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

• Status: Active, not recruiting
• Trial end date: 2021-11-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Denver Health and Hospital Authority
• Collaborators: Ben Taub Hospital; Beth Israel Deaconess Medical Center; Genentech, Inc.; Genentech, Inc., University of Colorado Denver, National Jewish, Beth Israel Deaconess Medical Center, and Long Island Jewish Hospital; Long Island Jewish Medical Center; Methodist Dallas Medical Center; National Jewish Health; Scripps Health; St. Mary's Medical Center; University of Colorado, Denver; University of Miami
• Treatments: Tissue Plasminogen Activator

Criteria

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