Trial Outcomes & Findings for Nebulised Rt-PA for ARDS Due to COVID-19 (NCT NCT04356833)

NCT ID: NCT04356833

Last Updated: 2025-08-11

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 35 participants
• Primary outcome timeframe: Day 14 and last value available on treatment (which could occur up to 14 days, death or discharge may have occurred within 14 days)
• Results posted on: 2025-08-11

Participant Flow

In Cohort 1, as an observational arm, matched historical controls who received SOC were also recruited at a ratio of 2 controls to every 1 treatment arm patient, resulting in 18 historical controls.

Participant milestones

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV Arm nebulised recombinant tissue-Plasminogen Activator (rt-PA) - cohort 2 IMV arm - Patients on IMV received 60mg daily over three doses for up to 14 day	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV Arm nebulised recombinant tissue-Plasminogen Activator (rt-PA) - cohort 2 NIV arm -NIV patients received 60mg daily over 3 doses for two days, followed by 12 days receiving 40mg daily over two doses (for a maximum of 12 days, and doses were changed if patient required IMV)
Overall Study STARTED	9	18	12	14
Overall Study COMPLETED	9	18	12	14
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=9 Participants Patients in the rt-PA group received the first dose as soon as possible after registration. Initial dosing regime: 10 mg of rt-PA dissolved in 5 ml of diluent given every 6 hrs (resulting in a total daily dose of 40mg) for a maximum of 66 hrs, in addition to standard of care for COVID-19 acute respiratory distress syndrome (ARDS). Following protocol amendment, dosing duration was increased from 3 days to up to 14 days of rt-PA treatment. Six patients were receiving Invasive mechanical ventilation and 3 were receiving non-invasive ventilation.	Historical Matched Controls - Cohort 1 n=18 Participants Matched historical controls who received standard of care were also recruited at a ratio of 2 controls to every 1 treatment arm patient. Matching was done according to the following criteria in the order stated: 1. Ventilation and oxygen type (IMV and non-invasive oxygen support) 2. Severity as determined by PaO2/FiO2 ratio 3. Gender 4. Age (+/- 2 years, up to a maximum of 10 years) 5. Ethnicity	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=12 Participants In cohort 2, fewer timepoints were collected, which allowed for more rapid recruitment while at the same time not compromising safety monitoring. A more flexible dosing regimen for rtPA was utilised. Patients on IMV received 60mg daily over three doses for up to 14 days	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV n=14 Participants In cohort 2, fewer timepoints were collected, which allowed for more rapid recruitment while at the same time not compromising safety monitoring. A more flexible dosing regimen for rtPA was utilised. Patients on NIV received 60mg daily for over 3 doses for two days, followed by 12 days receiving 40mg daily over two doses (for a maximum of 12 days, and doses were changed if patient required IMV).	Total n=53 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=9 Participants	0 Participants n=18 Participants	0 Participants n=12 Participants	0 Participants n=14 Participants	0 Participants n=53 Participants
Age, Categorical Between 18 and 65 years	4 Participants n=9 Participants	8 Participants n=18 Participants	8 Participants n=12 Participants	8 Participants n=14 Participants	28 Participants n=53 Participants
Age, Categorical >=65 years	5 Participants n=9 Participants	10 Participants n=18 Participants	4 Participants n=12 Participants	6 Participants n=14 Participants	25 Participants n=53 Participants
Sex: Female, Male Female	5 Participants n=9 Participants	9 Participants n=18 Participants	5 Participants n=12 Participants	2 Participants n=14 Participants	21 Participants n=53 Participants
Sex: Female, Male Male	4 Participants n=9 Participants	9 Participants n=18 Participants	7 Participants n=12 Participants	12 Participants n=14 Participants	32 Participants n=53 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=9 Participants	0 Participants n=18 Participants	0 Participants n=12 Participants	0 Participants n=14 Participants	0 Participants n=53 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	9 Participants n=9 Participants	14 Participants n=18 Participants	12 Participants n=12 Participants	11 Participants n=14 Participants	46 Participants n=53 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=9 Participants	4 Participants n=18 Participants	0 Participants n=12 Participants	3 Participants n=14 Participants	7 Participants n=53 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=9 Participants	0 Participants n=18 Participants	0 Participants n=12 Participants	0 Participants n=14 Participants	0 Participants n=53 Participants
Race (NIH/OMB) Asian	3 Participants n=9 Participants	4 Participants n=18 Participants	3 Participants n=12 Participants	6 Participants n=14 Participants	16 Participants n=53 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=9 Participants	0 Participants n=18 Participants	0 Participants n=12 Participants	0 Participants n=14 Participants	0 Participants n=53 Participants
Race (NIH/OMB) Black or African American	0 Participants n=9 Participants	0 Participants n=18 Participants	0 Participants n=12 Participants	1 Participants n=14 Participants	1 Participants n=53 Participants
Race (NIH/OMB) White	6 Participants n=9 Participants	10 Participants n=18 Participants	4 Participants n=12 Participants	4 Participants n=14 Participants	24 Participants n=53 Participants
Race (NIH/OMB) More than one race	0 Participants n=9 Participants	0 Participants n=18 Participants	0 Participants n=12 Participants	0 Participants n=14 Participants	0 Participants n=53 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=9 Participants	4 Participants n=18 Participants	5 Participants n=12 Participants	3 Participants n=14 Participants	12 Participants n=53 Participants
Race and Ethnicity Not Collected	—	—	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment United Kingdom	9 participants n=9 Participants	18 participants n=18 Participants	12 participants n=12 Participants	14 participants n=14 Participants	53 participants n=53 Participants
PaO2/FiO2 Ratio	154 mmHg (rounded) STANDARD_DEVIATION 53 • n=9 Participants	154 mmHg (rounded) STANDARD_DEVIATION 73 • n=18 Participants	120 mmHg (rounded) STANDARD_DEVIATION 28 • n=12 Participants	126 mmHg (rounded) STANDARD_DEVIATION 42 • n=14 Participants	139 mmHg (rounded) STANDARD_DEVIATION 55 • n=53 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=9 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=4 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=12 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV n=14 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
Efficacy - PaO2/FiO2 Ratio Day 14	227 mmHg (rounded) Standard Deviation 83	209 mmHg (rounded) Standard Deviation 49	155 mmHg (rounded) Standard Deviation 104	248 mmHg (rounded) Standard Deviation 89
Efficacy - PaO2/FiO2 Ratio Last On-Treatment Day	218 mmHg (rounded) Standard Deviation 73	—	169 mmHg (rounded) Standard Deviation 108	240 mmHg (rounded) Standard Deviation 104

