Acute Respiratory Distress Syndrome, Respiratory Failure, Severe Acute Respiratory Syndrome
Conditions
Keywords
COVID-19, ARDS, SARS-CoV-2, Betacoronavirus
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.
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.
Interventions
DRUGAlteplase 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.
Sponsors
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
The Methodist Hospital Research Institute
Denver Health and Hospital Authority
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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. |
| 28 Days In-hospital Mortality | 28 days post randomization | 28 days mortality for hospitalized patients |
| 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 |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 Control 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. | 17 |
| Phase 1 Alteplase-50 Bolus 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. | 19 |
| Phase 2 Control 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. | 8 |
| Phase 2 Alteplase-50 Drip 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. | 6 |
| Total | 50 |
Baseline characteristics
| Characteristic | Phase 1 Control | Phase 1 Alteplase-50 Bolus | Phase 2 Control | Phase 2 Alteplase-50 Drip | Total |
|---|---|---|---|---|---|
| Age, Continuous | 60 years | 59 years | 60.5 years | 64.5 years | 60 years |
| aPTT | 30 seconds | 32.3 seconds | 31.1 seconds | 31 seconds | 30.5 seconds |
| BMI (body mass index) | 36.8 kg/m^2 | 37.1 kg/m^2 | 30.9 kg/m^2 | 29.5 kg/m^2 | 36.8 kg/m^2 |
| Cardiac disease | 14 Participants | 18 Participants | 1 Participants | 0 Participants | 33 Participants |
| Concurrent infections | 10 Participants | 13 Participants | 5 Participants | 4 Participants | 32 Participants |
| COPD | 13 Participants | 15 Participants | 0 Participants | 3 Participants | 31 Participants |
| D-dimer | 1900 ng/mL | 2105 ng/mL | 4180 ng/mL | 2652 ng/mL | 1900 ng/mL |
| Dexamethasone | 11 Participants | 9 Participants | 3 Participants | 3 Participants | 26 Participants |
| Diabetes | 6 Participants | 6 Participants | 3 Participants | 2 Participants | 17 Participants |
| Essential hypertension | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 13 Participants | 5 Participants | 3 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 5 Participants | 3 Participants | 3 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Fibrinogen | 668.5 mg/dL | 685 mg/dL | 560 mg/dL | 695.5 mg/dL | 685 mg/dL |
| Hyperlipidemia | 6 Participants | 5 Participants | 1 Participants | 1 Participants | 13 Participants |
| International normalized ratio (INR) | 1.3 ratio | 1.1 ratio | 1.3 ratio | 1.1 ratio | 1.2 ratio |
| National Early Warning Score (NEWS) 2 | 6 units on a scale | 6 units on a scale | 10 units on a scale | 6 units on a scale | 6 units on a scale |
| Other comorbidities | 5 Participants | 7 Participants | 5 Participants | 4 Participants | 21 Participants |
| Pa/FiO2 ratio | 107 ratio | 113.3 ratio | 99.5 ratio | 109.7 ratio | 112.3 ratio |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 8 Participants | 1 Participants | 1 Participants | 15 Participants |
| Race (NIH/OMB) White | 11 Participants | 11 Participants | 6 Participants | 2 Participants | 30 Participants |
| Remdesivir | 8 Participants | 9 Participants | 2 Participants | 1 Participants | 20 Participants |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 2 Participants | 0 Participants | 13 Participants |
| Sex: Female, Male Male | 10 Participants | 15 Participants | 6 Participants | 6 Participants | 37 Participants |
| Time from admission to randomization | 2 days | 2 days | 1 days | 5 days | 2 days |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 11 / 25 | 4 / 19 | 5 / 6 |
| other Total, other adverse events | 20 / 25 | 14 / 19 | 4 / 6 |
| serious Total, serious adverse events | 6 / 25 | 7 / 19 | 1 / 6 |
Outcome results
Primary
PaO2/FiO2 Change (Increase) From Pre-to-post Intervention
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | PaO2/FiO2 Change (Increase) From Pre-to-post Intervention | -11.9 percent change |
| Alteplase-50 Bolus | PaO2/FiO2 Change (Increase) From Pre-to-post Intervention | -19.6 percent change |
Primary
PaO2/FiO2 Change (Increase) From Pre-to-post Intervention
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
