Extracorporeal Blood Purification as a Treatment Modality for COVID-19

• ClinicalTrials.gov Identifier: NCT04478539
• Recruitment Status: Completed
• First Posted: July 20, 2020
• Last Update Posted: December 1, 2022
• Sponsor: Zan Mitrev Clinic
• Information provided by (Responsible Party): Zan Mitrev Clinic

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment
Covid19	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 Design

• Study Type: Observational
• Actual Enrollment: 35 participants
• Observational Model: Cohort
• Time Perspective: Retrospective
• Official Title: Clinical Efficacy and Safety of Extracorporeal Blood Purification to Control Hyperinflammation and Hypercoagulability in COVID-19 Patients
• Actual Study Start Date: June 1, 2020
• Actual Primary Completion Date: July 1, 2021
• Actual Study Completion Date: July 1, 2021

Groups and Cohorts

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).

Outcome Measures

Primary Outcome Measures :

1. Changes in cytokine levels of Interleukin (IL) 6, IL-8 and Tumor Necrosis Factor-α (pg/mL) [ Time Frame: Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first) ]

   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

2. Changes in inflammatory markers; C-Reactive Protein (CRP) (mg/L) [ Time Frame: Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first) ]

   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.

3. Changes in thrombocyte counts (10^3 counts/microL) [ Time Frame: Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first) ]

   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.

4. Changes in the coagulation marker Fibrinogen (g/L) [ Time Frame: Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first) ]

   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

5. ICU length of stay after admission (days) [ Time Frame: An expected average of 4 - 14 hospitalisation days or until hospital discharge (whichever comes first) ]

   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.

Secondary Outcome Measures :

1. Changes in Neutrophil-to-Lymphocyte Ratio [ Time Frame: Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first) ]

   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.

2. Changes in the coagulation marker D-Dimers (ng/mL) [ Time Frame: Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first) ]

   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

3. Changes in the Activation Clotting Time (seconds). [ Time Frame: Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first) ]

   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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

COVID positive patients admitted to ICU

Criteria

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

Contacts and Locations

Locations

North Macedonia

Zan Mitrev Clinic

Skopje, North Macedonia, 1000

Sponsors and Collaborators

Zan Mitrev Clinic

Investigators

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

More Information

Additional Information:

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

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.

• Responsible Party: Zan Mitrev Clinic
• ClinicalTrials.gov Identifier: NCT04478539
• Other Study ID Numbers: EBPZ.357
• First Posted: July 20, 2020
• Last Update Posted: December 1, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Zan Mitrev Clinic:

SARS-CoV-2; cytokine storm; Interleukin 6; hypercoagulability; Fibrinogen; D-dimer

Additional relevant MeSH terms:

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases