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

Acute Respiratory Distress Syndrome Clinical Trial

Official title:

Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection: A Phase 2a Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04357730
• Other study ID #: 20-0880
• Status: Completed
• Phase: Phase 2
• Start date: May 14, 2020
• Est. completion date: September 30, 2021

Study information

• Verified date: January 2022
• Source: Denver Health and Hospital Authority
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: September 30, 2021
• Est. primary completion date: March 21, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome
• COVID-19
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Newborn
• Respiratory Failure
• Respiratory Insufficiency
• Severe Acute Respiratory Syndrome
• Syndrome

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	University of Colorado, Denver	Aurora	Colorado
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Methodist Dallas Medical Center	Dallas	Texas
United States	Denver Health Medical Center	Denver	Colorado
United States	National Jewish Health	Denver	Colorado
United States	Ben Taub Hospital	Houston	Texas
United States	Scripps Memorial Hospital La Jolla	La Jolla	California
United States	Long Island Jewish Medical Center	New York	New York
United States	St. Mary's Medical Center	West Palm Beach	Florida

Sponsors (11)

Lead Sponsor	Collaborator
Denver Health and Hospital Authority	Ben Taub Hospital, Beth Israel Deaconess Medical Center, Genentech, Inc., 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

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	at 48 hours post randomization
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)	at 48 hours post randomization
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.	at 48 hours post randomization
Secondary	28 Days In-hospital Mortality	28 days mortality for hospitalized patients	28 days post randomization
Secondary	ICU-free Days	ICU-free days will be calculated based on (28 - number of days spent in the ICU) formula	28 days of hospital stay or until hospital discharge (whichever comes first)
Secondary	Ventilator-free Days	Ventilator-free days will be calculated based on (28 - number of days on mechanical ventilation) formula.	28 days of hospital stay or until hospital discharge (whichever comes first)