Interleukin-6 Antagonists in Critically-ill Covid-19 Patients (HEMOCOV)

• ClinicalTrials.gov Identifier: NCT05218369
• Recruitment Status: Not yet recruiting
• First Posted: February 1, 2022
• Last Update Posted: February 1, 2022
• Sponsor: University of Pecs
• Information provided by (Responsible Party): University of Pecs

Tracking Information

• First Submitted Date: January 29, 2022
• First Posted Date: February 1, 2022
• Last Update Posted Date: February 1, 2022
• Estimated Study Start Date: February 1, 2022
• Estimated Primary Completion Date: February 1, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 29, 2022)

• Change in the lysis time [ Time Frame: 48 hours ]
  Change of the fibrinolytic system before (T0) and after immunomodulation therapy, measured by the lysis time (LT).
• Change in the lysis onset time [ Time Frame: 48 hours ]
  Change of the fibrinolytic system before (T0) and after immunomodulation therapy, measured by the lysis onset time (LOT).

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: January 29, 2022)

• Change in the lysis time [ Time Frame: 24 hours and 7 days ]
  Change of the fibrinolytic system before (T0) and after immunomodulation therapy, measured by the lysis time (LT).
• Change in the lysis onset time [ Time Frame: 24 hours and 7 days ]
  Change of the fibrinolytic system before (T0) and after immunomodulation therapy, measured by the lysis onset time (LOT).
• Change in Clotpro assay [ Time Frame: 24 hours, 48 hours, and 7 days ]
  Change in blood coagulation parameters which evaluate hypercoagulable state before (T0) and after immunomodulation therapy (T1,2,3) measured by Clotpro device assays.
• Correlation between procalcitonin and Clotpro [ Time Frame: 24 hours, 48 hours, and 7 days ]
  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.
• Correlation between C reactive protein and Clotpro [ Time Frame: 24 hours, 48 hours, and 7 days ]
  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.
• Correlation between ferritin and Clotpro [ Time Frame: 24 hours, 48 hours, and 7 days ]
  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.
• Correlation between lactate dehydrogenase and Clotpro [ Time Frame: 24 hours, 48 hours, and 7 days ]
  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.
• Correlation between syndecan-1 and Clotpro [ Time Frame: 24 hours, 48 hours, and 7 days ]
  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.
• Correlation between thrombomodulin and Clotpro [ Time Frame: 24 hours, 48 hours, and 7 days ]
  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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Interleukin-6 Antagonists in Critically-ill Covid-19 Patients
• Official Title: Effects of Immunomodulation With Interleukin-6 Antagonists on the Coagulation System in Critically-ill Covid-19 Patients
• Brief 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.

Detailed 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.

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided
• Biospecimen: Not Provided
• Sampling Method: Probability Sample
• Study Population: All adult patients admitted to intensive care units (ICUs) requiring mechanical ventilation with proven COVID-19 infection and treated with interleukin-6 antagonist therapy.

Condition

• COVID-19
• Critical Illness

Intervention

Drug: IL6 Antagonist

Patients will receive IL-6 antagonist therapy at the consultant's discretion.

Study Groups/Cohorts

Critically ill COVID-19 patients

Patients in ICU due to critical COVID-19 infection, who receive early (within the first 24 hours, but no later than 48 hours after intubation) IL-6 antagonist therapy at the consultant's discretion.

Intervention: Drug: IL6 Antagonist

Publications *

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Kovacs EH, Rottler M, Dembrovszky F, Ocskay K, Szabo L, Hegyi P, Molnar Z, Tanczos K. Investigating the association between IL-6 antagonist therapy and blood coagulation in critically ill patients with COVID-19: a protocol for a prospective, observational, multicentre study. BMJ Open. 2022 Nov 4;12(11):e063856. doi: 10.1136/bmjopen-2022-063856.

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: January 29, 2022): 30
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 31, 2023
• Estimated Primary Completion Date: February 1, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 100 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Péter Hegyi, MD, PhD, Dsc, MAE; +3672/536-246; p.hegyi@tm-centre.org

Contact: Szilárd Váncsa, MD; +3672/536-246; vancsaszilard@gmail.com

• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT05218369
• Other Study ID Numbers: 1405-3/2022/EÜIG
• 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

• Plan to Share IPD: No
• Plan Description: Data will be presented at conferences and in the results part of the article.

• Current Responsible Party: University of Pecs
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Pecs
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: University of Pecs
• Verification Date: January 2022