Population: Of the 19 patients receiving the tPA-Bolus intervention, 8 required a second tPA dose due to transient PaO2/FiO2 improvement. No patients crossed over or withdrew.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | PaO2/FiO2 Change (Increase) From Pre-to-post Intervention | 16.9 percent change |
| Alteplase-50 Bolus | PaO2/FiO2 Change (Increase) From Pre-to-post Intervention | 29.8 percent change |
Secondary
28 Days In-hospital Mortality
28 days mortality for hospitalized patients
Time frame: 28 days post randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Control | 28 Days In-hospital Mortality | 5 Participants |
| Alteplase-50 Bolus | 28 Days In-hospital Mortality | 4 Participants |
Secondary
28 Days In-hospital Mortality
28 days mortality for hospitalized patients
Time frame: 28 days post randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Control | 28 Days In-hospital Mortality | 4 Participants |
| Alteplase-50 Bolus | 28 Days In-hospital Mortality | 4 Participants |
Secondary
Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2
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
Population: Of the 19 patients receiving the tPA-Bolus intervention, 8 required a second tPA dose due to transient PaO2/FiO2 improvement. No patients crossed over or withdrew.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Control | Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2 | 3 Participants |
| Alteplase-50 Bolus | Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2 | 1 Participants |
Secondary
Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2
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
Population: Of the 19 patients receiving the tPA-Bolus intervention, 8 required a second tPA dose due to transient PaO2/FiO2 improvement. No patients crossed over or withdrew.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Control | Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2 | 2 Participants |
| Alteplase-50 Bolus | Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2 | 9 Participants |
Secondary
ICU-free Days
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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | ICU-free Days | 0 days |
| Alteplase-50 Bolus | ICU-free Days | 0 days |
Secondary
ICU-free Days
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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | ICU-free Days | 0 days |
| Alteplase-50 Bolus | ICU-free Days | 6 days |
Secondary
National Early Warning Score 2 (NEWS2)
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | National Early Warning Score 2 (NEWS2) | -12.5 percent change |
| Alteplase-50 Bolus | National Early Warning Score 2 (NEWS2) | 65.7 percent change |
Secondary
National Early Warning Score 2 (NEWS2)
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | National Early Warning Score 2 (NEWS2) | 0 percent change |
| Alteplase-50 Bolus | National Early Warning Score 2 (NEWS2) | 0 percent change |
Secondary
Ventilator-free Days
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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | Ventilator-free Days | 0 days |
| Alteplase-50 Bolus | Ventilator-free Days | 12 days |
Secondary
Ventilator-free Days
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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | Ventilator-free Days | 0 days |
| Alteplase-50 Bolus | Ventilator-free Days | 0 days |
Post Hoc
aPTT at 24 Hours
This outcome measure shows patients' median aPTT at 24 hours post randomization.
Time frame: at 24 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | aPTT at 24 Hours | 35.6 seconds |
| Alteplase-50 Bolus | aPTT at 24 Hours | 27.7 seconds |
Post Hoc
aPTT at 24 Hours
This outcome measure shows patients' median aPTT at 24 hours post randomization.
Time frame: at 24 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | aPTT at 24 Hours | 32.9 seconds |
| Alteplase-50 Bolus | aPTT at 24 Hours | 51.7 seconds |
Post Hoc
aPTT at 48 Hours
This outcome measure shows patients' median aPTT at 48 hours post randomization.
Time frame: at 48 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | aPTT at 48 Hours | 30 seconds |
| Alteplase-50 Bolus | aPTT at 48 Hours | 64.3 seconds |
Post Hoc
aPTT at 48 Hours
This outcome measure shows patients' median aPTT at 48 hours post randomization.
Time frame: at 48 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | aPTT at 48 Hours | 53.1 seconds |
| Alteplase-50 Bolus | aPTT at 48 Hours | 33 seconds |
Post Hoc
D-dimer at 24 Hours
This outcome measure shows patients' median D-dimer (ng/mL) at 24 hours post randomization.
