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

• Sponsor: Denver Health and Hospital Authority (Other)
• Overall Status: Completed
• CT.gov ID: NCT04357730
• Collaborator: Genentech, Inc. (Industry), University of Colorado, Denver (Other), National Jewish Health (Other), Beth Israel Deaconess Medical Center (Other), Long Island Jewish Medical Center (Other), Scripps Health (Other), St. Mary's Medical Center (Other), University of Miami (Other), Ben Taub Hospital (Other), Methodist Dallas Medical Center (Other)
• Enrollment: 50
• Locations: 9
• Arms: 3
• Actual Duration (Months): 16.6
• Patients Per Site: 5.6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The global pandemic COVID-19 has overwhelmed the medical capacity to accommodate a large surge of patients with acute respiratory distress syndrome (ARDS). In the United States, the number of cases of COVID-19 ARDS is projected to exceed the number of available ventilators. Reports from China and Italy indicate that 22-64% of critically ill COVID-19 patients with ARDS will die. ARDS currently has no evidence-based treatments other than low tidal ventilation to limit mechanical stress on the lung and prone positioning. A new therapeutic approach capable of rapidly treating and attenuating ARDS secondary to COVID-19 is urgently needed.

The dominant pathologic feature of viral-induced ARDS is fibrin accumulation in the microvasculature and airspaces. Substantial preclinical work suggests antifibrinolytic therapy attenuates infection provoked ARDS. In 2001, a phase I trial 7 demonstrated the urokinase and streptokinase were effective in patients with terminal ARDS, markedly improving oxygen delivery and reducing an expected mortality in that specific patient cohort from 100% to 70%. A more contemporary approach to thrombolytic therapy is tissue plasminogen activator (tPA) due to its higher efficacy of clot lysis with comparable bleeding risk 8. We therefore propose a phase IIa clinical trial with two intravenous (IV) tPA treatment arms and a control arm to test the efficacy and safety of IV tPA in improving respiratory function and oxygenation, and consequently, successful extubation, duration of mechanical ventilation and survival.

Condition or Disease	Intervention/Treatment	Phase
Severe Acute Respiratory Syndrome; Respiratory Failure; Acute Respiratory Distress Syndrome	Drug: Alteplase 50 MG [Activase]; Drug: Alteplase 50 MG [Activase]	Phase 2

Detailed Description

As the COVID-19 pandemic accelerates, cases have grown exponentially around the world. Other countries' experience suggests that 5-16% of COVID-19 in-patients will undergo prolonged intensive care with 50-70% needing mechanical ventilation(MV) threatening to overwhelm hospital capacity. ARDS has no effective treatment besides supportive care, the use of ventilation strategies encompassing low tidal volumes that limit trans-pulmonary pressures, and prone positioning in severe disease. Most current trials in clinicaltrials.gov for COVID-19-induced ARDS aim at modulating the inflammatory response or test anti-viral drugs. Sarilumab and tocilizumab that block IL-6 effects are being tested in RCT for patients hospitalized with severe COVID-19 (NCT04317092, NCT04322773, NCT04327388). The World Health Organization international trial SOLIDARITY will test remdesivir; chloroquine + hydroxychloroquine; lopinavir + ritonavir; and lopinavir + ritonavir and interferon-beta (NCT04321616). Yet studies targeting the coagulation system, which is intrinsically intertwined with the inflammatory response are lacking.

A consistent finding in ARDS is the deposition of fibrin in the airspaces and lung parenchyma, along with fibrin-platelet microthrombi in the pulmonary vasculature, which contribute to the development of progressive respiratory dysfunction and right heart failure. Similar to pathologic findings of ARDS, microthrombi have now been observed in lung specimens from patients infected with COVID-19.

