Trial Outcomes & Findings for Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection (NCT NCT04357730)

NCT ID: NCT04357730

Last Updated: 2022-01-20

Results Overview

PaO2/FiO2 change (increase) from pre-to-post intervention at 48 hours post randomization. Ideally, the PaO2/FiO2 will be measured with the patient in the same prone/supine position as in baseline, as change in positions may artificially reduce the change (increase) attributable to the study drug. However, given the pragmatic nature of the trial, the prone/supine position will be determined by the attending physician, in which case, we will use as an outcome the PaO2/FiO2 closest to the 48 hours obtained prior to the change in position as the outcome.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 50 participants
• Primary outcome timeframe: at 48 hours post randomization
• Results posted on: 2022-01-20

Participant Flow

Participant milestones

Measure	Control Patients randomized to Control arm will receive no study medication; the treatment will be standard of care according to the institution's protocol for ARDS.	Alteplase-50 Bolus Patients randomized to Alteplase-50 group will receive 50 mg of Alteplase intravenous bolus administration over 2 hours. Re-bolusing of Alteplase, at the same dose, is permitted in those patients who show an initial transient response. The repeat dose will be given between 24 and 36 hours after the initial Alteplase administration. Alteplase 50 MG \[Activase\]: Patients randomized to Alteplase-50 group will receive 50 mg of Alteplase intravenous bolus administration over 2 hours, given as a 10 mg push followed by the remaining 40 mgs over a total time of 2 hrs. Immediately following the Alteplase infusion, 5000 units (U) of unfractionated heparin (UFH) will be delivered and the heparin drip will be continued to maintain the activated partial thromboplastin time (aPTT) at 60-80sec (2.0 to 2.5 times the upper limit of normal). Re-bolusing of Alteplase, at the same dose, is permitted in the Alteplase-50 intervention group in those patients who show an initial transient response (\>20% improvement of PaO2/FiO2 over pre-infusion of Alteplase at any of the measurements at 2, 6, 12 or 18 hours, but \<50% improvement of PaO2/FiO2 at 24 hours after randomization); the repeat dose will be given between 24 and 36 hours after the initial Alteplase administration.	Alteplase-50 Bolus Plus Drip Patients randomized to Alteplase-50 plus drip group will receive 50 mg of Alteplase intravenous bolus administration over 2 hours. Immediately following this initial Alteplase infusion, a drip of 2 mg/hr of Alteplase will be initiated over the ensuing 24 hours (total 48 mg infusion). Alteplase 50 MG \[Activase\]: wed by the remaining 40 mgs over a total time of 2 hrs. Immediately following this initial Alteplase infusion, we will initiate a drip of 2 mg/hr Alteplase over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of 500 units per hour (U/hr) heparin during the Alteplase drip. After this, heparin dose will be increased slowly to maintain aPTT between 60 and 80 sec, titrated per attending's discretion.
Phase 1 STARTED	17	19	0
Phase 1 COMPLETED	17	19	0
Phase 1 NOT COMPLETED	0	0	0
Phase 2 STARTED	8	0	6
Phase 2 COMPLETED	8	0	6
Phase 2 NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection

Baseline characteristics by cohort

Measure	Phase 1 Control n=17 Participants Phase 1 (patients 1 to 36): at randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Phase 1 Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.	Phase 2 Control n=8 Participants Phase 2 (patients 37 to 50): at randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Phase 2 Alteplase-50 Drip n=6 Participants Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.	Total n=50 Participants Total of all reporting groups
Age, Continuous	60 years n=5 Participants	59 years n=7 Participants	60.5 years n=5 Participants	64.5 years n=4 Participants	60 years n=21 Participants
Sex: Female, Male Female	7 Participants n=5 Participants	4 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	13 Participants n=21 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	15 Participants n=7 Participants	6 Participants n=5 Participants	6 Participants n=4 Participants	37 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	11 Participants n=5 Participants	13 Participants n=7 Participants	5 Participants n=5 Participants	3 Participants n=4 Participants	32 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	5 Participants n=5 Participants	5 Participants n=7 Participants	3 Participants n=5 Participants	3 Participants n=4 Participants	16 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) White	11 Participants n=5 Participants	11 Participants n=7 Participants	6 Participants n=5 Participants	2 Participants n=4 Participants	30 Participants n=21 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants n=5 Participants	8 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	15 Participants n=21 Participants
BMI (body mass index)	36.8 kg/m^2 n=5 Participants	37.1 kg/m^2 n=7 Participants	30.9 kg/m^2 n=5 Participants	29.5 kg/m^2 n=4 Participants	36.8 kg/m^2 n=21 Participants
Time from admission to randomization	2 days n=5 Participants	2 days n=7 Participants	1 days n=5 Participants	5 days n=4 Participants	2 days n=21 Participants
Diabetes	6 Participants n=5 Participants	6 Participants n=7 Participants	3 Participants n=5 Participants	2 Participants n=4 Participants	17 Participants n=21 Participants
Cardiac disease	14 Participants n=5 Participants	18 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	33 Participants n=21 Participants
Essential hypertension	4 Participants n=5 Participants	4 Participants n=7 Participants	4 Participants n=5 Participants	4 Participants n=4 Participants	16 Participants n=21 Participants
COPD	13 Participants n=5 Participants	15 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants	31 Participants n=21 Participants
Hyperlipidemia	6 Participants n=5 Participants	5 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	13 Participants n=21 Participants
Other comorbidities	5 Participants n=5 Participants	7 Participants n=7 Participants	5 Participants n=5 Participants	4 Participants n=4 Participants	21 Participants n=21 Participants
Concurrent infections	10 Participants n=5 Participants	13 Participants n=7 Participants	5 Participants n=5 Participants	4 Participants n=4 Participants	32 Participants n=21 Participants
Dexamethasone	11 Participants n=5 Participants	9 Participants n=7 Participants	3 Participants n=5 Participants	3 Participants n=4 Participants	26 Participants n=21 Participants
Remdesivir	8 Participants n=5 Participants	9 Participants n=7 Participants	2 Participants n=5 Participants	1 Participants n=4 Participants	20 Participants n=21 Participants
Pa/FiO2 ratio	107 ratio n=5 Participants	113.3 ratio n=7 Participants	99.5 ratio n=5 Participants	109.7 ratio n=4 Participants	112.3 ratio n=21 Participants
National Early Warning Score (NEWS) 2	6 units on a scale n=5 Participants	6 units on a scale n=7 Participants	10 units on a scale n=5 Participants	6 units on a scale n=4 Participants	6 units on a scale n=21 Participants
aPTT	30 seconds n=5 Participants	32.3 seconds n=7 Participants	31.1 seconds n=5 Participants	31 seconds n=4 Participants	30.5 seconds n=21 Participants
International normalized ratio (INR)	1.3 ratio n=5 Participants	1.1 ratio n=7 Participants	1.3 ratio n=5 Participants	1.1 ratio n=4 Participants	1.2 ratio n=21 Participants
Fibrinogen	668.5 mg/dL n=5 Participants	685 mg/dL n=7 Participants	560 mg/dL n=5 Participants	695.5 mg/dL n=4 Participants	685 mg/dL n=21 Participants
D-dimer	1900 ng/mL n=5 Participants	2105 ng/mL n=7 Participants	4180 ng/mL n=5 Participants	2652 ng/mL n=4 Participants	1900 ng/mL n=21 Participants

PRIMARY outcome

Timeframe: at 48 hours post randomization

Population: Of the 19 patients receiving the tPA-Bolus intervention, 8 required a second tPA dose due to transient PaO2/FiO2 improvement. No patients crossed over or withdrew.

PaO2/FiO2 change (increase) from pre-to-post intervention at 48 hours post randomization. Ideally, the PaO2/FiO2 will be measured with the patient in the same prone/supine position as in baseline, as change in positions may artificially reduce the change (increase) attributable to the study drug. However, given the pragmatic nature of the trial, the prone/supine position will be determined by the attending physician, in which case, we will use as an outcome the PaO2/FiO2 closest to the 48 hours obtained prior to the change in position as the outcome.

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
PaO2/FiO2 Change (Increase) From Pre-to-post Intervention	16.9 percent change Interval -8.3 to 36.8	29.8 percent change Interval 4.5 to 88.7

PRIMARY outcome

Timeframe: at 48 hours post randomization

PaO2/FiO2 change (increase) from pre-to-post intervention at 48 hours post randomization. Ideally, the PaO2/FiO2 will be measured with the patient in the same prone/supine position as in baseline, as change in positions may artificially reduce the change (increase) attributable to the study drug. However, given the pragmatic nature of the trial, the prone/supine position will be determined by the attending physician, in which case, we will use as an outcome the PaO2/FiO2 closest to the 48 hours obtained prior to the change in position as the outcome.

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
PaO2/FiO2 Change (Increase) From Pre-to-post Intervention	-11.9 percent change Interval -24.3 to 136.0	-19.6 percent change Interval -21.7 to 2.3

SECONDARY outcome

Timeframe: at 48 hours post randomization

Population: Of the 19 patients receiving the tPA-Bolus intervention, 8 required a second tPA dose due to transient PaO2/FiO2 improvement. No patients crossed over or withdrew.

Number of Participants with Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2 (whatever is lower)

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2	2 Participants	9 Participants

SECONDARY outcome

Timeframe: at 48 hours post randomization

Population: Of the 19 patients receiving the tPA-Bolus intervention, 8 required a second tPA dose due to transient PaO2/FiO2 improvement. No patients crossed over or withdrew.

Number of Participants with Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2 (whatever is lower)

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2	3 Participants	1 Participants

SECONDARY outcome

Timeframe: at 48 hours post randomization

NEWS2 is a standardised clinical scoring system developed to improve detection of deterioration in acutely ill patients. It is based on aggregate scoring of six physiological parameters; respiratory rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness or new confusion, and body temperature. A NEWS2 score of 5 or 6 is considered a key threshold that may indicate clinical deterioration and should prompt urgent response by a clinician or a team with competence in assessment and treatment of acutely ill patients.The total score range is 0 to 20.

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
National Early Warning Score 2 (NEWS2)	0 percent change Interval -22.2 to 40.0	0 percent change Interval -22.2 to 20.0

SECONDARY outcome

Timeframe: at 48 hours post randomization

NEWS2 is a standardised clinical scoring system developed to improve detection of deterioration in acutely ill patients. It is based on aggregate scoring of six physiological parameters; respiratory rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness or new confusion, and body temperature. A NEWS2 score of 5 or 6 is considered a key threshold that may indicate clinical deterioration and should prompt urgent response by a clinician or a team with competence in assessment and treatment of acutely ill patients.The total score range is 0 to 20.

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
National Early Warning Score 2 (NEWS2)	-12.5 percent change Interval -26.8 to 18.8	65.7 percent change Interval 0.0 to 80.0

SECONDARY outcome

Timeframe: 28 days post randomization

28 days mortality for hospitalized patients

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
28 Days In-hospital Mortality	5 Participants	4 Participants

SECONDARY outcome

Timeframe: 28 days post randomization

28 days mortality for hospitalized patients

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
28 Days In-hospital Mortality	4 Participants	4 Participants

SECONDARY outcome

Timeframe: 28 days of hospital stay or until hospital discharge (whichever comes first)

ICU-free days will be calculated based on (28 - number of days spent in the ICU) formula

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
ICU-free Days	0 days Interval 0.0 to 10.0	6 days Interval 0.0 to 15.0

SECONDARY outcome

Timeframe: 28 days of hospital stay or until hospital discharge (whichever comes first)

ICU-free days will be calculated based on (28 - number of days spent in the ICU) formula

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
ICU-free Days	0 days Interval 0.0 to 0.0	0 days Interval 0.0 to 0.0

SECONDARY outcome

Timeframe: 28 days of hospital stay or until hospital discharge (whichever comes first)

Ventilator-free days will be calculated based on (28 - number of days on mechanical ventilation) formula.

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Ventilator-free Days	0 days Interval 0.0 to 9.0	12 days Interval 0.0 to 19.0

SECONDARY outcome

Timeframe: 28 days of hospital stay or until hospital discharge (whichever comes first)

Ventilator-free days will be calculated based on (28 - number of days on mechanical ventilation) formula.

