Extracorporeal Blood Purification as a Treatment Modality for COVID-19

Clinical Efficacy and Safety of Extracorporeal Blood Purification to Control Hyperinflammation and Hypercoagulability in COVID-19 Patients

Several studies have suggested a potential clinical benefit of controlling hyper inflammation triggered by SARS-CoV-2/COVID-19. Blood purification, the removal of excessive proinflammatory mediators may control disease progression and support clinical recovery.

For this purpose, COVID-19 patients might benefit from treatment with AN69ST hemofilter based extracorporeal blood purification.

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Device: Extracorporeal blood purification using the oXiris® (AN69ST) hemofilter

Detailed Description

COVID-19 disease progression is associated with dysregulated immunity, commonly referred to as cytokine storm, in particular, aberrant Interleukin (IL) 6 levels that promote numerous pathological downstream effects. Hyperinflammation is a well-established trigger of multiorgan failure, for example, acute kidney injury. Moreover, recent reports point to a link between hyper inflammation and COVID-19 induced coagulopathy as a result of increased production of clotting factors by the liver.

Despite several lines of evidence pointing to a potential clinical benefit of controlling hyperinflammation triggered by COVID-19, management of COVID-19 remains mostly supportive built around continuous respiratory support.

To this end, considering the underlying immunological character of COVID-19 disease and the high risk of SARS-CoV-2 hyperinflammation to trigger ARDS, hypercoagulability and Acute Kidney Injury (AKI) this study aims to monitor selected biochemical, immunological and coagulation parameters in combination with radiological imaging to guide clinical practice and to tailor therapy consisting of 1) early initiation of blood purification using the oXiris® (AN69ST) filter, 2) systemic heparinisation and 3) respiratory support

• Study Type: Observational
• Enrollment (Actual): 35

Contacts and Locations

Study Locations

• North Macedonia
  • Skopje, North Macedonia, 1000
    • Zan Mitrev Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

COVID positive patients admitted to ICU

Description

Inclusion Criteria:

Confirmed COVID-19 disease:

• RT-PCR
• Atypical Pneumonia; X-Ray and/or Computed Tomography
• ≥ 1 oXiris® blood purification cycle

Exclusion Criteria:

• Pregnancy
• Heart failure; severe systolic dysfunction, left ventricular ejection fraction < 25% requiring urgent surgery
• Aortic Aneurysms, dissection or rupture requiring urgent surgery
• Recent Myocardial Infarction; cardiovascular disease patients requiring urgent surgery

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

COVID-19 patients admitted to the ICU; COVID-19 patients will be treated with the Prismaflex® oXiris® system in the ICU. Treatment will be initiated within 4 - 12 hours after admission upon establishing control of the haemostasis, ACT = Activated Coagulation Time of 180 seconds

Device: Extracorporeal blood purification using the oXiris® (AN69ST) hemofilter; Admitted patients will receive at least 1 cycle of extracorporeal blood purification using the oXiris® (AN69ST) hemofilter (Baxter, IL, USA). The number of cycles of blood purification is determined based on multiple biochemical, immunological, coagulation parameters, radiological imaging and overall clinical condition. The patient is connected to the Prismaflex® oXiris® system via a double lumen catheter placed in the femoral vein or vena subclavia. Flow rates will be maintained as follow; effluent dose 35 mL/Kg/h, dialysate 14 - 16 mL/Kg/h, blood 150 mL/min, replacement 16 -18 mL/Kg/h; patient fluid removal is tailored to the individual's volume status, ≈ 100 - 250 mL/h. The oXiris® extracorporeal and organ support modality will be chosen according to the patient's kidney function; continuous venovenous hemofiltration (CVVH), continuous venovenous hemodiafiltration (CVVHDF) or slow continuous ultrafiltration (SCUF).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in cytokine levels of Interleukin (IL) 6, IL-8 and Tumor Necrosis Factor-α (pg/mL)	Systemic levels of IL-6, IL-8 and TNF-α are evaluated to assess the effect of blood purification. Measurement points: at admission, "before and after a blood purification cycle" and before discharge	Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)
Changes in inflammatory markers; C-Reactive Protein (CRP) (mg/L)	Systemic levels of proinflammatory mediators are measured as a marker for disease severity. Measurement points: at admission, "before and after a blood purification cycle" and before discharge.	Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)
Changes in thrombocyte counts (10^3 counts/microL)	Systemic levels of thrombocytes are measured as a marker for disease severity. Measurement points: at admission, "before and after a blood purification cycle" and before discharge.	Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)
Changes in the coagulation marker Fibrinogen (g/L)	Coagulation markers will be followed to assess the effect of systemic heparinisation, Measurement points, at admission, "before and after a blood purification cycle" and before discharge	Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)
ICU length of stay after admission (days)	Duration of intensive care will be determined in relation to the number of blood purification cycles Patients will be followed for the duration of ICU stay.	An expected average of 4 - 14 hospitalisation days or until hospital discharge (whichever comes first)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Neutrophil-to-Lymphocyte Ratio	Systemic levels of proinflammatory mediators are measured as a marker for disease severity. Measurement points: at admission, "before and after a blood purification cycle" and before discharge.	Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)
Changes in the coagulation marker D-Dimers (ng/mL)	Coagulation markers will be followed to assess the effect of systemic heparinisation, Measurement points, at admission, "before and after a blood purification cycle" and before discharge	Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)
Changes in the Activation Clotting Time (seconds).	Coagulation markers will be followed to assess the effect of systemic heparinisation, Measurement points, at admission, "before and after a blood purification cycle" and before discharge	Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)

Collaborators and Investigators

• Sponsor: Zan Mitrev Clinic
• Investigators: Study Director: Zan K Mitrev, MD, Zan Mitrev Clinic; Principal Investigator: Rodney A Rosalia, PhD, Zan Mitrev Clinic

Publications and helpful links

General Publications

• Malard B, Lambert C, Kellum JA. In vitro comparison of the adsorption of inflammatory mediators by blood purification devices. Intensive Care Med Exp. 2018 May 4;6(1):12. doi: 10.1186/s40635-018-0177-2.
• Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16. No abstract available.
• The Lancet Haematology. COVID-19 coagulopathy: an evolving story. Lancet Haematol. 2020 Jun;7(6):e425. doi: 10.1016/S2352-3026(20)30151-4. No abstract available.
• Herold T, Jurinovic V, Arnreich C, Lipworth BJ, Hellmuth JC, von Bergwelt-Baildon M, Klein M, Weinberger T. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol. 2020 Jul;146(1):128-136.e4. doi: 10.1016/j.jaci.2020.05.008. Epub 2020 May 18.
• Zhang Y, Yu L, Tang L, Zhu M, Jin Y, Wang Z, Li L. A Promising Anti-Cytokine-Storm Targeted Therapy for COVID-19: The Artificial-Liver Blood-Purification System. Engineering (Beijing). 2021 Jan;7(1):11-13. doi: 10.1016/j.eng.2020.03.006. Epub 2020 Mar 20. No abstract available.

Helpful Links

• FDA Emergency Use Authorization for Oxiris Blood Purification Filter for COVID-19 Treatment

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2020
• Primary Completion (Actual): July 1, 2021
• Study Completion (Actual): July 1, 2021

Study Registration Dates

• First Submitted: July 14, 2020
• First Submitted That Met QC Criteria: July 17, 2020
• First Posted (Actual): July 20, 2020

Study Record Updates

• Last Update Posted (Actual): December 1, 2022
• Last Update Submitted That Met QC Criteria: November 28, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Interleukin 6; D-dimer; cytokine storm; hypercoagulability; Fibrinogen
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: EBPZ.357

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: Yes
• product manufactured in and exported from the U.S.: Yes