Inappropriate activation of the clotting system in ARDS results from enhanced activation and propagation of clot formation as well as suppression of fibrinolysis. Our group has shown that low fibrinolysis is associated with ARDS. Studies starting decades ago have demonstrated the systemic and local effects of dysfunctional coagulation in ARDS, specifically related to fibrin. This occurs largely because of excessive amounts of tissue factor that is produced by alveolar epithelial cells and activated alveolar macrophages, and high levels of plasminogen activator inhibitor-1 (PAI-1) produced and released by endothelial cells. Consistent with this, generalized derangements of the hemostatic system with prolongation of the prothrombin time, elevated D-dimer and fibrin degradation products have been reported in severely ill COVID-19 patients, particularly in non-survivors. These laboratory findings, in combination with the large clot burden seen in the pulmonary microvasculature, mirrors what is seen in human sepsis, experimental endotoxemia, and massive tissue trauma. Targeting the coagulation and fibrinolytic systems to improve the treatment of ARDS has been proposed for at least the past two decades. In particular, the use of plasminogen activators to limit ARDS progression and reduce ARDS-induced death has received strong support from animal models, and a phase 1 human clinical trial. In 2001, Hardaway and colleagues showed that administration of either urokinase or streptokinase to patients with terminal ARDS reduced the expected mortality from 100% to 70% with no adverse bleeding events. Importantly, the majority of patients who ultimately succumbed died from renal or hepatic failure, rather than pulmonary failure.

Consideration of therapies that are widely available but not recognized for this indication and traditionally considered "high-risk" such as fibrinolytic agents is warranted in this unprecedented public health emergency, since the risk of adverse events from tPA is far outweighed by the extremely high risk of death in the patient's meeting the eligibility criteria for this trial. While the prior studies by Hardaway et al evaluating fibrinolytic therapy for treatment of ARDS used urokinase and streptokinase, the more contemporary approach to thrombolytic therapy involves the use of tissue-type plasminogen activator (tPA) due to higher efficacy of clot lysis with comparable bleeding risk to the other fibrinolytic agents.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: This is a Phase IIa clinical trial, open label, with a modified stepped-wedge design, testing systemic administration of fibrinolytic therapy with alteplase (tPA) versus standard of care for patients infected with COVID-19 resulting in severe respiratory failure. The design is a rapidly adaptive, pragmatic clinical trial, with 3 interim analyses and 1 final look at the data.This is a Phase IIa clinical trial, open label, with a modified stepped-wedge design, testing systemic administration of fibrinolytic therapy with alteplase (tPA) versus standard of care for patients infected with COVID-19 resulting in severe respiratory failure. The design is a rapidly adaptive, pragmatic clinical trial, with 3 interim analyses and 1 final look at the data.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection: A Phase 2a Clinical Trial
• Actual Study Start Date: May 14, 2020
• Actual Primary Completion Date: Mar 21, 2021
• Actual Study Completion Date: Sep 30, 2021

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: 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.
Experimental: 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.	Drug: 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.
Experimental: 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).	Drug: 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.

Outcome Measures

Primary Outcome Measures

1. PaO2/FiO2 Change (Increase) From Pre-to-post Intervention [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.

Secondary Outcome Measures

1. Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2 [at 48 hours post randomization]

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

2. National Early Warning Score 2 (NEWS2) [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.

3. 28 Days In-hospital Mortality [28 days post randomization]

   28 days mortality for hospitalized patients

4. ICU-free Days [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

5. Ventilator-free Days [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria: We will include adult patients ages 18-75 years old with known or suspected COVID-19 infection with a PaO2/FiO2 ratio < 150 or inferred PaO2/FiO2 ratio from SpO2 if ABG is unavailable (Table) persisting for > 4 hours despite optimal mechanical ventilation management according to each institution's ventilation protocols, and a neurological exam without focal signs or new deficits at time of enrollment (if patient is on paralytics, patient has been aroused sufficiently to allow a neurological examination to exclude new focal deficits or has MRI/CT scan in the last 4.5 hours with no evidence of stroke. Finally, patients must be on the ventilator for <=10 days to be eligible. Based on experience with critically ill patients, longer ventilation time may be associated with increased risk of bleeding. Patients will be enrolled based on clinical features, without consideration of language (using hospital interpreters and translated consent), race/ethnicity, or gender. A neurological exam or CT/MRI scan to demonstrate no evidence of an acute stroke is needed due to a recent case-report of large-vessel stroke as a presenting feature of COVID-19 in young individuals.