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Ventilator-free Days	0 days Interval 0.0 to 1.0	0 days Interval 0.0 to 0.0

POST_HOC outcome

Timeframe: 24 hours post-randomization

PaO2/FiO2 ratio measured at 24 hours post-randomization

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
PaO2/FiO2 Ratio at 24 Hours	146.7 ratio Interval 98.8 to 174.0	144 ratio Interval 122.9 to 217.1

POST_HOC outcome

Timeframe: 24 hours post-randomization

PaO2/FiO2 ratio measured at 24 hours post-randomization

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
PaO2/FiO2 at 24 Hours	119.2 ratio Interval 111.9 to 131.3	94.5 ratio Interval 71.0 to 114.5

POST_HOC outcome

Timeframe: 48 hours post-randomization

PaO2/FiO2 ratio measured at 48 hours post-randomization

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
PaO2/FiO2 at 48 Hours	125 ratio Interval 87.5 to 147.5	157.1 ratio Interval 130.0 to 188.0

POST_HOC outcome

Timeframe: 48 hours post-randomization

PaO2/FiO2 ratio measured at 48 hours post-randomization

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
PaO2/FiO2 at 48 Hours	113.7 ratio Interval 88.8 to 160.0	103.5 ratio Interval 78.8 to 105.0

POST_HOC outcome

Timeframe: at 24 hours post randomization

This outcome measure shows patients' median aPTT at 24 hours post randomization.

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
aPTT at 24 Hours	32.9 seconds Interval 28.0 to 36.1	51.7 seconds Interval 36.9 to 65.6

POST_HOC outcome

Timeframe: at 24 hours post randomization

This outcome measure shows patients' median aPTT at 24 hours post randomization.

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
aPTT at 24 Hours	35.6 seconds Interval 29.0 to 51.2	27.7 seconds Interval 26.8 to 30.0

POST_HOC outcome

Timeframe: at 48 hours post randomization

This outcome measure shows patients' median aPTT at 48 hours post randomization.

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
aPTT at 48 Hours	30 seconds Interval 26.9 to 36.2	64.3 seconds Interval 55.7 to 73.6

POST_HOC outcome

Timeframe: at 48 hours post randomization

This outcome measure shows patients' median aPTT at 48 hours post randomization.

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
aPTT at 48 Hours	53.1 seconds Interval 28.5 to 95.9	33 seconds Interval 28.5 to 57.4

POST_HOC outcome

Timeframe: 48 hours post-randomization

Number of patients who required paralytics 48 hours post-randomization

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Number of Patients Who Required Paralytics 48 Hours Post-randomization	10 Participants	8 Participants

POST_HOC outcome

Timeframe: 48 hours post-randomization

Number of patients who required paralytics 48 hours post-randomization

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Number of Patients Who Required Paralytics 48 Hours Post-randomization	6 Participants	4 Participants

POST_HOC outcome

Timeframe: at 24 hours post randomization

This outcome measure shows patients' median INR at 24 hours post randomization.

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
INR at 24 Hours	1.3 ratio Interval 1.2 to 1.3	1.2 ratio Interval 1.1 to 1.2

POST_HOC outcome

Timeframe: at 24 hours post randomization

This outcome measure shows patients' median INR at 24 hours post randomization.

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
INR at 24 Hours	1.1 ratio Interval 1.0 to 1.3	1.1 ratio Interval 1.0 to 1.2

POST_HOC outcome

Timeframe: at 48 hours post randomization

This outcome measure shows patients' median INR at 48 hours post randomization.

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
INR at 48 Hours	1.2 ratio Interval 1.1 to 1.3	1.2 ratio Interval 1.1 to 1.3

POST_HOC outcome

Timeframe: at 48 hours post randomization

This outcome measure shows patients' median INR at 48 hours post randomization.

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
INR at 48 Hours	1.2 ratio Interval 1.1 to 1.3	1.2 ratio Interval 1.1 to 1.4

POST_HOC outcome

Timeframe: at 24 hours post randomization

This outcome measure shows patients' median Fibrinogen (mg/dL) at 24 hours post randomization.