PRIMARY outcome

Timeframe: 28 days

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

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

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=9 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=12 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=14 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
Safety- Participants With Major Bleeding Events Directly Attributable to Study Drug	0 Participants	1 Participants	0 Participants	—

PRIMARY outcome

Timeframe: 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

Number of Participants with serious adverse events causally related to treatment.

Adverse events (other than bleeding events) were not recorded in the study.

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=9 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=12 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=14 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
Safety- Participants With Serious Adverse Events Causally Related to Treatment	0 Participants	0 Participants	0 Participants	—

PRIMARY outcome

Timeframe: 28 days

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

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

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=9 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=12 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=14 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
Safety- Participants With Decrease in Fibrinogen Levels to < 1gm/L	0 Participants	0 Participants	0 Participants	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=6 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=12 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
Lung Compliance	40.4 mL/cmH2O Standard Deviation 22.5	37.6 mL/cmH2O Standard Deviation 42.8	—	—

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=12 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=14 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
Clinical Status as Determined by a 7-point WHO Ordinal Scale 1. Limitation of activities	0 Participants	0 Participants	—	—
Clinical Status as Determined by a 7-point WHO Ordinal Scale 2. Hospitalized, no oxygen therapy	0 Participants	0 Participants	—	—
Clinical Status as Determined by a 7-point WHO Ordinal Scale 3. Oxygen by mask or nasal prongs	1 Participants	2 Participants	—	—
Clinical Status as Determined by a 7-point WHO Ordinal Scale 4. Non-invasive ventilation or high-flow oxygen	0 Participants	0 Participants	—	—
Clinical Status as Determined by a 7-point WHO Ordinal Scale 5. Intubation and mechanical ventilation	2 Participants	0 Participants	—	—
Clinical Status as Determined by a 7-point WHO Ordinal Scale 6. Ventilation+ additional organ support vasopressor, RRT, ECMO)	1 Participants	0 Participants	—	—
Clinical Status as Determined by a 7-point WHO Ordinal Scale 7. Death	0 Participants	0 Participants	—	—
Clinical Status as Determined by a 7-point WHO Ordinal Scale Data Missing	8 Participants	12 Participants	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=7 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=2 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=6 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV n=4 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
Sequential Organ Failure Assessment (SOFA) Score	7.71 score on a scale Standard Deviation 4.82	7 score on a scale Standard Deviation 7.07	10.7 score on a scale Standard Deviation 1.63	4.8 score on a scale Standard Deviation 4.92

