Low-Dose Tenecteplase in Covid-19 Diagnosed With Pulmonary Embolism
Condition: Pulmonary Embolism; COVID
MeSH terms: Pulmonary Embolism; Embolism
Intervention: TNKase; Placebo; Enoxaparin
Intervention description: Tenecteplase (0.25 mg/kg) supplied by Genentech, Inc. as a sterile, lyophilized powder, diluted with 10mL sterile water.; Placebo to match supplied by Genentech, Inc. as a sterile, lyophilized powder, diluted with 10mL sterile water.; All participants must also receive standard of care anticoagulation therapy.
Intervention MeSH terms: Heparin; Calcium heparin; Enoxaparin; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin; Tenecteplase; Enoxaparin sodium
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      -  There is a knowledge gap associated with the management of patients with COVID-19 lung
           injury and a laboratory picture compatible with disseminated intravascular coagulation
           (DIC). Clinical data to date support that COVID-19 is associated with a prothrombotic
           state that is not simply explained by an influx of more critically ill individuals.

        -  These patients suffer from severe respiratory failure; hypoxemia and ventilator
           dependence are the primary concerns; ARDS with respiratory failure is frequently the
           cause of death. Macroscopic and probable microvascular thromboembolic events are a major
           concern in this population.

        -  When DIC is associated with COVID-19, it predicts a very poor prognosis.

        -  This study will evaluate the clinical efficacy and safety of low-dose IV bolus
           tenecteplase (TNK) together with anticoagulation compared with control patients on
           therapeutic anticoagulation alone in hospitalized adults diagnosed with COVID-19 and
           acute intermediate-risk PE.

        -  Prospective, multicenter, randomized two-arm trial enrolling consecutive patients who
           meet enrollment criteria.

        -  The study will generate evidence that low-dose TNK together with anticoagulation is
           beneficial in these patients
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male or non-pregnant female adult ≥18 years of age, but < 75 years of age at time of
             enrollment.

          2. Laboratory-confirmed SARS-CoV-2 infection as determined by PCR, or other commercial or
             public health assay in any specimen < 28 days prior to randomization, OR person under
             investigation (PUI) of COVID-19 with pulmonary infiltrates and elevated ferritin and
             CRP level.

          3. Acute intermediate-risk pulmonary embolism defined as:

               -  Presence of acute pulmonary embolism confirmed by diagnostic imaging (computed
                  tomographic angiography, ventilation-perfusion scan, or invasive pulmonary
                  angiography) AND

               -  Presence of clot burden with at least one lobar artery involved OR bilateral with
                  at least segmental branches OR unilateral clot in at least multiple segmental
                  branches.

          4. Subject (or legally authorized representative) provides written informed consent prior
             to the performance of any study procedures.

          5. In the Investigator's judgement, patient has the ability to comply with the study
             protocol, and understands and agrees to comply with planned TNK bolus versus placebo.

        Exclusion Criteria:

          1. Anticipated transfer to another hospital (which is not a study site) within 72 hours

          2. Allergy or contraindications to TNK

          3. Contraindications to systemic anticoagulation

          4. Active bleeding

          5. Known significant bleeding risk (although recent exposure to aspirin or any other
             antiplatelet therapy is not an exclusion criterion). While there is no specific
             hemoglobin cut-off value for enrollment, Investigators will gauge the severity /
             stability of the Hgb and exclude patients deemed inappropriate.

          6. Major GI or GU bleed within the past 3 weeks

          7. History of hemorrhagic stroke

          8. History of acute ischemic stroke in the last 90 days

          9. High-risk (massive) acute PE (PE associated with hypotension (systolic BP < 90 mmHg
             for > 15 min).

         10. PE associated with syncope and any degree of head trauma

         11. PE meeting criteria for intermediate-risk PE and thus for enrollment, but with
             clinical evidence of deterioration such that the Investigator deems the patient not
             appropriate for enrollment.

         12. Administration of thrombolytic agent within the previous 7 days

         13. Pulmonary thrombectomy within the previous 30 days

         14. Uncontrolled hypertension defined as systolic blood pressure >180 mm Hg and/or
             diastolic blood pressure >110 mm Hg at randomization

         15. Severe ARDS (P/F ratio < 100)

         16. Platelet count lower than 80,000/mm3

         17. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency;
             recent oral anticoagulant therapy with INR >1.7

         18. Arterial puncture at a non-compressible site within the past 5 days

         19. Prior brain surgery

         20. Severe trauma in the prior 2 weeks

         21. Major surgery in the prior 2 weeks

         22. Brain malignancy / metastases, brain tumor in past 5 years

         23. Brain AVM or ruptured aneurysm at any time

         24. Acute myocardial infarction or history of myocardial infarction within the past 3
             weeks or cardiac arrest during hospitalization

         25. Cardiac tamponade

         26. Lumbar puncture with in past 7 days

         27. Known abdominal or thoracic aneurysm

         28. Acute or chronic renal failure requiring dialysis

         29. Chronic liver failure (acutely elevated liver function tests not an exclusion
             criterion)

         30. Bacterial endocarditis at time of study entry

         31. Seizure during pre-hospital course or during hospitalization for COVID-19

         32. Currently on ECMO

         33. Pregnancy, lactation or parturition within the previous 30 days

         34. Patients, in whom, in the opinion of the Investigator, are critically ill from
             concomitant comorbid cardiopulmonary disease, and unlikely to benefit.

         35. Any other condition that the Investigator felt would place the patient at increased
             risk if the investigational therapy were initiated

         36. Previous enrollment in this study