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Fibrinogen at 24 Hours	595 mg/dL Interval 521.0 to 828.0	627 mg/dL Interval 567.0 to 800.0

POST_HOC outcome

Timeframe: at 24 hours post randomization

This outcome measure shows patients' median Fibrinogen (mg/dL) at 24 hours post randomization.

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Fibrinogen at 24 Hours	588.5 mg/dL Interval 441.0 to 768.0	612 mg/dL Interval 542.0 to 822.0

POST_HOC outcome

Timeframe: at 48 hours post randomization

This outcome measure shows patients' median Fibrinogen (mg/dL) at 48 hours post randomization.

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Fibrinogen at 48 Hours	612 mg/dL Interval 450.0 to 817.0	567 mg/dL Interval 520.0 to 786.0

POST_HOC outcome

Timeframe: at 48 hours post randomization

This outcome measure shows patients' median Fibrinogen (mg/dL) at 48 hours post randomization.

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Fibrinogen at 48 Hours	480.5 mg/dL Interval 395.5 to 638.5	698.5 mg/dL Interval 542.0 to 821.0

POST_HOC outcome

Timeframe: at 24 hours post randomization

This outcome measure shows patients' median D-dimer (ng/mL) at 24 hours post randomization.

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
D-dimer at 24 Hours	1426 ng/mL Interval 730.0 to 3970.0	2296 ng/mL Interval 1330.0 to 9700.0

POST_HOC outcome

Timeframe: at 24 hours post randomization

This outcome measure shows patients' median D-dimer (ng/mL) at 24 hours post randomization.

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
D-dimer at 24 Hours	3855 ng/mL Interval 1996.0 to 8500.0	8477 ng/mL Interval 5540.0 to 11510.0

POST_HOC outcome

Timeframe: at 48 hours post randomization

This outcome measure shows patients' median D-dimer (ng/mL) at 48 hours post randomization.

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
D-dimer at 48 Hours	1326 ng/mL Interval 870.0 to 2970.0	1975 ng/mL Interval 1010.0 to 3650.0

POST_HOC outcome

Timeframe: at 48 hours post randomization

This outcome measure shows patients' median D-dimer (ng/mL) at 48 hours post randomization.

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
D-dimer at 48 Hours	3480.5 ng/mL Interval 2713.5 to 4750.0	4957.5 ng/mL Interval 4261.0 to 7650.0

POST_HOC outcome

Timeframe: Duration of hospital stay, up to 28 days

Number of days patient required ventilation support

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Ventilation Days	18 days Interval 9.0 to 28.0	13 days Interval 8.0 to 25.0

POST_HOC outcome

Timeframe: Duration of hospital stay, up to 28 days

Number of days patient required ventilation support

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Ventilation Days	24.5 days Interval 12.0 to 27.0	17.5 days Interval 16.0 to 25.0

POST_HOC outcome

Timeframe: Duration of hospital stay, up to 28 days

Number of Participants with Adverse Events

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Number of Participants With Adverse Events	13 Participants	13 Participants

POST_HOC outcome

Timeframe: Duration of hospital stay, up to 28 days

Number of Participants with Adverse Events

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Number of Participants With Adverse Events	5 Participants	2 Participants

POST_HOC outcome

Timeframe: Duration of hospital stay, up to 28 days

Number of Participants with Bleeding Events

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Number of Participants With Bleeding Events	2 Participants	3 Participants

POST_HOC outcome

Timeframe: Duration of hospital stay, up to 28 days

Number of Participants with Bleeding Events

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Number of Participants With Bleeding Events	1 Participants	0 Participants

POST_HOC outcome

Timeframe: Duration of hospital stay, up to 28 days

Outcome measures

Measure	Phase 1 Control n=17 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=19 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Intensive Care Unit (ICU) Days	18 days Interval 12.0 to 28.0	16 days Interval 11.0 to 28.0

POST_HOC outcome

Timeframe: Duration of hospital stay, up to 28 days

Outcome measures

Measure	Phase 1 Control n=8 Participants At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.	Alteplase-50 Bolus n=6 Participants Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.
Intensive Care Unit (ICU) Days	27 days Interval 12.0 to 30.5	19 days Interval 17.0 to 25.0