Time frame: at 24 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | D-dimer at 24 Hours | 1426 ng/mL |
| Alteplase-50 Bolus | D-dimer at 24 Hours | 2296 ng/mL |
Post Hoc
D-dimer at 24 Hours
This outcome measure shows patients' median D-dimer (ng/mL) at 24 hours post randomization.
Time frame: at 24 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | D-dimer at 24 Hours | 3855 ng/mL |
| Alteplase-50 Bolus | D-dimer at 24 Hours | 8477 ng/mL |
Post Hoc
D-dimer at 48 Hours
This outcome measure shows patients' median D-dimer (ng/mL) at 48 hours post randomization.
Time frame: at 48 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | D-dimer at 48 Hours | 3480.5 ng/mL |
| Alteplase-50 Bolus | D-dimer at 48 Hours | 4957.5 ng/mL |
Post Hoc
D-dimer at 48 Hours
This outcome measure shows patients' median D-dimer (ng/mL) at 48 hours post randomization.
Time frame: at 48 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | D-dimer at 48 Hours | 1326 ng/mL |
| Alteplase-50 Bolus | D-dimer at 48 Hours | 1975 ng/mL |
Post Hoc
Fibrinogen at 24 Hours
This outcome measure shows patients' median Fibrinogen (mg/dL) at 24 hours post randomization.
Time frame: at 24 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | Fibrinogen at 24 Hours | 588.5 mg/dL |
| Alteplase-50 Bolus | Fibrinogen at 24 Hours | 612 mg/dL |
Post Hoc
Fibrinogen at 24 Hours
This outcome measure shows patients' median Fibrinogen (mg/dL) at 24 hours post randomization.
Time frame: at 24 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | Fibrinogen at 24 Hours | 595 mg/dL |
| Alteplase-50 Bolus | Fibrinogen at 24 Hours | 627 mg/dL |
Post Hoc
Fibrinogen at 48 Hours
This outcome measure shows patients' median Fibrinogen (mg/dL) at 48 hours post randomization.
Time frame: at 48 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | Fibrinogen at 48 Hours | 480.5 mg/dL |
| Alteplase-50 Bolus | Fibrinogen at 48 Hours | 698.5 mg/dL |
Post Hoc
Fibrinogen at 48 Hours
This outcome measure shows patients' median Fibrinogen (mg/dL) at 48 hours post randomization.
Time frame: at 48 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | Fibrinogen at 48 Hours | 612 mg/dL |
| Alteplase-50 Bolus | Fibrinogen at 48 Hours | 567 mg/dL |
Post Hoc
INR at 24 Hours
This outcome measure shows patients' median INR at 24 hours post randomization.
Time frame: at 24 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | INR at 24 Hours | 1.3 ratio |
| Alteplase-50 Bolus | INR at 24 Hours | 1.2 ratio |
Post Hoc
INR at 24 Hours
This outcome measure shows patients' median INR at 24 hours post randomization.
Time frame: at 24 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | INR at 24 Hours | 1.1 ratio |
| Alteplase-50 Bolus | INR at 24 Hours | 1.1 ratio |
Post Hoc
INR at 48 Hours
This outcome measure shows patients' median INR at 48 hours post randomization.
Time frame: at 48 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | INR at 48 Hours | 1.2 ratio |
| Alteplase-50 Bolus | INR at 48 Hours | 1.2 ratio |
Post Hoc
INR at 48 Hours
This outcome measure shows patients' median INR at 48 hours post randomization.
