Interleukin-6 Antagonists in Critically-ill Covid-19 Patients

COVID-19 Clinical Trial

— HEMOCOV  

Official title:

Effects of Immunomodulation With Interleukin-6 Antagonists on the Coagulation System in Critically-ill Covid-19 Patients

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05218369
• Other study ID #: 1405-3/2022/EÜIG
• Status: Recruiting
• Start date: February 6, 2022
• Est. completion date: December 1, 2024

Study information

• Verified date: April 2023
• Source: University of Pecs
• Contact: Péter Hegyi, MD, PhD, Dsc, MAE
• Phone: +3672/536-246
• Email: p.hegyi[@]tm-centre.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The emerging SARS-COV2 virus has shed a new light on the cross-talks between the immune and the hemostatic system. In this study we aim to evaluate the dynamic change in coagulation caused by the modulation of the inflammatory response by interleukin-6 antagonist as assessed by viscoelastic methods in critically ill COVID-19 patients. Furthermore we try to draw attention to possible associations between the endothelial cell injury, inflammation and coagulation.

Description:

The emerging SARS-COV2 virus has shed new light on the cross-talk between the immune and the hemostatic system. Pathophysiologically in COVID-19 infection the thrombo-inflammatory process is initiated by the host's exaggerated systemic inflammatory response, also called "dysregulated immune response" that activates both the inflammatory and the coagulation cascade directly by inflammatory mediators and indirectly by causing endothelial cell injury. These mechanisms altogether contribute to the imbalance of the hemostasis that is characterized by a procoagulant state.

In this multicenter prospective observational study, we aim to evaluate the dynamic change in coagulation as a result of immunomodulation by interleukin-6 antagonists in critically ill COVID-19 patients. We will assess the hemostatic system by a viscoelastic hemostasis assay (Clotpro, Haemonetics Corporation, Boston). Furthermore, we try to draw attention to possible associations between endothelial cell injury, inflammation, and coagulation. To compare these parameters we will draw blood for analysis before administration of IL-6 antagonist then 24h after, 48h after, and 7 days after.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: December 1, 2024
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

Inclusion Criteria:

• Adults (>18 years old)

• Clinical diagnosis of SARS-CoV2 infection with rtPCR confirmation

• Disease severity with the indication of immunomodulation therapy with interleukin-6 antagonist: acute respiratory failure that requires invasive, noninvasive ventilation , or high flow nasal oxygen therapy with the following parameters: FiO2 > 0,4, flow > 30L/min and C Reactive Protein > 75 mg/L

Exclusion Criteria:

• The patient had previously been administered one of the following immunomodulating drug: anakinra, tocilizumab, sarilumab

• Presence of any condition or drug in the medical history that can lead to immunosuppression

• Suspicion of infection (active tuberculosis, bacterial, viral, fungal) or level of procalcitonine higher than 0,5 ng/ml at the enrollment of the patient

• Number of thrombocyte lower than 50 x 109 / L

• More than >120 hours passed between the admission to the ICU and the administration of interleukin-6 antagonist

• Administration of any of the following drugs the week before or during the study:

fibrinolytic therapy, factor products (PCC, ATIII, FVIIa, FXIII), fibrinogen, desmopressin, tranexamic acid, blood products (FFP, thrombocyte concentrate)

• Pregnancy

• The patient or his legal guardian does not sign the consent

Related Conditions & MeSH terms

• COVID-19
• Critical Illness

Intervention

Drug:
• IL6 Antagonist
Patients will receive IL-6 antagonist therapy at the consultant's discretion.

Locations

Country	Name	City	State
Hungary	Department of Anaesthesiology and Intensive Therapy, Pest Megyei Flór Ferenc Hospital	Kistarcsa	Pest
Hungary	Department of Anaesthesiology and Intensive Therapye, Medical School, University of Pécs	Pécs	Baranya
Hungary	Central Department of Anesthesiology and Intensive Care, Szent György University Teaching Hospital of County Fejér	Székesfehérvár	Fejér

Sponsors (1)

Lead Sponsor	Collaborator
University of Pecs

Country where clinical trial is conducted

Hungary, 

References & Publications (7)

Bester J, Pretorius E. Effects of IL-1beta, IL-6 and IL-8 on erythrocytes, platelets and clot viscoelasticity. Sci Rep. 2016 Aug 26;6:32188. doi: 10.1038/srep32188. — View Citation

Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, Bikdeli B, Ahluwalia N, Ausiello JC, Wan EY, Freedberg DE, Kirtane AJ, Parikh SA, Maurer MS, Nordvig AS, Accili D, Bathon JM, Mohan S, Bauer KA, Leon MB, Krumholz HM, Uriel N, Mehra MR, Elkind MSV, Stone GW, Schwartz A, Ho DD, Bilezikian JP, Landry DW. Extrapulmonary manifestations of COVID-19. Nat Med. 2020 Jul;26(7):1017-1032. doi: 10.1038/s41591-020-0968-3. Epub 2020 Jul 10. — View Citation

Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood. 2019 Feb 28;133(9):906-918. doi: 10.1182/blood-2018-11-882993. Epub 2019 Jan 14. — View Citation

Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol. 2020 Jun;7(6):e438-e440. doi: 10.1016/S2352-3026(20)30145-9. Epub 2020 May 11. No abstract available. — View Citation

Levy JH, Iba T, Olson LB, Corey KM, Ghadimi K, Connors JM. COVID-19: Thrombosis, thromboinflammation, and anticoagulation considerations. Int J Lab Hematol. 2021 Jul;43 Suppl 1(Suppl 1):29-35. doi: 10.1111/ijlh.13500. — View Citation

Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Apr;18(4):844-847. doi: 10.1111/jth.14768. Epub 2020 Mar 13. — View Citation

Tleyjeh IM, Kashour Z, Damlaj M, Riaz M, Tlayjeh H, Altannir M, Altannir Y, Al-Tannir M, Tleyjeh R, Hassett L, Kashour T. Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review and meta-analysis. Clin Microbiol Infect. 2021 Feb;27(2):215-227. doi: 10.1016/j.cmi.2020.10.036. Epub 2020 Nov 5. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in the lysis time	Change of the fibrinolytic system before (T0) and after immunomodulation therapy, measured by the lysis time (LT).	48 hours
Primary	Change in the lysis onset time	Change of the fibrinolytic system before (T0) and after immunomodulation therapy, measured by the lysis onset time (LOT).	48 hours
Secondary	Change in the lysis time	Change of the fibrinolytic system before (T0) and after immunomodulation therapy, measured by the lysis time (LT).	24 hours and 7 days
Secondary	Change in the lysis onset time	Change of the fibrinolytic system before (T0) and after immunomodulation therapy, measured by the lysis onset time (LOT).	24 hours and 7 days
Secondary	Change in Clotpro assay	Change in blood coagulation parameters which evaluate hypercoagulable state before (T0) and after immunomodulation therapy (T1,2,3) measured by Clotpro device assays.	24 hours, 48 hours, and 7 days
Secondary	Correlation between procalcitonin and Clotpro	Correlation between inflammatory and blood coagulation parameters. For the assessment of this endpoint, we will use the results of the inflammatory laboratory parameters as procalcitonin and the blood coagulation parameters measured by the Clotpro.	24 hours, 48 hours, and 7 days
Secondary	Correlation between C reactive protein and Clotpro	Correlation between inflammatory and blood coagulation parameters. For the assessment of this endpoint, we will use the results of the inflammatory laboratory parameters as C reactive protein and the blood coagulation parameters measured by the Clotpro.	24 hours, 48 hours, and 7 days
Secondary	Correlation between ferritin and Clotpro	Correlation between inflammatory and blood coagulation parameters. For the assessment of this endpoint, we will use the results of the inflammatory laboratory parameters as ferritin and the blood coagulation parameters measured by the Clotpro.	24 hours, 48 hours, and 7 days
Secondary	Correlation between lactate dehydrogenase and Clotpro	Correlation between inflammatory and blood coagulation parameters. For the assessment of this endpoint, we will use the results of the inflammatory laboratory parameters as lactate dehydrogenase and the blood coagulation parameters measured by the Clotpro.	24 hours, 48 hours, and 7 days
Secondary	Correlation between syndecan-1 and Clotpro	Correlation between biomarkers of endothelial injury and blood coagulation parameters. For the assessment of this endpoint, we will use the results of the biomarkers of the endothelial damage as syndecan-1 and the blood coagulation parameters measured by the Clotpro.	24 hours, 48 hours, and 7 days
Secondary	Correlation between thrombomodulin and Clotpro	Correlation between biomarkers of endothelial injury and blood coagulation parameters. For the assessment of this endpoint, we will use the results of the biomarkers of the endothelial damage as thrombomodulin and the blood coagulation parameters measured by the Clotpro.	24 hours, 48 hours, and 7 days

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