Tenecteplase in Patients With COVID-19
Condition: COVID-19; Respiratory Failure; ARDS
MeSH terms: COVID-19; Respiratory Insufficiency
Intervention: Tenecteplase; Placebo
Intervention description: 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.; Patients will receive placebo with concomitant heparin to maintain activated partial thromboplastin time between 2.0 and 2.5 upper limit of normal.
Intervention MeSH terms: Tenecteplase
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
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.
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: COVID-19; ARDS; thrombolysis; tenecteplase

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.
    

Eligibility 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