SECONDARY outcome

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

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

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=12 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=14 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=9 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV n=18 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
Number of Oxygenation Free Days	0 days Interval 0.0 to 5.0	0.5 days Interval 0.0 to 6.0	0 days Interval 0.0 to 10.0	0 days Interval 0.0 to 12.0

SECONDARY outcome

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

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

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=12 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=14 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=6 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV n=10 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
Number of Ventilator Free Days	0 Days Interval 0.0 to 8.0	7.5 Days Interval 0.0 to 23.0	0 Days Interval 0.0 to 13.0	1.5 Days Interval 0.0 to 13.0

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=8 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=12 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=8 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV n=2 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
Intensive Care Stay	19 Days Interval 5.0 to 28.0	12 Days Interval 2.0 to 28.0	9 Days Interval 1.0 to 13.0	5 Days Interval 1.0 to 8.0

SECONDARY outcome

Timeframe: 28 days

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.

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=12 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=14 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=6 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV n=10 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
Number of Days of New Mechanical Ventilation Use During in the First 28 Days	14.5 Days Interval 2.0 to 23.0	0 Days Interval 0.0 to 12.0	23 Days Interval 13.0 to 28.0	10.5 Days Interval 2.0 to 28.0

SECONDARY outcome

Timeframe: Day 28

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

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=12 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=14 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=2 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV n=5 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
Number of Days of Non-invasive Ventilation Use	0.5 days Interval 0.0 to 8.0	6 days Interval 0.0 to 23.0	6.5 days Interval 5.0 to 8.0	3 days Interval 1.0 to 3.0

SECONDARY outcome

Timeframe: 28 days

In-hospital mortality.

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=9 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=18 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=12 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV n=14 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
In-hospital Mortality	1 Participants	10 Participants	5 Participants	3 Participants

POST_HOC outcome

Timeframe: 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.

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.

.

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=6 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=12 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=14 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV n=10 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
Number of Ventilator Free Days (With Imputation)	4.3 days Standard Deviation 6.8	5.75 days Standard Deviation 9.94	21.4 days Standard Deviation 9.68	8.4 days Standard Deviation 9.6

POST_HOC outcome

Timeframe: 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.

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.

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=9 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=12 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=14 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV n=18 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
Number of Oxygen Free Days (With Imputation)	6.2 days Standard Deviation 9.5	4.42 days Standard Deviation 8.1	13.43 days Standard Deviation 11.1	6.7 days Standard Deviation 9.2

POST_HOC outcome

Timeframe: 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.

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.

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=9 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=12 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=14 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
Number of Particpants With "New IMV (Deterioration)"	0 Participants	1 Participants	2 Participants	—

POST_HOC outcome

Timeframe: 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.

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.

Outcome measures

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=9 Participants nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1: Patients in the cohort 1 rt-PA group received the first dose as soon as possible after registration.	Historical Matched Controls - Cohort 1 n=12 Participants Matched historical controls who received standard of care were recruited at a ratio of 2 controls to every 1 treatment arm.	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=14 Participants Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 invasive mechanical ventilation	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 non-invasive ventilation/non-invasive respiratory support
Numer of Participants With "New Oxygen Use (Relapse)"	0 Participants	1 Participants	0 Participants	—

