The primary outcome will be the PaO2/FiO2 ratio 72 hours after randomization. The PaO2/FiO2 ratio will be calculated based on the arterial gas closest to the time-point of 72 hours after randomization. If no clinically-indicated arterial gas is performed or planned within ± 2 hours of the time-point, an arterial gas will be performed. The ratio will be calculated based on the PaO2 from the arterial gas and the FiO2 at the same time point. If the patient is receiving mechanical ventilation (invasive or non-invasive) or is receiving oxygen through a high-flow nasal cannula, the FiO2 will be obtained directly from the ventilator. If the patient is receiving oxygen through a regular nasal cannula, the FiO2 will be calculated based on the following: FiO2 = 21% + 4%/(l/min) x O2 flow in l/min. For face masks, with or without reservoir, the FiO2 will be estimated based on the approach used in EPIC2.40,41 Patients who dies prior to the 72-hour time point will be handled as described in Section 6.2.3. The PaO2/FiO2 ratio is a commonly used measure of illness severity in patients with acute lung injury and ARDS and is used to define these two conditions.17 Furthermore, the PaO2/FiO2 ratio is associated with mortality17,20 making it a potential useful surrogate outcome for phase II trials. Although data is sparse, a lower PaO2/FiO2 ratio has also been associated with worse outcomes in patients with COVID-19.10,42 Furthermore, animal studies in mice have shown that Senicapoc improves the PaO2/FiO2 ratio in experimentally induced ARDS (Section 1.3.2). Based on these considerations, and the fact that hypoxemic respiratory failure is the hallmark of severe COVID-19 infection, the PaO2/FiO2 ratio is a reasonable primary outcome for a phase II trial. The primary measure of the PaO2/FiO2 ratio will be done 72-hours after randomization. This time-point was chosen to allow adequate time for the intervention to work while avoiding missing data due to deaths.

The primary outcome will be the PaO2/FiO2 ratio 72 hours after randomization. The PaO2/FiO2 ratio will be calculated based on the arterial gas closest to the time-point of 72 hours after randomization. If no clinically-indicated arterial gas is performed or planned within ± 2 hours of the time-point, an arterial gas will be performed. The ratio will be calculated based on the PaO2 from the arterial gas and the FiO2 at the same time point. If the patient is receiving mechanical ventilation (invasive or non-invasive) or is receiving oxygen through a high-flow nasal cannula, the FiO2 will be obtained directly from the ventilator. If the patient is receiving oxygen through a regular nasal cannula, the FiO2 will be calculated based on the following: FiO2 = 21% + 4%/(l/min) x O2 flow in l/min. For face masks, with or without reservoir, the FiO2 will be estimated based on the approach used in EPIC2.40,41 Patients who dies prior to the 72-hour time point will be handled as described in Section 6.2.3. The PaO2/FiO2 ratio is a commonly used measure of illness severity in patients with acute lung injury and ARDS and is used to define these two conditions.17 Furthermore, the PaO2/FiO2 ratio is associated with mortality17,20 making it a potential useful surrogate outcome for phase II trials. Although data is sparse, a lower PaO2/FiO2 ratio has also been associated with worse outcomes in patients with COVID-19.10,42 Furthermore, animal studies in mice have shown that Senicapoc improves the PaO2/FiO2 ratio in experimentally induced ARDS (Section 1.3.2). Based on these considerations, and the fact that hypoxemic respiratory failure is the hallmark of severe COVID-19 infection, the PaO2/FiO2 ratio is a reasonable primary outcome for a phase II trial. The primary measure of the PaO2/FiO2 ratio will be done 72-hours after randomization. This time-point was chosen to allow adequate time for the intervention to work while avoiding missing data due to deaths.