Time frame: at 48 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | INR at 48 Hours | 1.2 ratio |
| Alteplase-50 Bolus | INR at 48 Hours | 1.2 ratio |
Post Hoc
Intensive Care Unit (ICU) Days
Time frame: Duration of hospital stay, up to 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | Intensive Care Unit (ICU) Days | 18 days |
| Alteplase-50 Bolus | Intensive Care Unit (ICU) Days | 16 days |
Post Hoc
Intensive Care Unit (ICU) Days
Time frame: Duration of hospital stay, up to 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | Intensive Care Unit (ICU) Days | 27 days |
| Alteplase-50 Bolus | Intensive Care Unit (ICU) Days | 19 days |
Post Hoc
Number of Participants With Adverse Events
Number of Participants with Adverse Events
Time frame: Duration of hospital stay, up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Control | Number of Participants With Adverse Events | 13 Participants |
| Alteplase-50 Bolus | Number of Participants With Adverse Events | 13 Participants |
Post Hoc
Number of Participants With Adverse Events
Number of Participants with Adverse Events
Time frame: Duration of hospital stay, up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Control | Number of Participants With Adverse Events | 5 Participants |
| Alteplase-50 Bolus | Number of Participants With Adverse Events | 2 Participants |
Post Hoc
Number of Participants With Bleeding Events
Number of Participants with Bleeding Events
Time frame: Duration of hospital stay, up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Control | Number of Participants With Bleeding Events | 1 Participants |
| Alteplase-50 Bolus | Number of Participants With Bleeding Events | 0 Participants |
Post Hoc
Number of Participants With Bleeding Events
Number of Participants with Bleeding Events
Time frame: Duration of hospital stay, up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Control | Number of Participants With Bleeding Events | 2 Participants |
| Alteplase-50 Bolus | Number of Participants With Bleeding Events | 3 Participants |
Post Hoc
Number of Patients Who Required Paralytics 48 Hours Post-randomization
Number of patients who required paralytics 48 hours post-randomization
Time frame: 48 hours post-randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Control | Number of Patients Who Required Paralytics 48 Hours Post-randomization | 6 Participants |
| Alteplase-50 Bolus | Number of Patients Who Required Paralytics 48 Hours Post-randomization | 4 Participants |
Post Hoc
Number of Patients Who Required Paralytics 48 Hours Post-randomization
Number of patients who required paralytics 48 hours post-randomization
Time frame: 48 hours post-randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Control | Number of Patients Who Required Paralytics 48 Hours Post-randomization | 10 Participants |
| Alteplase-50 Bolus | Number of Patients Who Required Paralytics 48 Hours Post-randomization | 8 Participants |
Post Hoc
PaO2/FiO2 at 24 Hours
PaO2/FiO2 ratio measured at 24 hours post-randomization
Time frame: 24 hours post-randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | PaO2/FiO2 at 24 Hours | 119.2 ratio |
| Alteplase-50 Bolus | PaO2/FiO2 at 24 Hours | 94.5 ratio |
Post Hoc
PaO2/FiO2 at 48 Hours
PaO2/FiO2 ratio measured at 48 hours post-randomization
Time frame: 48 hours post-randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | PaO2/FiO2 at 48 Hours | 113.7 ratio |
| Alteplase-50 Bolus | PaO2/FiO2 at 48 Hours | 103.5 ratio |
Post Hoc
PaO2/FiO2 at 48 Hours
PaO2/FiO2 ratio measured at 48 hours post-randomization
Time frame: 48 hours post-randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | PaO2/FiO2 at 48 Hours | 125 ratio |
| Alteplase-50 Bolus | PaO2/FiO2 at 48 Hours | 157.1 ratio |
Post Hoc
PaO2/FiO2 Ratio at 24 Hours
PaO2/FiO2 ratio measured at 24 hours post-randomization
Time frame: 24 hours post-randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | PaO2/FiO2 Ratio at 24 Hours | 146.7 ratio |
| Alteplase-50 Bolus | PaO2/FiO2 Ratio at 24 Hours | 144 ratio |
Post Hoc
Ventilation Days
Number of days patient required ventilation support
Time frame: Duration of hospital stay, up to 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | Ventilation Days | 24.5 days |
| Alteplase-50 Bolus | Ventilation Days | 17.5 days |
Post Hoc
Ventilation Days
Number of days patient required ventilation support
Time frame: Duration of hospital stay, up to 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Control | Ventilation Days | 18 days |
| Alteplase-50 Bolus | Ventilation Days | 13 days |