Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection
Condition: Severe Acute Respiratory Syndrome; Respiratory Failure; Acute Respiratory Distress Syndrome
MeSH terms: Severe Acute Respiratory Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Respiratory Insufficiency; Acute Lung Injury; Syndrome
Intervention: Alteplase 50 MG [Activase]; Alteplase 50 MG [Activase]
Intervention description: 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.; 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.
Intervention MeSH terms: Tissue Plasminogen Activator
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
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.
Masking: None (Open Label)
Enrollment: 50.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: COVID-19; ARDS; SARS-CoV-2; Betacoronavirus

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.
    

Eligibility 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