A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study
Abstract Background The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in whi...
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BMC
2020-12-01
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| Series: | Trials |
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| Online Access: | https://doi.org/10.1186/s13063-020-04878-y |
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| author | T. Vanassche M. M. Engelen Q. Van Thillo J. Wauters J. Gunst C. Wouters C. Vandenbriele S. Rex L. Liesenborghs A. Wilmer P. Meersseman G. Van den Berghe D. Dauwe G. Verbeke M. Thomeer T. Fivez D. Mesotten D. Ruttens L. Heytens I. Dapper S. Tuyls B. De Tavernier P. Verhamme DAWn consortium members |
| author_facet | T. Vanassche M. M. Engelen Q. Van Thillo J. Wauters J. Gunst C. Wouters C. Vandenbriele S. Rex L. Liesenborghs A. Wilmer P. Meersseman G. Van den Berghe D. Dauwe G. Verbeke M. Thomeer T. Fivez D. Mesotten D. Ruttens L. Heytens I. Dapper S. Tuyls B. De Tavernier P. Verhamme DAWn consortium members |
| author_sort | T. Vanassche |
| collection | DOAJ |
| description | Abstract Background The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. Methods In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily—or 75 IU anti-Xa twice daily for intensive care (ICU) patients—in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. Discussion In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. Trial registration The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020. |
| first_indexed | 2024-12-14T16:52:30Z |
| format | Article |
| id | doaj.art-db7c466255624cae9d005a020f65877e |
| institution | Directory Open Access Journal |
| issn | 1745-6215 |
| language | English |
| last_indexed | 2024-12-14T16:52:30Z |
| publishDate | 2020-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Trials |
| spelling | doaj.art-db7c466255624cae9d005a020f65877e2022-12-21T22:54:03ZengBMCTrials1745-62152020-12-0121111410.1186/s13063-020-04878-yA randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico studyT. Vanassche0M. M. Engelen1Q. Van Thillo2J. Wauters3J. Gunst4C. Wouters5C. Vandenbriele6S. Rex7L. Liesenborghs8A. Wilmer9P. Meersseman10G. Van den Berghe11D. Dauwe12G. Verbeke13M. Thomeer14T. Fivez15D. Mesotten16D. Ruttens17L. Heytens18I. Dapper19S. Tuyls20B. De Tavernier21P. Verhamme22DAWn consortium membersCenter for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, KU LeuvenCenter for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, KU LeuvenCenter for Cancer Biology, VIBDepartment of General Internal Medicine, Medical Intensive Care Unit, University Hospitals LeuvenClinical Department and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenPediatric Rheumatology, University Hospitals LeuvenCenter for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, KU LeuvenDepartment of Cardiovascular Sciences, University Hospitals LeuvenCenter for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, KU LeuvenDepartment of General Internal Medicine, Medical Intensive Care Unit, University Hospitals LeuvenDepartment of General Internal Medicine, Medical Intensive Care Unit, University Hospitals LeuvenClinical Department and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenClinical Department and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenInteruniversity Institute for Biostatistics and statistical Bioinformatics (I-BioStat), KU Leuven, Leuven, and Hasselt University (UHasselt)Department of Respiratory Medicine, Ziekenhuis Oost-LimburgDepartment of Medicine and Life Sciences, Hasselt UniversityDepartment of Medicine and Life Sciences, Hasselt UniversityDepartment of Respiratory Medicine, Ziekenhuis Oost-LimburgDepartment of Anesthestiology, GZA hospital groupEmergency Medicine and Intensive Care, GZA hospital groupRespiratory Medicine, GZA hospital groupEmergency Medicine and Intensive Care, GZA hospital groupCenter for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, KU LeuvenAbstract Background The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. Methods In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily—or 75 IU anti-Xa twice daily for intensive care (ICU) patients—in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. Discussion In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. Trial registration The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.https://doi.org/10.1186/s13063-020-04878-yCOVID-19SARS-CoV-2Low molecular weight heparinsAprotininAnakinraThromboinflammatory response |
| spellingShingle | T. Vanassche M. M. Engelen Q. Van Thillo J. Wauters J. Gunst C. Wouters C. Vandenbriele S. Rex L. Liesenborghs A. Wilmer P. Meersseman G. Van den Berghe D. Dauwe G. Verbeke M. Thomeer T. Fivez D. Mesotten D. Ruttens L. Heytens I. Dapper S. Tuyls B. De Tavernier P. Verhamme DAWn consortium members A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study Trials COVID-19 SARS-CoV-2 Low molecular weight heparins Aprotinin Anakinra Thromboinflammatory response |
| title | A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study |
| title_full | A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study |
| title_fullStr | A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study |
| title_full_unstemmed | A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study |
| title_short | A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study |
| title_sort | randomized open label adaptive proof of concept clinical trial of modulation of host thromboinflammatory response in patients with covid 19 the dawn antico study |
| topic | COVID-19 SARS-CoV-2 Low molecular weight heparins Aprotinin Anakinra Thromboinflammatory response |
| url | https://doi.org/10.1186/s13063-020-04878-y |
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