Exclusion Criteria:

• Active bleeding

• Acute myocardial infarction or history of myocardial infarction within the past 3 weeks or cardiac arrest during hospitalization

• Hemodynamic instability with Noradrenaline >0.2mcg/Kg/min

• Acute renal failure requiring dialysis

• Liver failure (escalating liver failure with total Bilirubin > 3 mg/dL)

• Suspicion of cirrhosis due to history of cirrhosis diagnosis, hepatic encephalopathy, documentation of portal hypertension, bleeding from esophageal varices, ascites, imaging or operative finding suggestive of liver cirrhosis, or constellation of abnormal laboratory test results suggestive of depressed hepatic function

• Cardiac tamponade

• Bacterial endocarditis

• Severe uncontrolled hypertension defined as SBP>185mmHg or DBP>110mmHg

• CVA (stroke), history of severe head injury within prior 3 months, or prior history of intracranial hemorrhage

• Seizure during pre-hospital course or during hospitalization for COVID-19

• Diagnosis of brain tumor, arterio-venous malformation (AVM) or ruptured aneurysm

• Currently on ECMO

• Major surgery or major trauma within the past 2 weeks

• GI or GU bleed within the past 3 weeks

• Known bleeding disorder

• P2Y12 receptor inhibitor medication (anti-platelet) within 5 days of enrollment

• Arterial puncture at a non-compressible site within the past 7 days

• Lumbar puncture within past 7 days

• Pregnancy

• INR > 1.7 (with or without concurrent use of warfarin)

• Platelet count < 100 x 109/L or history of HITT

• Fibrinogen < 300mg/dL

• Known abdominal or thoracic aneurysm

• History of CNS malignancy or CNS metastasis within past 5 years

• History of non-CNS malignancy within the past 5 years that commonly metastasizes to the brain (lung, breast, melanoma)

• Prisoner status

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Scripps Memorial Hospital La Jolla	La Jolla	California	United States	92037
2	University of Colorado, Denver	Aurora	Colorado	United States	80045
3	Denver Health Medical Center	Denver	Colorado	United States	80204
4	National Jewish Health	Denver	Colorado	United States	80206
5	St. Mary's Medical Center	West Palm Beach	Florida	United States	33407
6	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
7	Long Island Jewish Medical Center	New York	New York	United States	11040
8	Methodist Dallas Medical Center	Dallas	Texas	United States	75203
9	Ben Taub Hospital	Houston	Texas	United States	77030

Sponsors and Collaborators

• Denver Health and Hospital Authority
• Genentech, Inc.
• University of Colorado, Denver
• National Jewish Health
• Beth Israel Deaconess Medical Center
• Long Island Jewish Medical Center
• Scripps Health
• St. Mary's Medical Center
• University of Miami
• Ben Taub Hospital
• Methodist Dallas Medical Center

Investigators

• Principal Investigator: Ernest E Moore, MD, Denver Health Medical Center (DHMC)

Study Documents (Full-Text)

• Study Protocol - Nov 30, 2020
• Statistical Analysis Plan - Nov 30, 2020

More Information

Publications

None provided.

• Responsible Party: Ernest E. Moore, MD, Director of Surgical Research, Ernest E Moore Shock Trauma Center at Denver Health, Denver Health and Hospital Authority
• ClinicalTrials.gov Identifier: NCT04357730
• Other Study ID Numbers: 20-0880
• First Posted: Apr 22, 2020
• Last Update Posted: Jan 20, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Ernest E. Moore, MD, Director of Surgical Research, Ernest E Moore Shock Trauma Center at Denver Health, Denver Health and Hospital Authority: COVID-19; ARDS; SARS-CoV-2; Betacoronavirus
• Additional relevant MeSH terms: COVID-19; Severe Acute Respiratory Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Respiratory Insufficiency; Acute Lung Injury; Syndrome; Tissue Plasminogen Activator

Study Results

Participant Flow

Arm/Group Title	Control	Alteplase-50 Bolus	Alteplase-50 Bolus Plus Drip
Arm/Group Description	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.	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.	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.
Period Title: Phase 1
STARTED	17	19	0
COMPLETED	17	19	0
NOT COMPLETED	0	0	0
Period Title: Phase 1
STARTED	8	0	6
COMPLETED	8	0	6
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Phase 1 Control	Phase 1 Alteplase-50 Bolus	Phase 2 Control	Phase 2 Alteplase-50 Drip	Total
Arm/Group Description	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 (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 (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 (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 of all reporting groups
Overall Participants	17	19	8	6	50
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	60	59	60.5	64.5	60
Sex: Female, Male (Count of Participants)
Female	7 41.2%	4 21.1%	2 25%	0 0%	13 26%
Male	10 58.8%	15 78.9%	6 75%	6 100%	37 74%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	11 64.7%	13 68.4%	5 62.5%	3 50%	32 64%
Not Hispanic or Latino	5 29.4%	5 26.3%	3 37.5%	3 50%	16 32%
Unknown or Not Reported	1 5.9%	1 5.3%	0 0%	0 0%	2 4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	1 12.5%	1 16.7%	2 4%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	1 16.7%	1 2%
White	11 64.7%	11 57.9%	6 75%	2 33.3%	30 60%
More than one race	1 5.9%	0 0%	0 0%	1 16.7%	2 4%
Unknown or Not Reported	5 29.4%	8 42.1%	1 12.5%	1 16.7%	15 30%
BMI (body mass index) (kg/m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m^2]	36.8	37.1	30.9	29.5	36.8
Time from admission to randomization (days) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [days]	2	2	1	5	2
Diabetes (Count of Participants)
Count of Participants [Participants]	6 35.3%	6 31.6%	3 37.5%	2 33.3%	17 34%
Cardiac disease (Count of Participants)
Count of Participants [Participants]	14 82.4%	18 94.7%	1 12.5%	0 0%	33 66%
Essential hypertension (Count of Participants)
Count of Participants [Participants]	4 23.5%	4 21.1%	4 50%	4 66.7%	16 32%
COPD (Count of Participants)
Count of Participants [Participants]	13 76.5%	15 78.9%	0 0%	3 50%	31 62%
Hyperlipidemia (Count of Participants)
Count of Participants [Participants]	6 35.3%	5 26.3%	1 12.5%	1 16.7%	13 26%
Other comorbidities (Count of Participants)
Count of Participants [Participants]	5 29.4%	7 36.8%	5 62.5%	4 66.7%	21 42%
Concurrent infections (Count of Participants)
Count of Participants [Participants]	10 58.8%	13 68.4%	5 62.5%	4 66.7%	32 64%
Dexamethasone (Count of Participants)
Count of Participants [Participants]	11 64.7%	9 47.4%	3 37.5%	3 50%	26 52%
Remdesivir (Count of Participants)
Count of Participants [Participants]	8 47.1%	9 47.4%	2 25%	1 16.7%	20 40%
Pa/FiO2 ratio (ratio) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [ratio]	107	113.3	99.5	109.7	112.3
National Early Warning Score (NEWS) 2 (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	6	6	10	6	6
aPTT (seconds) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [seconds]	30	32.3	31.1	31	30.5
International normalized ratio (INR) (ratio) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [ratio]	1.3	1.1	1.3	1.1	1.2
Fibrinogen (mg/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/dL]	668.5	685	560	695.5	685
D-dimer (ng/mL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [ng/mL]	1900	2105	4180	2652	1900

Outcome Measures

1. Primary Outcome

Title	PaO2/FiO2 Change (Increase) From Pre-to-post Intervention
Description	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.
Time Frame	at 48 hours post randomization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Median (Inter-Quartile Range) [percent change]	16.9	29.8

2. Primary Outcome

Title	PaO2/FiO2 Change (Increase) From Pre-to-post Intervention
Description	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.
Time Frame	at 48 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Median (Inter-Quartile Range) [percent change]	-11.9	-19.6

3. Secondary Outcome

Title	Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2
Description	Number of Participants with Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2 (whatever is lower)
Time Frame	at 48 hours post randomization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Count of Participants [Participants]	2 11.8%	9 47.4%

4. Secondary Outcome

Title	Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2
Description	Number of Participants with Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2 (whatever is lower)
Time Frame	at 48 hours post randomization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Count of Participants [Participants]	3 17.6%	1 5.3%

5. Secondary Outcome

Title	National Early Warning Score 2 (NEWS2)
Description	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.
Time Frame	at 48 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 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.
Measure Participants	17	19
Median (Inter-Quartile Range) [percent change]	0	0

6. Secondary Outcome

Title	National Early Warning Score 2 (NEWS2)
Description	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.
Time Frame	at 48 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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.	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.
Measure Participants	8	6
Median (Inter-Quartile Range) [percent change]	-12.5	65.7

7. Secondary Outcome

Title	28 Days In-hospital Mortality
Description	28 days mortality for hospitalized patients
Time Frame	28 days post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 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.
Measure Participants	17	19
Count of Participants [Participants]	5 29.4%	4 21.1%

