Nebulised Rt-PA for ARDS Due to COVID-19

PaO2/FiO2 measured at multiple timepoints: baseline, during treatment, end of treatment, 3 days post end of treatment and 5 days post end of treatment. For Cohort 1, all available values were extracted per day and summarised every 4 hours (± 2h). For Cohort 2, up to six values were extracted per days including the worst ratio over the preceding day; Cohort 2 included only the lowest value for the day. PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure to fractional inspired oxygen. It is a widely used clinical indicator of hypoxaemia and is used to classify severity of acute respiratory distress syndrome. Limited data was observed due to patient discharge or death: Day 14 is presented below, and the last value available on treatment regardless of the duration of treatment (death or discharge may have occurred within 14 days) was summarised post-hoc. Summarized values were rounded to the nearest integer.

Time frame: Day 14 and last value available on treatment (which could occur up to 14 days, death or discharge may have occurred within 14 days)

Population: Limited data was observed due to patient discharge or death: Day 14 is presented below, and the last value available on nebulized Rt-PA treatment regardless of the duration of nebulized Rt-PA treatment (death or discharge may have occurred within 14 days) was summarised post-hoc. The historical matched controls were not treated with nebulized Rt-PA and therefore no data is available in the post-hoc analysis of the last on-treatment day.

Number of participants with a decrease in fibrinogen levels to \< 1gm/L during the treatment period and 48 hours after the last dose.

Time frame: 28 days

Population: Fibrinogen levels were not recorded for the historical matched controls (cohort 1)

Number of patients with major bleeding events assessed as related to the study drug summarised in each group.

Time frame: 28 days

Population: Bleeding events were not recorded in historical matched controls (cohort 1)

Number of Participants with serious adverse events causally related to treatment. Adverse events (other than bleeding events) were not recorded in the study.

Time frame: 28 days

Population: Bleeding events were not recorded in historical matched controls (cohort 1) Adverse events (other than bleeding events) were not recorded in the study

Clinical status as assessed by a 7-point WHO ordinal scale at baseline and daily up to 5 days post end of treatment and at day 28, discharge or death (whichever comes first). 1. Limitation of activities 2. Hospitalized, no oxygen therapy 3. Oxygen by mask or nasal prongs 4. Non-invasive ventilation or high-flow oxygen 5. Intubation and mechanical ventilation 6. Ventilation+ additional organ support (vasopressor, RRT, ECMO) 7. Death

Time frame: Day 28

Population: This outcome measure was modified between cohort 1 and 2, and the 7-point WHO scale was only collected from patients in cohort 2. Limited data was observed due to patient discharge or death, therefore only data for cohort 2 are presented. During the COVID pandemic, investigations and observations were done less rigorously than compared to routine care. Many of the secondary outcome measures were based on the standard of care rather than being study specific observations.

In-hospital mortality.

Time frame: 28 days

Intensive care stay, up to 28 days or death or discharge, whichever occurs first, was a secondary outcome as defined in the protocol. However, due to protocol amendments, difficulties in collecting this data, differences in study design between cohort 1 and cohort 2 and limited comparability of this outcome measure between groups, results are presented but have limited interpretation and should not be used or compared. For cohort 1, the number of days in ICU were limited to the 1st admission.

Time frame: 28 days

Population: Due to protocol amendments, difficulties in collecting this data (owing to a combination of death, recovery and a smaller data set used for monitoring patients during COVID), differences in study design between cohort 1 \& cohort 2, and limited comparability of this outcome measure between groups, results are presented but have limited interpretation and should not be used or compared. For cohort 1, the number of days in ICU were limited to the 1st admission.

Changes in lung compliance (defined as tidal volume / (peak inspiratory pressure - PEEP) from baseline (same day as start of treatment but prior to start of treatment) was a secondary outcome as defined in the protocol. Limited data was observed due to patient discharge or death, therefore the last value available on treatment regardless of the duration of treatment (death or discharge may have occurred within 14 days) was summarised post-hoc and presented below. For cohort 2, the daily measurement coinciding with the worst PF ratio (as close as possible in date and time) was used for the summaries.

