Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection
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|ClinicalTrials.gov Identifier: NCT04357730|
Recruitment Status : Recruiting
First Posted : April 22, 2020
Last Update Posted : June 17, 2020
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.
|Condition or disease||Intervention/treatment||Phase|
|Severe Acute Respiratory Syndrome Respiratory Failure Acute Respiratory Distress Syndrome||Drug: Alteplase 50 MG [Activase] Drug: Alteplase 100 MG [Activase]||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||60 participants|
|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)|
|Official Title:||Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection: A Phase 2a Clinical Trial|
|Actual Study Start Date :||May 14, 2020|
|Estimated Primary Completion Date :||September 2020|
|Estimated Study Completion Date :||November 2020|
No Intervention: Control
Patients randomized to Control arm will receive no study medication; the treatment will be standard of care according to the institution's protocol for ARDS.
Patients randomized to Alteplase-50 group will receive 50 mg of Alteplase intravenous administration over 2 hours.
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 hours. Immediately following the Alteplase infusion, 5000 IU of unfracionated heparin (UFH) will be delivered intravenously and the heparin drip will be continued to maintain the activated partial thromboplastin time at 60-80sec (2.0 to 2.5 times the upper limit of normal).
Patients randomized to Alteplase-100 group will receive 100 mg of Alteplase intravenous administration over 2 hours.
Drug: Alteplase 100 MG [Activase]
Patients randomized to Alteplase-100 group will receive 100 mg of Alteplase intravenous bolus administration over 2 hours, given as a 10 mg push followed by the remaining 90 mgs over a total time of 2 hours. Immediately following the Alteplase infusion, 5000 IU of unfracionated heparin (UFH) will be delivered intravenously and the heparin drip will be continued to maintain the activated partial thromboplastin time at 60-80sec (2.0 to 2.5 times the upper limit of normal).
- PaO2/FiO2 improvement from pre-to-post intervention [ Time Frame: 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 improvement 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.
- Achievement of PaO2/FiO2 ≥ 200 or 50% increase in PaO2/FiO2 [ Time Frame: at 48 hours post randomization ]Achievement of PaO2/FiO2 ≥ 200 or 50% increase in PaO2/FiO2 (whatever is lower)
- National Early Warning Score 2 (NEWS2) [ Time Frame: at 48 hours post randomization ]This score is based on seven clinical features (respiration rate, hypercapnic respiratory failure, any supplemental oxygen, temperature, systolic blood pressure, heart rate and level of consciousness) and determines the degree of illness of a patient and prompts critical care intervention.
- National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale [ Time Frame: at 48 hours post randomization ]The ordinal scale is an assessment of the clinical status as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities. (combined items 7 and 8 as our study is limited to hospital).
- 48 hour in-hospital mortality [ Time Frame: at 48 hours post randomization ]48 hour mortality for hospitalized patients
- 14 days in-hospital mortality [ Time Frame: 14 days post randomization ]14 days mortality for hospitalized patients
- 28 days in-hospital mortality [ Time Frame: 28 days post randomization ]28 days mortality for hospitalized patients
- ICU-free days [ Time Frame: 28 days of hospital stay or until hospital discharge (whichever comes first) ]ICU-free days will be calculated based on (28 - number of days spent in the ICU) formula
- In-hospital coagulation-related event-free (arterial and venous) days [ Time Frame: 28 days of hospital stay or until hospital discharge (whichever comes first) ]In-hospital coagulation-related events include bleeding, stroke, myocardial infarction and venous thromboembolism (VTE). In-hospital coagulation-related event-free (arterial and venous) days will be calculated based on (28 - number of days without coagulation-related event) formula.
- Ventilator-free days [ Time Frame: 28 days of hospital stay or until hospital discharge (whichever comes first) ]Ventilator-free days will be calculated based on (28 - number of days on mechanical ventilation) formula.
- Successful extubation [ Time Frame: Day 4 after initial extubation ]Calculated for patients who was on a mechanical ventilation any period of time during hospitalization. The extubation will be considered successful if no re-intubation occurred for more than 3 days have passed after the initial extubation.
- Successful weaning from paralysis [ Time Frame: Day 4 after initial termination of paralytics ]Calculated for patients who was on paralytics at the time of randomization. The weaning will be considered successful if no paralytics were used for more than 3 days have passed after termination of paralytics.
- Survival to discharge [ Time Frame: 28 days of hospital stay or until hospital discharge (whichever comes first) ]Is counted for the patients who was alive at the time of discharge.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04357730
|Contact: Ernest E Moore, MD||(303) email@example.com|
|Contact: Arsen Ghasabyan, MPH||(303) firstname.lastname@example.org|
|United States, Colorado|
|Denver Health Medical Center||Recruiting|
|Denver, Colorado, United States, 80204|
|Contact: Ernest E Moore, MD 303-602-1820 email@example.com|
|Principal Investigator: Ernest E Moore, MD|
|Principal Investigator:||Ernest E Moore, MD||Denver Health Medical Center (DHMC)|