Adverse Events

Alteplase-50 Bolus

Serious events: 7 serious events

Other events: 14 other events

Deaths: 4 deaths

Alteplase-50 Drip

Serious events: 1 serious events

Other events: 4 other events

Deaths: 5 deaths

Control

Serious events: 6 serious events

Other events: 20 other events

Deaths: 11 deaths

Serious adverse events

Measure	Alteplase-50 Bolus n=19 participants at risk Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.	Alteplase-50 Drip n=6 participants at risk Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.	Control n=25 participants at risk Patients randomized to Control arm will receive no study medication; the treatment will be standard of care according to the institution's protocol for ARDS.
Cardiac disorders Arrest	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	8.0% 2/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders Aspiration	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Infections and infestations Candidiasis	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Cardiac disorders Cardiac arrhythmia	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Psychiatric disorders Delirium	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Vascular disorders Deep venous thrombosis	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders Failed extubation	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Metabolism and nutrition disorders Hypercalemia	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Gastrointestinal disorders Ileus	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Hepatobiliary disorders Liver failure	0.00% 0/19 • 28 days following randomization	16.7% 1/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Surgical and medical procedures Peritonitis	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders Pneumonia	15.8% 3/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	8.0% 2/25 • 28 days following randomization
Renal and urinary disorders Renal failure	0.00% 0/19 • 28 days following randomization	16.7% 1/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Infections and infestations Sepsis	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Infections and infestations Septic shock	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	8.0% 2/25 • 28 days following randomization
Renal and urinary disorders Urinary track infection	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders Worsening of lung function	5.3% 1/19 • 28 days following randomization	16.7% 1/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization

