STudy of Alteplase for Respiratory failure in SARS-Cov2 COVID-19 (STARS): A Vanguard Multicenter, Rapidly Adaptive, Pragmatic, Randomized, Controlled Trial.

Abstract Background Pulmonary vascular microthrombi are a proposed mechanism of COVID19 respiratory failure. We hypothesized that early administration of tissue-plasminogen activator(tPA) followed by therapeutic heparin would improve pulmonary function in these patients. Research Question Does tPA improve pulmonary function in severe COVID-19 respiratory failure, and is it safe? Study Design and Methods Adults with COVID-19-induced respiratory failure were randomized May14,2020-March 3,2021 in two phases: Phase-1(n=36): control (standard-of-care) vs tPA-Bolus(50mg tPA IV-bolus followed by 7 days of heparin (goal aPTT=60-80s); Phase-2(n=14): control vs tPA-Drip(50 mg of tPA IV-bolus, followed by tPA drip 2mg/hr plus heparin 500U/hour over 24 hours, then heparin to maintain aPTT 60-80s/7 days). Patients were excluded from enrollment if they did not have a neurologic exam or cross-sectional brain imaging within the previous 4.5 hours to rule out stroke and potential for hemorrhagic conversion. The primary outcome was PaO2/FiO2 improvement from baseline at 48 hours post-randomization. Secondary outcomes included: PaO2/FiO2 improvement>50% or PaO2/FiO2>=200 at 48hrs(COMPOSITE), ventilator-free days(VFD) and mortality. Results Fifty patients were randomized: Phase 1: 17 control, 19 tPA-Bolus; Phase 2: 8 control, 6 tPA-Drip. There were no severe bleeding events. In tPA-Bolus patients, the PaO2/FiO2 ratio was significantly(p Interpretation The combination tPA-Bolus+heparin is safe in severe COVID-19 respiratory failure. A Phase 3 study is warranted given improvements in oxygenation and promising observations in VFD and mortality.