Study of alteplase for respiratory failure in severe acute respiratory syndrome coronavirus 2/COVID-19: Study design of the phase IIa STARS trial

Background The coronavirus disease 2019 (COVID-19) pandemic has caused a large surge of acute respiratory distress syndrome (ARDS). Prior phase I trials (non-COVID-19) demonstrated improvement in pulmonary function in patients ARDS using fibrinolytic therapy. A follow-up trial using the widely available tissue-type plasminogen activator (t-PA) alteplase is now needed to assess optimal dosing and safety in this critically ill patient population. Objective To describe the design and rationale of a phase IIa trial to evaluate the safety and efficacy of alteplase treatment for moderate/severe COVID-19-induced ARDS. Patients/Methods A rapidly adaptive, pragmatic, open-label, randomized, controlled, phase IIa clinical trial will be conducted with 3 groups: intravenous alteplase 50 mg, intravenous alteplase 100 mg, and control (standard-of-care). Inclusion criteria are known/suspected COVID-19 infection with PaO2/FiO(2)ratio 4 hours despite maximal mechanical ventilation management. Alteplase will be delivered through an initial bolus of 50 mg or 100 mg followed by heparin infusion for systemic anticoagulation, with alteplase redosing if there is a >20% PaO2/FiO(2)improvement not sustained by 24 hours. Results The primary outcome is improvement in PaO2/FiO(2)at 48 hours after randomization. Other outcomes include ventilator- and intensive care unit-free days, successful extubation (no reintubation <= 3 days after initial extubation), and mortality. Fifty eligible patients will be enrolled in a rapidly adaptive, modified stepped-wedge design with 4 looks at the data. Conclusion Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).