Time frame: Last value available on treatment (which could occur up to 14 days, death or discharge may have occurred within 14 days)

Population: Lung compliance was not recorded in the historical matched controls (cohort 1) or in patients in the NIV group. During the COVID pandemic, investigations and observations were done less rigorously than compared to routine care. Many of the secondary outcome measures were based on the standard of care rather than being study specific observations.

incidence and number of days of new mechanical ventilation use during in the first 28 days was a secondary outcome measure as defined in the protocol.

Time frame: 28 days

Number of days of new oxygen use, non-invasive ventilation or high flow oxygen devices

Time frame: Day 28

Number of oxygen free days, up to 28 days or death or discharge, whichever occured first.

Time frame: up to 28 days or death or discharge, whichever occurred first

Number of ventilator free days, up to 28 days or death or discharge, whichever occured first

Time frame: up to 28 days or death or discharge, whichever occured first

The Sequential Organ Failure Assessment (SOFA) is a morbidity severity score and mortality estimation tool developed from a large sample of ICU patients throughout the world. The SOFA was designed to focus on organ dysfunction and morbidity, with less of an emphasis on mortality prediction. It requires the following (worst value within past 24 hours): FiO2, PaO2, Mechanical ventilation, Platelets, Bilirubin, Glasgow coma scale, Mean arterial pressure, Vasopressors, Creatinine, Urine output, and can be calculated by entering the results above into an online tool: https://clincalc.com/IcuMortality/SOFA.aspx. The SOFA Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems. A higher value for each organ system is associated with higher mortality, and here total score was used. The total possible score ranges from 0 to 24.

Time frame: 28 days (day 14 presented)

Population: During the COVID pandemic, investigations and observations were done less rigorously than compared to routine care. Many of the secondary outcome measures were based on the standard of care rather than being study specific observations.

Number of oxygen free days, up to 28 days or death or discharge, whichever occurs first was a secondary outcome as defined in the protocol. However, a post-hoc exploration of the data recalculated the number of Oxygen free days, taking into account the number of days post-discharge. For this new calculation, days post-discharge up to 28 days, were assumed to be days when the patient did not receive oxygen or ventilation.

Time frame: up to 28 days or death, whichever occurred first

Population: During the COVID pandemic, investigations and observations were done less rigorously than compared to routine care. Many of the secondary outcome measures were based on the standard of care rather than being study specific observations.

Incidence and number of days of new mechanical ventilation use during in the first 28 days was a secondary outcome measure as defined in the protocol. However, a post-hoc exploration of the data redefined New IMV (deterioration) as any patient requiring mechanical ventilation (IMV) after a period of non-mechanical ventilation after receiving r-tPA.

Time frame: 28 days

Population: New IMV (deterioration) was not recorded in the historical matched controls (cohort 1). During the COVID pandemic, investigations and observations were done less rigorously than compared to routine care. Many of the secondary outcome measures were based on the standard of care rather than being study specific observations.

Number of ventilator free days, up to 28 days or death or discharge, whichever occurs first was a secondary outcome as defined in the protocol. However, a post-hoc exploration of the data recalculated the number of ventilator free days, taking into account the number of days post-discharge. For this new calculation, days post-discharge up to 28 days, were assumed to be days when the patient did not receive oxygen or ventilation. .

Time frame: up to 28 days or death, whichever occurred first

Population: During the COVID pandemic, investigations and observations were done less rigorously than compared to routine care. Many of the secondary outcome measures were based on the standard of care rather than being study specific observations.

Incidence and number of days of new oxygen use, non-invasive ventilation or high flow oxygen devices in the first 28 days was a secondary outcome as defined in the protocol, however a post-hoc clarification of the endpoint redefined New Oxygen use (relapse) as any patient requiring oxygen support after being on room air for a whole day.

Time frame: 28 days

Population: New oxygen use was not recorded in the historical matched controls (cohort 1). During the COVID pandemic, investigations and observations were done less rigorously than compared to routine care. Many of the secondary outcome measures were based on the standard of care rather than being study specific observations.