Covid 19: A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic Strategies in Hospitalized Adults with COVID-19 (ACTIV-4)

ACTIV-4 Abstract The severe acute respiratory syndrome coronavirus 2, which causes the highly contagious coronavirus disease 2019 (COVID-19), has resulted in a global pandemic. The clinical spectrum of COVID-19 infection is broad, encompassing asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia with respiratory failure and death. The risk of thrombotic complications is increased, even as compared to other viral respiratory illnesses, such as influenza. A pro-inflammatory cytokine response as well as induction of procoagulant factors associated with COVID-19 has been proposed to contribute to thrombosis as well as plaque rupture through local inflammation. Patients with COVID-19 are at increased risk for arterial and vein thromboembolism, with high rates observed despite thromboprophylaxis. Autopsy reports have noted micro and macro vascular thrombosis across multiple organ beds consistent with an early hypercoagulable state. A large body of literature links inflammation and coagulation; altered hemostasis is a known complication of respiratory viral infections. Procoagulant markers are severely elevated in viral infections. Specifically, proinflammatory cytokines in viral infections upregulate expression of tissue factor, markers of thrombin generation, platelet activation, and down-regulate natural anticoagulant proteins C and S. The ACTIV-4 ACUTE investigators postulate that an antithrombotic regimen will improve clinical outcomes in COVID-19 patients. This protocol intends to define the optimal regimen in an adaptive randomized trial of patients hospitalized with COVID-19 at risk for adverse clinical outcomes. The primary outcome will be the number of days free of organ support within 21 days after randomization. This primary outcome was selected because thrombosis is thought to contribute to the pathogenesis of multi-organ failure in COVID-19, because it is pragmatic and yet clinically relevant, and to align with ongoing studies that may or may not involve antithrombotic therapy, in a time frame relevant to acute illness. Organ support free days is defined by days in which patient is not on invasive or non-invasive mechanical ventilation, high flow nasal oxygen, vasopressor therapy, or ECMO support, with death assigned the value of –1 days.