Adverse Events

Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1

Serious events: 0 serious events

Other events: 4 other events

Deaths: 1 deaths

Historical Matched Controls - Cohort 1

Serious events: 0 serious events

Other events: 0 other events

Deaths: 10 deaths

Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV

Serious events: 1 serious events

Other events: 9 other events

Deaths: 5 deaths

Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV

Serious events: 0 serious events

Other events: 4 other events

Deaths: 3 deaths

Serious adverse events

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=9 participants at risk Patients in the rt-PA group received the first dose as soon as possible after registration. Initial dosing regime: 10 mg of rt-PA dissolved in 5 ml of diluent given every 6 hrs (resulting in a total daily dose of 40mg) for a maximum of 66 hrs, in addition to standard of care for COVID-19 acute respiratory distress syndrome (ARDS). Following a protocol amendment, dosing duration was increased from 3 days to up to 14 days of rt-PA treatment. Six patients were receiving Invasive mechanical ventilation and 3 were receiving non-invasive ventilation.	Historical Matched Controls - Cohort 1 Historical matched controls were recruited at a ratio of 2 controls to every 1 rtPA + SOC arm patient, and were matched according to the following characteristics: 1. Ventilation and oxygen type (IMV and non-invasive oxygen support) 2. Severity as determined by PaO2/FiO2 ratio 3. Gender 4. Age (+/- 2 years, up to a maximum of 10 years) 5. Ethnicity	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=12 participants at risk In cohort 2, fewer timepoints were collected, which will allowed for more rapid recruitment while at the same time not compromising safety monitoring. A more flexible dosing regimen for rtPA was utilised. Patients on IMV received 60mg daily over three doses for up to 14 days	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV n=14 participants at risk In cohort 2, fewer timepoints were collected, which will allowed for more rapid recruitment while at the same time not compromising safety monitoring. A more flexible dosing regimen for rtPA was utilised. Patients on NIV received 60mg daily for over 3 doses for two days, followed by 12 days receiving 40mg daily over two doses.
Nervous system disorders Cerebral bleed	0.00% 0/9 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	— 0/0 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	8.3% 1/12 • Number of events 1 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	0.00% 0/14 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).

Other adverse events

Measure	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 1 n=9 participants at risk Patients in the rt-PA group received the first dose as soon as possible after registration. Initial dosing regime: 10 mg of rt-PA dissolved in 5 ml of diluent given every 6 hrs (resulting in a total daily dose of 40mg) for a maximum of 66 hrs, in addition to standard of care for COVID-19 acute respiratory distress syndrome (ARDS). Following a protocol amendment, dosing duration was increased from 3 days to up to 14 days of rt-PA treatment. Six patients were receiving Invasive mechanical ventilation and 3 were receiving non-invasive ventilation.	Historical Matched Controls - Cohort 1 Historical matched controls were recruited at a ratio of 2 controls to every 1 rtPA + SOC arm patient, and were matched according to the following characteristics: 1. Ventilation and oxygen type (IMV and non-invasive oxygen support) 2. Severity as determined by PaO2/FiO2 ratio 3. Gender 4. Age (+/- 2 years, up to a maximum of 10 years) 5. Ethnicity	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 IMV n=12 participants at risk In cohort 2, fewer timepoints were collected, which will allowed for more rapid recruitment while at the same time not compromising safety monitoring. A more flexible dosing regimen for rtPA was utilised. Patients on IMV received 60mg daily over three doses for up to 14 days	Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA) - Cohort 2 NIV n=14 participants at risk In cohort 2, fewer timepoints were collected, which will allowed for more rapid recruitment while at the same time not compromising safety monitoring. A more flexible dosing regimen for rtPA was utilised. Patients on NIV received 60mg daily for over 3 doses for two days, followed by 12 days receiving 40mg daily over two doses.
Surgical and medical procedures Bleed: Central venous catheters access site	22.2% 2/9 • Number of events 2 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	— 0/0 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	0.00% 0/12 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	0.00% 0/14 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).
Gastrointestinal disorders Gastro-intestinal bleed	11.1% 1/9 • Number of events 1 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	— 0/0 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	0.00% 0/12 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	14.3% 2/14 • Number of events 2 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).
Surgical and medical procedures Blood-stained tracheobronchial secretion	11.1% 1/9 • Number of events 1 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	— 0/0 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	58.3% 7/12 • Number of events 12 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	7.1% 1/14 • Number of events 2 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).
Surgical and medical procedures Tracheostomy site bleed	22.2% 2/9 • Number of events 2 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	— 0/0 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	8.3% 1/12 • Number of events 1 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	0.00% 0/14 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).
Surgical and medical procedures Bleed: chest-drain related	0.00% 0/9 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	— 0/0 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	8.3% 1/12 • Number of events 1 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	0.00% 0/14 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).
Ear and labyrinth disorders Epistaxis	0.00% 0/9 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	— 0/0 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	0.00% 0/12 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	7.1% 1/14 • Number of events 3 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).
General disorders Other	11.1% 1/9 • Number of events 1 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	— 0/0 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	16.7% 2/12 • Number of events 2 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).	7.1% 1/14 • Number of events 1 • Maximum of 28 days per patient, starting from dosing day 1 Only serious adverse events related to the IMP, and all bleeding events were collected/reported. Bleeding events were identified as adverse events of special interest (AESI). In addition, the ISTH (International Society of Haemostasis and Thrombosis) classification for bleed severity as used for anticoagulation studies was implemented. Events were not collected/recorded in historical matched controls (cohort 1).

Additional Information

Professor Pratima Chowdary

Royal Free London NHS Foundation Trust

Phone: 0207 794 0500

Email: p.chowdary@nhs.net

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place