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
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
Affiliations
T. Vanassche
Center for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, KU Leuven
M. M. Engelen
Center for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, KU Leuven
Q. Van Thillo
Center for Cancer Biology, VIB
J. Wauters
Department of General Internal Medicine, Medical Intensive Care Unit, University Hospitals Leuven
J. Gunst
Clinical Department and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven
C. Wouters
Pediatric Rheumatology, University Hospitals Leuven
C. Vandenbriele
Center for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, KU Leuven
S. Rex
Department of Cardiovascular Sciences, University Hospitals Leuven
L. Liesenborghs
Center for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, KU Leuven
A. Wilmer
Department of General Internal Medicine, Medical Intensive Care Unit, University Hospitals Leuven
P. Meersseman
Department of General Internal Medicine, Medical Intensive Care Unit, University Hospitals Leuven
G. Van den Berghe
Clinical Department and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven
D. Dauwe
Clinical Department and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven
G. Verbeke
Interuniversity Institute for Biostatistics and statistical Bioinformatics (I-BioStat), KU Leuven, Leuven, and Hasselt University (UHasselt)
M. Thomeer
Department of Respiratory Medicine, Ziekenhuis Oost-Limburg
T. Fivez
Department of Medicine and Life Sciences, Hasselt University
D. Mesotten
Department of Medicine and Life Sciences, Hasselt University
D. Ruttens
Department of Respiratory Medicine, Ziekenhuis Oost-Limburg
L. Heytens
Department of Anesthestiology, GZA hospital group
I. Dapper
Emergency Medicine and Intensive Care, GZA hospital group
S. Tuyls
Respiratory Medicine, GZA hospital group
B. De Tavernier
Emergency Medicine and Intensive Care, GZA hospital group
P. Verhamme
Center for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, KU Leuven
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.