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.
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.
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.
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.
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
Scripps Memorial Hospital La Jolla
La Jolla, California, United States
University of Colorado, Denver
Aurora, Colorado, United States
Denver Health Medical Center
Denver, Colorado, United States
National Jewish Health
Denver, Colorado, United States
St. Mary's Medical Center
West Palm Beach, Florida, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
Long Island Jewish Medical Center
New York, New York, United States
Methodist Dallas Medical Center
Dallas, Texas, United States
Ben Taub Hospital
Houston, Texas, United States
Ernest E Moore, MD, Principal Investigator
Denver Health Medical Center (DHMC)