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Tenecteplase in Patients With COVID-19

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ClinicalTrials.gov Identifier: NCT04505592
Recruitment Status : Enrolling by invitation
First Posted : August 10, 2020
Last Update Posted : September 21, 2021
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Hooman Poor, Icahn School of Medicine at Mount Sinai

Brief Summary:
This is a placebo-controlled, double blind, randomized, Phase II dose escalation study intended to evaluate the potential safety and efficacy of tenecteplase for the treatment of COVID-19 associated respiratory failure. The hypothesis is that administration of the drug, in conjunction with heparin anticoagulation, will improve patients' clinical outcomes.

Condition or disease Intervention/treatment Phase
COVID-19 Respiratory Failure ARDS Drug: Tenecteplase Drug: Placebo Phase 2

Detailed Description:
Patients with COVID-19 who suffer from acute hypoxemic respiratory failure have a poor prognosis. COVID-19 has been associated with a hyperinflammatory and hypercoagulable state, leading to a range of thromboembolic complications from pulmonary embolism to ischemic stroke. Furthermore, emerging data suggest that the associated acute respiratory failure is, at least in part, due to pulmonary vascular disease caused by micro- and/or macro-emboli, creating pulmonary vascular shunting and dead-space ventilation. In this placebo-controlled, double blind, randomized, Phase II dose escalation study, we plan to evaluate the clinical efficacy and safety of low-dose IV bolus tenecteplase together with anticoagulation compared with control patients on therapeutic anticoagulation alone in hospitalized adults diagnosed with COVID-19 respiratory failure with elevated D-dimer. We believe these patients can be successfully treated without significantly increasing the risk of major bleeding while improving recovery rates, shorten hospitalization time, and perhaps ultimately prove to improve survival.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Subjects will be randomized in a 2:1 ratio to treatment or control in blocks of 15, performed twice per dose (low and high) with randomization stratified by site.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: Patients and study investigators will be blinded to subject treatment.
Primary Purpose: Treatment
Official Title: Tenecteplase With Concomitant Anticoagulation for Severe Acute Respiratory Failure in Patients With COVID-19
Actual Study Start Date : September 25, 2020
Estimated Primary Completion Date : October 2021
Estimated Study Completion Date : October 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Tenecteplase
First 20 patients randomized to treatment will receive tenecteplase 0.25 mg/kg (maximum 25 mg). Last 20 patients randomized to treatment will receive tenecteplase 0.50 mg/kg (maximum 40 mg).
Drug: Tenecteplase
First 20 patients randomized to treatment arm will receive 0.25 mg/kg of tenecteplase. Next 20 patients randomized to treatment arm will receive 0.50 mg/kg of tenecteplase. Both will receive concomitant heparin to maintain activated partial thromboplastin time between 2.0 and 2.5 upper limit of normal.

Placebo Comparator: Placebo
Placebo control
Drug: Placebo
Patients will receive placebo with concomitant heparin to maintain activated partial thromboplastin time between 2.0 and 2.5 upper limit of normal.




Primary Outcome Measures :
  1. Number of participants free of respiratory failure [ Time Frame: 28 Days ]
    The number of patients free of respiratory failure defined as not requiring high flow nasal cannula, non-rebreather, noninvasive positive pressure ventilation, or mechanical ventilation at 28 days

  2. Number of occurrences of bleeding [ Time Frame: 28 days ]
    Safety as assessed by number of occurrences of intracranial bleeding or major bleeding


Secondary Outcome Measures :
  1. Number of participants with in-hospital deaths at 14 days [ Time Frame: 14 days ]
  2. Number of participants with death at 28 days [ Time Frame: 28 days ]
  3. Number of ventilator-free days [ Time Frame: 28 days ]
  4. Number of respiratory failure-free days [ Time Frame: 28 days ]
    Respiratory failure-free defined as not requiring high flow nasal cannula, non-rebreather, noninvasive positive pressure ventilation, or mechanical ventilation

  5. Number of vasopressor-free days [ Time Frame: 28 days ]
  6. Vasopressor doses at 24 hours [ Time Frame: 24 hours ]
  7. Vasopressor doses at 72 hours [ Time Frame: 72 hours ]
  8. P/F ratio at 24 hours [ Time Frame: 24 hours ]
    The P/F ratio equals the arterial pO2 ("P") from the ABG divided by the FIO2 ("F") - the fraction (percent) of inspired oxygen that the patient is receiving expressed as a decimal (40% oxygen = FIO2 of 0.40).

