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 which the host thrombotic and inflammatory responses seems 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 This trial is registered in the EU Clinical Trials Register. Registration number: 2020-001739-28. Registered on 2020-04-10.

Efeito Do Covid-19 Sobre Eventos Tromboembólicos E Controle Deste Com Anticoagulantes

“…20 Em outros estudos não concluídos, houve viés de seleção, porém os autores garantem a publicação dos resultados completos, bem como alocação e randomização quando a pesquisa for finalizada. 15,18 Outrossim, estudos observacionais não avaliaram desfechos em relação à totalidade da dose de tromboprofilaxia, sendo os pacientes agrupados de acordo com a dose inicial na admissão em UTI. Faz-se necessário a interpretação e o monitoramento cuidadoso dos pacientes em relação ao risco de sangramento, visto que o tamanho da amostra foi limitado.…”

Aprotinin treatment against SARS‐CoV‐2: A randomized phase III study to evaluate the safety and efficacy of a pan‐protease inhibitor for moderate COVID‐19

“…Thirdly, aprotinin could restore the imbalance in hypercoagulability (activation of kallikreins, plasmin, and complement and platelet aggregation) and hyperfibrinolysis in SARS‐CoV‐2‐infected patients 27 and reduce endotheliopathy due to the expression of ACE2 and serine proteases in endothelial cells 28 . A clinical trial (DAWn‐Antico) investigated the role that aprotinin may play in the coagulation contact pathway and the kallikrein–bradykinin pathway in severe COVID‐19 29 . The results of this study may shed light on the role of aprotinin in the multi‐level thromboinflammatory response of patients.…”

Itraconazole for COVID-19: Preclinical Studies and a Proof-of-Concept Pilot Clinical Study

“…We thus designed a pilot proof-of-concept clinical trial and did not communicate the in vitro findings to avoid a potential rush on the drug. As we anticipated that insights in the clinical management would evolve rapidly, we opted for a flexible trial design that is also used for the evaluation of other antiviral strategies [11][12][13].…”

“…The protocol was approved by the institutional Ethics Committee and by the Belgian Federal Agency for Medicines and Health Products (EudraCT 2020-001243-15). The trial was part of the DAWn clinical studies [11][12][13]. An independent Data Safety Monitoring Board (DSMB) reviewed trial safety outcomes.…”