Other adverse events

Measure	Alteplase-50 Bolus n=19 participants at risk Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.	Alteplase-50 Drip n=6 participants at risk Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.	Control n=25 participants at risk Patients randomized to Control arm will receive no study medication; the treatment will be standard of care according to the institution's protocol for ARDS.
Metabolism and nutrition disorders ACIDOSIS (RESPIRATORY)	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Nervous system disorders AGITATION	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Metabolism and nutrition disorders ALKALOSIS METABOLIC	10.5% 2/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	8.0% 2/25 • 28 days following randomization
Blood and lymphatic system disorders ANEMIA	21.1% 4/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	20.0% 5/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders ASPIRATION	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	12.0% 3/25 • 28 days following randomization
Infections and infestations BACTEREMIA	0.00% 0/19 • 28 days following randomization	16.7% 1/6 • 28 days following randomization	12.0% 3/25 • 28 days following randomization
Psychiatric disorders BENZODIAZEPIN/OPIATE WITHDRAWAL	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Hepatobiliary disorders BILIARY DILATION	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Gastrointestinal disorders BLEEDING ABDOMINAL	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders BLEEDING HEMOPTYSIS	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders BLEEDING NASAL	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Gastrointestinal disorders BLEEDING ORAL	10.5% 2/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	8.0% 2/25 • 28 days following randomization
Gastrointestinal disorders BLEEDING RECTAL TEAR	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Renal and urinary disorders BLEEDING URINARY	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Reproductive system and breast disorders BLEEDING VAGINAL	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders BRONCHIAL OBSTRUCTION	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Infections and infestations CANDIDIASIS	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Cardiac disorders CARDIAC ARRHYTMIA	26.3% 5/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	20.0% 5/25 • 28 days following randomization
Gastrointestinal disorders CONSTIPATION	26.3% 5/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	8.0% 2/25 • 28 days following randomization
General disorders DEHYDRATION	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Psychiatric disorders DELIRIUM	15.8% 3/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	24.0% 6/25 • 28 days following randomization
Gastrointestinal disorders DIARRHEA	10.5% 2/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	8.0% 2/25 • 28 days following randomization
Vascular disorders DEEP VENOUS THROMBOSIS	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	24.0% 6/25 • 28 days following randomization
Gastrointestinal disorders DYSPHAGIA	10.5% 2/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Ear and labyrinth disorders DYSPHONIA	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	8.0% 2/25 • 28 days following randomization
Infections and infestations EPSTEIN BARR VIRUS	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Nervous system disorders ENCEPHALOPATHY	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	8.0% 2/25 • 28 days following randomization
Blood and lymphatic system disorders EOSINOPHILIA	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Musculoskeletal and connective tissue disorders FACIAL EDEMA	0.00% 0/19 • 28 days following randomization	16.7% 1/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders FAILURE TO WEAN OFF VENTILATION	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
General disorders FALL	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
General disorders FEVER	10.5% 2/19 • 28 days following randomization	16.7% 1/6 • 28 days following randomization	28.0% 7/25 • 28 days following randomization
Musculoskeletal and connective tissue disorders FRACTURE	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Infections and infestations HERPES SIMPLEX VIRUS	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Blood and lymphatic system disorders HYERPFIBRINOGENEMIA	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Metabolism and nutrition disorders HYPERGLYCEMIA	5.3% 1/19 • 28 days following randomization	16.7% 1/6 • 28 days following randomization	12.0% 3/25 • 28 days following randomization
Metabolism and nutrition disorders HYPERKALEMIA	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Metabolism and nutrition disorders HYPERNATREMIA	15.8% 3/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	8.0% 2/25 • 28 days following randomization
General disorders HYPERTENSION	10.5% 2/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	8.0% 2/25 • 28 days following randomization
General disorders HYPERVOLEMIA	5.3% 1/19 • 28 days following randomization	16.7% 1/6 • 28 days following randomization	8.0% 2/25 • 28 days following randomization
Metabolism and nutrition disorders HYPOGLYCEMIA	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Metabolism and nutrition disorders HYPOKALEMIA	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Metabolism and nutrition disorders HYPONATREMIA	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
General disorders HYPOTENSION	21.1% 4/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	36.0% 9/25 • 28 days following randomization
General disorders HYPOVOLEMIA	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Gastrointestinal disorders ILEUS	15.8% 3/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Blood and lymphatic system disorders LEUKOCYTOSIS	15.8% 3/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	8.0% 2/25 • 28 days following randomization
General disorders MULTIPLE ORGAN FAILURE	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Musculoskeletal and connective tissue disorders MYOPATHY	26.3% 5/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	24.0% 6/25 • 28 days following randomization
Reproductive system and breast disorders PARAPHIMOSIS	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders PULMONARY EMBOLISM	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders PLEURAL EFFUSION	10.5% 2/19 • 28 days following randomization	16.7% 1/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders PNEUMATOCELE	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders PNEUMONIA	21.1% 4/19 • 28 days following randomization	16.7% 1/6 • 28 days following randomization	24.0% 6/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders PNEUMOTHORAX	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Skin and subcutaneous tissue disorders PRESSURE ULCER	10.5% 2/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders PULMONARY HYPERTENSION	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	8.0% 2/25 • 28 days following randomization
Skin and subcutaneous tissue disorders RASH	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Renal and urinary disorders RENAL FAILURE	21.1% 4/19 • 28 days following randomization	16.7% 1/6 • 28 days following randomization	24.0% 6/25 • 28 days following randomization
Renal and urinary disorders RENAL TUBULAR ACIDOSIS	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders SINUSITES	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Blood and lymphatic system disorders THROMBOCYTOSIS	10.5% 2/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Vascular disorders THROMBOSIS ARTERIAL	0.00% 0/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
General disorders TONGUE EDEMA	0.00% 0/19 • 28 days following randomization	16.7% 1/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Hepatobiliary disorders TRANSAMINITIS	5.3% 1/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Renal and urinary disorders URINARY RETENTION	10.5% 2/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Renal and urinary disorders URINARY TRACT INFECTION	10.5% 2/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	4.0% 1/25 • 28 days following randomization
Gastrointestinal disorders VOMIT	10.5% 2/19 • 28 days following randomization	0.00% 0/6 • 28 days following randomization	0.00% 0/25 • 28 days following randomization
Respiratory, thoracic and mediastinal disorders WORSENING OF LUNG FUNCTION	10.5% 2/19 • 28 days following randomization	16.7% 1/6 • 28 days following randomization	44.0% 11/25 • 28 days following randomization

Additional Information

Dr. Ernest Moore, Director of Surgical Research

Denver Health Medical Center

Phone: 3036021820

Email: ernest.moore@dhha.org

Results disclosure agreements

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