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. Supplementary information The online version contains supplementary material available at 10.1186/s13063-020-04878-y.
【저자키워드】 Low molecular weight heparins, Aprotinin, Anakinra, Thromboinflammatory response, 【초록키워드】 COVID-19, SARS-CoV-2, randomized clinical trial, vaccination, clinical trial, Trial, Open-label, Low molecular weight heparins, Aprotinin, Anakinra, adaptive, intensive care, severe COVID-19, Thrombotic complications, COVID-19 pandemic, Infection, D-dimer, Intervention, drug, in vitro, outcome, heparin, fibrinolysis, ICU, COVID-19 disease, Coagulation, clinical status, Disease progression, Viral, viral replication, bradykinin, hyperinflammation, Patient, pathway, Clinical improvement, complications, second wave, cellular entry, receptor, incidence, multicenter, inhibitor, information, Thrombotic events, severe COVID-19 disease, marker, Ordinal Scale, Combination, Inflammatory response, dose, Contact, Prognostic factor, inflammatory parameters, regimen, low molecular weight, receptor antagonist, Activation, Kallikrein, Primary outcome, hospitalized COVID-19 patients, Trial registration, supplementary material, inhibitory effect, high mortality, thrombotic, EU Clinical Trials, heparins, local inflammatory response, standard thromboprophylaxis, WHO ordinal scale, Host, country, effective, initial, defined, shown, develop, investigated, added, modulate, reached, reduce, the WHO, EU Clinical Trial, pathophysiological, 【제목키워드】 Open-label, adaptive, Randomized, Patient, modulation, Host, proof-of-concept clinical trial,