8. Secondary Outcome

Title	28 Days In-hospital Mortality
Description	28 days mortality for hospitalized patients
Time Frame	28 days post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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.	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.
Measure Participants	8	6
Count of Participants [Participants]	4 23.5%	4 21.1%

9. Secondary Outcome

Title	ICU-free Days
Description	ICU-free days will be calculated based on (28 - number of days spent in the ICU) formula
Time Frame	28 days of hospital stay or until hospital discharge (whichever comes first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 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.
Measure Participants	17	19
Median (Inter-Quartile Range) [days]	0	6

10. Secondary Outcome

Title	ICU-free Days
Description	ICU-free days will be calculated based on (28 - number of days spent in the ICU) formula
Time Frame	28 days of hospital stay or until hospital discharge (whichever comes first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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.	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.
Measure Participants	8	6
Median (Inter-Quartile Range) [days]	0	0

11. Secondary Outcome

Title	Ventilator-free Days
Description	Ventilator-free days will be calculated based on (28 - number of days on mechanical ventilation) formula.
Time Frame	28 days of hospital stay or until hospital discharge (whichever comes first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 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.
Measure Participants	17	19
Median (Inter-Quartile Range) [days]	0	12

12. Secondary Outcome

Title	Ventilator-free Days
Description	Ventilator-free days will be calculated based on (28 - number of days on mechanical ventilation) formula.
Time Frame	28 days of hospital stay or until hospital discharge (whichever comes first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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.	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.
Measure Participants	8	6
Median (Inter-Quartile Range) [days]	0	0

13. Post-Hoc Outcome

Title	PaO2/FiO2 Ratio at 24 Hours
Description	PaO2/FiO2 ratio measured at 24 hours post-randomization
Time Frame	24 hours post-randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Median (Inter-Quartile Range) [ratio]	146.7	144

14. Post-Hoc Outcome

Title	PaO2/FiO2 at 24 Hours
Description	PaO2/FiO2 ratio measured at 24 hours post-randomization
Time Frame	24 hours post-randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Median (Inter-Quartile Range) [ratio]	119.2	94.5

15. Post-Hoc Outcome

Title	PaO2/FiO2 at 48 Hours
Description	PaO2/FiO2 ratio measured at 48 hours post-randomization
Time Frame	48 hours post-randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Median (Inter-Quartile Range) [ratio]	125	157.1

16. Post-Hoc Outcome

Title	PaO2/FiO2 at 48 Hours
Description	PaO2/FiO2 ratio measured at 48 hours post-randomization
Time Frame	48 hours post-randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Median (Inter-Quartile Range) [ratio]	113.7	103.5

17. Post-Hoc Outcome

Title	aPTT at 24 Hours
Description	This outcome measure shows patients' median aPTT at 24 hours post randomization.
Time Frame	at 24 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Median (Inter-Quartile Range) [seconds]	32.9	51.7

18. Post-Hoc Outcome

Title	aPTT at 24 Hours
Description	This outcome measure shows patients' median aPTT at 24 hours post randomization.
Time Frame	at 24 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Median (Inter-Quartile Range) [seconds]	35.6	27.7

19. Post-Hoc Outcome

Title	aPTT at 48 Hours
Description	This outcome measure shows patients' median aPTT at 48 hours post randomization.
Time Frame	at 48 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Median (Inter-Quartile Range) [seconds]	30	64.3

20. Post-Hoc Outcome

Title	aPTT at 48 Hours
Description	This outcome measure shows patients' median aPTT at 48 hours post randomization.
Time Frame	at 48 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Median (Inter-Quartile Range) [seconds]	53.1	33

21. Post-Hoc Outcome

Title	Number of Patients Who Required Paralytics 48 Hours Post-randomization
Description	Number of patients who required paralytics 48 hours post-randomization
Time Frame	48 hours post-randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Count of Participants [Participants]	10 58.8%	8 42.1%

22. Post-Hoc Outcome

Title	Number of Patients Who Required Paralytics 48 Hours Post-randomization
Description	Number of patients who required paralytics 48 hours post-randomization
Time Frame	48 hours post-randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Count of Participants [Participants]	6 35.3%	4 21.1%

