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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04357730
Recruitment Status : Recruiting
First Posted : April 22, 2020
Last Update Posted : June 17, 2020
Sponsor:
Collaborator:
Genentech, Inc., University of Colorado Denver, National Jewish, Beth Israel Deaconess Medical Center, and Long Island Jewish Hospital
Information provided by (Responsible Party):
Ernest E. Moore, MD, Denver Health and Hospital Authority

Tracking Information
First Submitted Date  ICMJE April 18, 2020
First Posted Date  ICMJE April 22, 2020
Last Update Posted Date June 17, 2020
Actual Study Start Date  ICMJE May 14, 2020
Estimated Primary Completion Date September 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 21, 2020)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 20, 2020)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 21, 2020)
  • 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)
  • 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: 28 days of hospital stay or until hospital discharge (whichever comes first) ]
    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 occured until discharge or more than 3 days have passed after the initial extubation.
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection
Official Title  ICMJE Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection: A Phase 2a Clinical Trial
Brief 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.

Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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)
Primary Purpose: Treatment
Condition  ICMJE
  • Severe Acute Respiratory Syndrome
  • Respiratory Failure
  • Acute Respiratory Distress Syndrome
Intervention  ICMJE
  • 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).
  • 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).
Study Arms  ICMJE
  • 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.
  • Experimental: Alteplase-50
    Patients randomized to Alteplase-50 group will receive 50 mg of Alteplase intravenous administration over 2 hours.
    Intervention: Drug: Alteplase 50 MG [Activase]
  • Experimental: Alteplase-100
    Patients randomized to Alteplase-100 group will receive 100 mg of Alteplase intravenous administration over 2 hours.
    Intervention: Drug: Alteplase 100 MG [Activase]
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 21, 2020)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2020
Estimated Primary Completion Date September 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
  • 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
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ernest E Moore, MD (303) 602-1820 ernest.moore@dhha.org
Contact: Arsen Ghasabyan, MPH (303) 602-3795 arsen.ghasabyan@dhha.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04357730
Other Study ID Numbers  ICMJE 20-0880
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: A de-identified dataset will be made available to other investigators who may submit proposals to the PI for additional analyses or validation.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Responsible Party Ernest E. Moore, MD, Denver Health and Hospital Authority
Study Sponsor  ICMJE Denver Health and Hospital Authority
Collaborators  ICMJE Genentech, Inc., University of Colorado Denver, National Jewish, Beth Israel Deaconess Medical Center, and Long Island Jewish Hospital
Investigators  ICMJE
Principal Investigator: Ernest E Moore, MD Denver Health Medical Center (DHMC)
PRS Account Denver Health and Hospital Authority
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP