Phase 2
N=36
Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection
Severe Acute Respiratory Syndrome · Respiratory Failure · Acute Respiratory Distress Syndrome
Bottom Line
View on ClinicalTrials.gov: NCT04357730 ↗Enrolled (actual)
36
Serious AEs
28.0%
Results posted
Jan 2022
Primary outcome: Primary: PaO2/FiO2 Change (Increase) From Pre-to-post Intervention — 16.9; 29.8 percent change
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- Alteplase 50 MG [Activase] (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Denver Health and Hospital Authority
- Primary completion
- Mar 2021
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY PaO2/FiO2 Change (Increase) From Pre-to-post Intervention |
-11.9; -19.6 | — |
| SECONDARY Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2 |
3; 1 | — |
| SECONDARY National Early Warning Score 2 (NEWS2) |
-12.5; 65.7 | — |
| SECONDARY 28 Days In-hospital Mortality |
4; 4 | — |
| SECONDARY ICU-free Days |
0; 0 | — |
| SECONDARY Ventilator-free Days |
0; 0 | — |
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 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 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
Data sourced from ClinicalTrials.gov (NCT04357730). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.