23. Post-Hoc Outcome

Title	INR at 24 Hours
Description	This outcome measure shows patients' median INR at 24 hours post randomization.
Time Frame	at 24 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Median (Inter-Quartile Range) [ratio]	1.3	1.2

24. Post-Hoc Outcome

Title	INR at 24 Hours
Description	This outcome measure shows patients' median INR at 24 hours post randomization.
Time Frame	at 24 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Median (Inter-Quartile Range) [ratio]	1.1	1.1

25. Post-Hoc Outcome

Title	INR at 48 Hours
Description	This outcome measure shows patients' median INR at 48 hours post randomization.
Time Frame	at 48 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Median (Inter-Quartile Range) [ratio]	1.2	1.2

26. Post-Hoc Outcome

Title	INR at 48 Hours
Description	This outcome measure shows patients' median INR at 48 hours post randomization.
Time Frame	at 48 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Median (Inter-Quartile Range) [ratio]	1.2	1.2

27. Post-Hoc Outcome

Title	Fibrinogen at 24 Hours
Description	This outcome measure shows patients' median Fibrinogen (mg/dL) at 24 hours post randomization.
Time Frame	at 24 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Median (Inter-Quartile Range) [mg/dL]	595	627

28. Post-Hoc Outcome

Title	Fibrinogen at 24 Hours
Description	This outcome measure shows patients' median Fibrinogen (mg/dL) at 24 hours post randomization.
Time Frame	at 24 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Median (Inter-Quartile Range) [mg/dL]	588.5	612

29. Post-Hoc Outcome

Title	Fibrinogen at 48 Hours
Description	This outcome measure shows patients' median Fibrinogen (mg/dL) at 48 hours post randomization.
Time Frame	at 48 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Median (Inter-Quartile Range) [mg/dL]	612	567

30. Post-Hoc Outcome

Title	Fibrinogen at 48 Hours
Description	This outcome measure shows patients' median Fibrinogen (mg/dL) at 48 hours post randomization.
Time Frame	at 48 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Median (Inter-Quartile Range) [mg/dL]	480.5	698.5

31. Post-Hoc Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Median (Inter-Quartile Range) [ng/mL]	1426	2296

32. Post-Hoc Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Median (Inter-Quartile Range) [ng/mL]	3855	8477

33. Post-Hoc Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Median (Inter-Quartile Range) [ng/mL]	1326	1975

34. Post-Hoc Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Median (Inter-Quartile Range) [ng/mL]	3480.5	4957.5

35. Post-Hoc Outcome

Title	Ventilation Days
Description	Number of days patient required ventilation support
Time Frame	Duration of hospital stay, up to 28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Median (Inter-Quartile Range) [days]	18	13

36. Post-Hoc Outcome

Title	Ventilation Days
Description	Number of days patient required ventilation support
Time Frame	Duration of hospital stay, up to 28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Median (Inter-Quartile Range) [days]	24.5	17.5

37. Post-Hoc Outcome

Title	Number of Participants With Adverse Events
Description	Number of Participants with Adverse Events
Time Frame	Duration of hospital stay, up to 28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Count of Participants [Participants]	13 76.5%	13 68.4%

38. Post-Hoc Outcome

Title	Number of Participants With Adverse Events
Description	Number of Participants with Adverse Events
Time Frame	Duration of hospital stay, up to 28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Count of Participants [Participants]	5 29.4%	2 10.5%

39. Post-Hoc Outcome

Title	Number of Participants With Bleeding Events
Description	Number of Participants with Bleeding Events
Time Frame	Duration of hospital stay, up to 28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Count of Participants [Participants]	2 11.8%	3 15.8%

40. Post-Hoc Outcome

Title	Number of Participants With Bleeding Events
Description	Number of Participants with Bleeding Events
Time Frame	Duration of hospital stay, up to 28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Count of Participants [Participants]	1 5.9%	0 0%

41. Post-Hoc Outcome

Title	Intensive Care Unit (ICU) Days
Time Frame	Duration of hospital stay, up to 28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Control	Alteplase-50 Bolus
Arm/Group Description	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 (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.
Measure Participants	17	19
Median (Inter-Quartile Range) [days]	18	16

42. Post-Hoc Outcome

Title	Intensive Care Unit (ICU) Days
Time Frame	Duration of hospital stay, up to 28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Control	Alteplase-50 Drip
Arm/Group Description	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 (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.
Measure Participants	8	6
Median (Inter-Quartile Range) [days]	27	19