  9. P/F ratio at 72 hours [ Time Frame: 72 hours ]
    The P/F ratio equals the arterial pO2 ("P") from the ABG divided by the FIO2 ("F") - the fraction (percent) of inspired oxygen that the patient is receiving expressed as a decimal (40% oxygen = FIO2 of 0.40).

  10. Number of ICU-free days [ Time Frame: 28 days ]
  11. Hospital length of stay [ Time Frame: 28 days ]
  12. Number of participants with new-onset renal failure [ Time Frame: 28 days ]
  13. Number of participants with need for renal replacement therapy [ Time Frame: 28 days ]


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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

  • Patient/legally authorized representative has completed the Informed Consent Form
  • Age ≥18 years
  • Ability to comply with the study protocol, in the investigator's judgment
  • Respiratory failure secondary to COVID-19 requiring mechanical ventilation for no greater than 24 hours, or high-flow nasal cannula (HFNC),non-rebreather (NRB) mask or non-invasive positive pressure ventilation (NIPPV) for no greater than 48 hours
  • Confirmed infection with SARS-CoV-2 virus (PCR positive within 14 days)
  • Elevated D-dimer (>6 times upper limit of normal within past 72 hours)
  • For patient who are intubated >12 hours prior to randomization or with any evidence of neurologic deficit a head CT within 12 hours demonstrating no evidence of acute or subacute infarct or hemorrhage

Exclusion Criteria

  • Current participation in another investigational drug study within the prior 7 days
  • Known hypersensitivity or allergy to any ingredients of tenecteplase
  • Active internal bleeding
  • Known bleeding diathesis
  • Use of one of the new oral anticoagulants within the last 48 hours (dabigatran, rivaroxaban, apixaban, edoxaban)
  • Treatment with a thrombolytic within the last 3 months prior to randomization (exception for the use of Cathflo alteplase for occlusions of central venous catheters)
  • Baseline platelet count <80,000/L (results must be available prior to treatment)
  • Baseline blood glucose >400 mg/dL (22.20 mmol/L)
  • Baseline blood glucose <50 mg/dL needs to be normalized prior to randomization
  • Intracranial or intraspinal surgery or trauma within 2 months
  • Other, non-COVID-19 related, serious, advanced, or terminal illness (investigator judgment) or life expectancy is less than 6 months
  • History of acute ischemic stroke in the last 90 days
  • History of intracranial bleeding, including hemorrhagic stroke
  • Presumed septic embolus; suspicion of bacterial endocarditis
  • Mechanical ventilation > 24 hours, HFNC, NRB, NIPPV, or any combination, for greater than 48 hours
  • Mechanical ventilation, HFNC, NRB, or NIPVV (for reasons other than obstructive sleep apnea) within the prior 30 days (excluding 48 hours prior to randomization)
  • Moribund status suggesting imminent vascular collapse and inability to survive > 72 hours (investigator determination)
  • Uncontrolled hypertension defined as systolic BP > 180 mm Hg and/or diastolic BP > 110 mm Hgb
  • Age > 75 years
  • History of traumatic brain injury within 2 months
  • Recent head trauma with fracture or brain injury
  • History of Heparin Induced Thrombocytopenia (HIT) and/or other hereditary or acquired hemorrhagic diathesis or coagulation factor deficiency
  • INR > 2 or recent oral anticoagulant therapy with INR >1.7
  • Pregnancy or lactation within the prior 30 days; women of childbearing age (<55 years old) should have documentation of a negative pregnancy test
  • Chronic liver disease defined as > Childs-Pugh Class B
  • Atrial fibrillation, mitral stenosis, or known left heart thrombosis
  • Any other condition that, in the opinion of the investigator, precludes administration of tenecteplase or poses a significant hazard to the patient receives tenecteplase

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): NCT04505592


Locations
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United States, New York
Mount Sinai Hospital
New York, New York, United States, 10029
Sponsors and Collaborators
Hooman Poor
Genentech, Inc.
Investigators
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Principal Investigator: Hooman Poor, MD Icahn School of Medicine at Mount Sinai
Study Director: J Mocco, MD Icahn School of Medicine at Mount Sinai
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Responsible Party: Hooman Poor, Assistant Professor of Medicine, Icahn School of Medicine at Mount Sinai
ClinicalTrials.gov Identifier: NCT04505592    
Other Study ID Numbers: GCO 20-1764
First Posted: August 10, 2020    Key Record Dates
Last Update Posted: September 21, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 Hooman Poor, Icahn School of Medicine at Mount Sinai:
COVID-19
ARDS
thrombolysis
tenecteplase
Additional relevant MeSH terms:
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COVID-19
Respiratory Insufficiency
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Tenecteplase
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action