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Trial record 2 of 4 for:    tPA and COVID-19

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 : May 22, 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

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.


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

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
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
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


Arm Intervention/treatment
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.
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).

Experimental: Alteplase-100
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).




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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)

  2. 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.

  3. 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).

  4. 48 hour in-hospital mortality [ Time Frame: at 48 hours post randomization ]
    48 hour mortality for hospitalized patients

  5. 14 days in-hospital mortality [ Time Frame: 14 days post randomization ]
    14 days mortality for hospitalized patients

  6. 28 days in-hospital mortality [ Time Frame: 28 days post randomization ]
    28 days mortality for hospitalized patients

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria: adult patients ages 18-75 years old with known or suspected COVID-19 infection with a PaO2/FiO2 ratio < 150 (at sea level) or inferred PaO2/FiO2 ratio from SpO2 if ABG is unavailable persisting for > 4 hours despite maximal mechanical ventilation management according to each institution's ventilation protocols (at least FiO2>= 60% and PEEP >=10cmH2O), 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. 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 (escalating renal failure with creatinine >3 times baseline)
  • Liver failure (escalating liver failure with ALT > 3 times baseline)
  • 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

Information from the National Library of Medicine

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


Contacts
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Contact: Ernest E Moore, MD (303) 602-1820 ernest.moore@dhha.org
Contact: Arsen Ghasabyan, MPH (303) 602-3795 arsen.ghasabyan@dhha.org

Locations
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United States, Colorado
Denver Health Medical Center Recruiting
Denver, Colorado, United States, 80204
Contact: Ernest E Moore, MD    303-602-1820    ernest.moore@dhha.org   
Principal Investigator: Ernest E Moore, MD         
Sponsors and Collaborators
Denver Health and Hospital Authority
Genentech, Inc., University of Colorado Denver, National Jewish, Beth Israel Deaconess Medical Center, and Long Island Jewish Hospital
Investigators
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Principal Investigator: Ernest E Moore, MD Denver Health Medical Center (DHMC)
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Responsible Party: Ernest E. Moore, MD, Director of Surgical Research, Ernest E Moore Shock Trauma Center at Denver Health, Denver Health and Hospital Authority
ClinicalTrials.gov Identifier: NCT04357730    
Other Study ID Numbers: 20-0880
First Posted: April 22, 2020    Key Record Dates
Last Update Posted: May 22, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
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
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ernest E. Moore, MD, Denver Health and Hospital Authority:
COVID-19
ARDS
SARS-CoV-2
Betacoronavirus
Additional relevant MeSH terms:
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Tissue Plasminogen Activator
Severe Acute Respiratory Syndrome
Coronavirus Infections
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Respiratory Insufficiency
Acute Lung Injury
Syndrome
Disease
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Lung Injury
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action