Adverse Events

Time Frame	28 days following randomization
Arm/Group Title	Control		Alteplase-50 Bolus		Alteplase-50 Drip
Arm/Group Description	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.		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 (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.
All Cause Mortality
	Control		Alteplase-50 Bolus		Alteplase-50 Drip
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/25 (44%)		4/19 (21.1%)		5/6 (83.3%)
Serious Adverse Events
	Control		Alteplase-50 Bolus		Alteplase-50 Drip
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/25 (24%)		7/19 (36.8%)		1/6 (16.7%)
Cardiac disorders
Arrest	2/25 (8%)		0/19 (0%)		0/6 (0%)
Cardiac arrhythmia	1/25 (4%)		0/19 (0%)		0/6 (0%)
Gastrointestinal disorders
Ileus	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
Hepatobiliary disorders
Liver failure	1/25 (4%)		0/19 (0%)		1/6 (16.7%)
Infections and infestations
Candidiasis	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
Sepsis	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
Septic shock	2/25 (8%)		0/19 (0%)		0/6 (0%)
Metabolism and nutrition disorders
Hypercalemia	1/25 (4%)		0/19 (0%)		0/6 (0%)
Psychiatric disorders
Delirium	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
Renal and urinary disorders
Renal failure	0/25 (0%)		0/19 (0%)		1/6 (16.7%)
Urinary track infection	1/25 (4%)		1/19 (5.3%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Aspiration	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
Failed extubation	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
Pulmonary embolism	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
Pneumonia	2/25 (8%)		3/19 (15.8%)		0/6 (0%)
Worsening of lung function	1/25 (4%)		1/19 (5.3%)		1/6 (16.7%)
Surgical and medical procedures
Peritonitis	1/25 (4%)		0/19 (0%)		0/6 (0%)
Vascular disorders
Deep venous thrombosis	1/25 (4%)		0/19 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Control		Alteplase-50 Bolus		Alteplase-50 Drip
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/25 (80%)		14/19 (73.7%)		4/6 (66.7%)
Blood and lymphatic system disorders
ANEMIA	5/25 (20%)		4/19 (21.1%)		0/6 (0%)
EOSINOPHILIA	1/25 (4%)		0/19 (0%)		0/6 (0%)
HYERPFIBRINOGENEMIA	1/25 (4%)		0/19 (0%)		0/6 (0%)
LEUKOCYTOSIS	2/25 (8%)		3/19 (15.8%)		0/6 (0%)
THROMBOCYTOSIS	0/25 (0%)		2/19 (10.5%)		0/6 (0%)
Cardiac disorders
CARDIAC ARRHYTMIA	5/25 (20%)		5/19 (26.3%)		0/6 (0%)
Ear and labyrinth disorders
DYSPHONIA	2/25 (8%)		0/19 (0%)		0/6 (0%)
Gastrointestinal disorders
BLEEDING ABDOMINAL	1/25 (4%)		0/19 (0%)		0/6 (0%)
BLEEDING ORAL	2/25 (8%)		2/19 (10.5%)		0/6 (0%)
BLEEDING RECTAL TEAR	1/25 (4%)		0/19 (0%)		0/6 (0%)
CONSTIPATION	2/25 (8%)		5/19 (26.3%)		0/6 (0%)
DIARRHEA	2/25 (8%)		2/19 (10.5%)		0/6 (0%)
DYSPHAGIA	0/25 (0%)		2/19 (10.5%)		0/6 (0%)
ILEUS	1/25 (4%)		3/19 (15.8%)		0/6 (0%)
VOMIT	0/25 (0%)		2/19 (10.5%)		0/6 (0%)
General disorders
DEHYDRATION	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
FALL	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
FEVER	7/25 (28%)		2/19 (10.5%)		1/6 (16.7%)
HYPERTENSION	2/25 (8%)		2/19 (10.5%)		0/6 (0%)
