adsorption in Patients With Severe COVID-19 Pneumonia Requiring Extracorporeal Membrane Oxygenation
Official title: Cytokine Adsorption in Patients With Severe COVID-19 Pneumonia Requiring Extracorporeal Membrane Oxygenation - Randomized, Controlled, Open-label Intervention, Multi-center Trial (CYCOV-II-study)
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: NA
Conditions: Coronavirus Infection
COVID
SARS-CoV 2
Respiratory Failure
Cytokine Storm
Extracorporeal Membrane Oxygenation
Keywords: COVID-19
ECMO
ARDS
Cytokine Adsorption
Lead sponsor: University Hospital Freiburg
Sponsor class: OTHER
Collaborators: name: Klinikum Ibbenbüren
name: Ludwig-Maximilians - University of Munich
name: University Hospital, Saarland
name: Klinikum Ludwigsburg
name: University of Ulm
name: SLK Kliniken Heilbronn GmbH
name: Martin-Luther-Universität Halle-Wittenberg
First posted: 2020-05-13
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: randomized controlled trial examining COVID-patients requiring vv-ECMO therapy (+/- cytokine adsorption)
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: IL-6 reduction by 75% or more after 72 hours as compared to the baseline measurement
timeFrame: 72 hours
measure: time to successful ECMO-explantation
timeFrame: 30 days
Secondary outcomes:
measure: Ventilator free days (VFD)
timeFrame: 30 days
measure: Time to extubation from ventilation and explantation from ECMO
timeFrame: 30 days
measure: Overall survival time
timeFrame: 30 days
measure: Days on intensive care unit (ICU)
timeFrame: 30 days
measure: Vasopressor dosage
timeFrame: 24, 48, 72 hours
measure: Fluid substitution and fluid balance
timeFrame: 24, 48, 72 hours
measure: Serum lactate
timeFrame: 24, 48, 72 hours
measure: Urine output
timeFrame: 24, 48, 72 hours
measure: Willebrand factor
timeFrame: 24, 48, 72 hours
measure: d-dimers
timeFrame: 24, 48, 72 hours
measure: interleukin-6 levels
timeFrame: 24, 48, 72 hours
measure: SOFA-Score
timeFrame: 24, 48, 72 hours
measure: serious adverse device effects
timeFrame: 30 days
measure: adverse event of special interest: air in the ECMO system
timeFrame: 30 days
measure: adverse event of special interest: blood-clotting in the ECMO system
timeFrame: 30 days
measure: adverse event of special interest: bleeding complications
timeFrame: 30 days
Other outcomes:
Locations:
city: Freiburg
country: Germany
facility: University Clinic Freiburg
city: Ibbenbueren
country: Germany
facility: Klinikum Ibbenbueren
city: Ludwigsburg
country: Germany
facility: Klinikum Ludwigsburg
Study officials:
affiliation: University Clinic Freiburg
name: Alexander Supady, Dr., MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Shekar K, McAuley DF, Brodie D. Cytokine adsorption during ECMO for COVID-19-related ARDS. Lancet Respir Med. 2021 Jul;9(7):680-682. doi: 10.1016/S2213-2600(21)00207-1. Epub 2021 May 14. No abstract available.
citation: Rieder M, Duerschmied D, Zahn T, Lang C, Benk C, Lother A, Biever P, Bode C, Wengenmayer T, Staudacher D, Supady A. Cytokine Adsorption in Severe Acute Respiratory Failure Requiring Veno-Venous Extracorporeal Membrane Oxygenation. ASAIO J. 2021 Mar 1;67(3):332-338. doi: 10.1097/MAT.0000000000001302.
citation: Rieder M, Schubach F, Schmoor C, von Spee-Mayer C, Wengenmayer T, Rilinger J, Staudacher D, Bode C, Duerschmied D, Supady A. Cytokine adsorption in patients with severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation: protocol for a randomised, controlled, open-label intervention, multicentre trial. BMJ Open. 2021 Jan 17;11(1):e043345. doi: 10.1136/bmjopen-2020-043345.