HYPERVOLEMIA	2/25 (8%)		1/19 (5.3%)		1/6 (16.7%)
HYPOTENSION	9/25 (36%)		4/19 (21.1%)		0/6 (0%)
HYPOVOLEMIA	1/25 (4%)		0/19 (0%)		0/6 (0%)
MULTIPLE ORGAN FAILURE	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
TONGUE EDEMA	0/25 (0%)		0/19 (0%)		1/6 (16.7%)
Hepatobiliary disorders
BILIARY DILATION	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
TRANSAMINITIS	1/25 (4%)		1/19 (5.3%)		0/6 (0%)
Infections and infestations
BACTEREMIA	3/25 (12%)		0/19 (0%)		1/6 (16.7%)
CANDIDIASIS	1/25 (4%)		0/19 (0%)		0/6 (0%)
EPSTEIN BARR VIRUS	1/25 (4%)		0/19 (0%)		0/6 (0%)
HERPES SIMPLEX VIRUS	1/25 (4%)		0/19 (0%)		0/6 (0%)
Metabolism and nutrition disorders
ACIDOSIS (RESPIRATORY)	1/25 (4%)		0/19 (0%)		0/6 (0%)
ALKALOSIS METABOLIC	2/25 (8%)		2/19 (10.5%)		0/6 (0%)
HYPERGLYCEMIA	3/25 (12%)		1/19 (5.3%)		1/6 (16.7%)
HYPERKALEMIA	1/25 (4%)		1/19 (5.3%)		0/6 (0%)
HYPERNATREMIA	2/25 (8%)		3/19 (15.8%)		0/6 (0%)
HYPOGLYCEMIA	1/25 (4%)		0/19 (0%)		0/6 (0%)
HYPOKALEMIA	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
HYPONATREMIA	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
Musculoskeletal and connective tissue disorders
FACIAL EDEMA	0/25 (0%)		0/19 (0%)		1/6 (16.7%)
FRACTURE	1/25 (4%)		0/19 (0%)		0/6 (0%)
MYOPATHY	6/25 (24%)		5/19 (26.3%)		0/6 (0%)
Nervous system disorders
AGITATION	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
ENCEPHALOPATHY	2/25 (8%)		0/19 (0%)		0/6 (0%)
Psychiatric disorders
BENZODIAZEPIN/OPIATE WITHDRAWAL	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
DELIRIUM	6/25 (24%)		3/19 (15.8%)		0/6 (0%)
Renal and urinary disorders
BLEEDING URINARY	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
RENAL FAILURE	6/25 (24%)		4/19 (21.1%)		1/6 (16.7%)
RENAL TUBULAR ACIDOSIS	1/25 (4%)		0/19 (0%)		0/6 (0%)
URINARY RETENTION	1/25 (4%)		2/19 (10.5%)		0/6 (0%)
URINARY TRACT INFECTION	1/25 (4%)		2/19 (10.5%)		0/6 (0%)
Reproductive system and breast disorders
BLEEDING VAGINAL	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
PARAPHIMOSIS	1/25 (4%)		0/19 (0%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
ASPIRATION	3/25 (12%)		1/19 (5.3%)		0/6 (0%)
BLEEDING HEMOPTYSIS	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
BLEEDING NASAL	1/25 (4%)		0/19 (0%)		0/6 (0%)
BRONCHIAL OBSTRUCTION	1/25 (4%)		0/19 (0%)		0/6 (0%)
FAILURE TO WEAN OFF VENTILATION	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
PULMONARY EMBOLISM	1/25 (4%)		0/19 (0%)		0/6 (0%)
PLEURAL EFFUSION	0/25 (0%)		2/19 (10.5%)		1/6 (16.7%)
PNEUMATOCELE	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
PNEUMONIA	6/25 (24%)		4/19 (21.1%)		1/6 (16.7%)
PNEUMOTHORAX	1/25 (4%)		0/19 (0%)		0/6 (0%)
PULMONARY HYPERTENSION	2/25 (8%)		0/19 (0%)		0/6 (0%)
SINUSITES	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
WORSENING OF LUNG FUNCTION	11/25 (44%)		2/19 (10.5%)		1/6 (16.7%)
Skin and subcutaneous tissue disorders
PRESSURE ULCER	1/25 (4%)		2/19 (10.5%)		0/6 (0%)
RASH	0/25 (0%)		1/19 (5.3%)		0/6 (0%)
Vascular disorders
DEEP VENOUS THROMBOSIS	6/25 (24%)		1/19 (5.3%)		0/6 (0%)
THROMBOSIS ARTERIAL	1/25 (4%)		0/19 (0%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.