Low-Dose Tenecteplase in Covid-19 Diagnosed With Pulmonary Embolism
Low-Dose Tenecteplase in Covid-19 Diagnosed With Pulmonary Embolism
-  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
This is a prospective, double-blind, placebo-controlled study randomizing patients with acute
 intermediate-risk PE who meet enrollment criteria in a 2:1 manner into intervention (TNK)
 versus placebo arms, respectively. There will be up to 6 sites. After 18 patients are
 enrolled, a safety assessment will be performed by an independent Data and Safety Monitoring
 Board, and if a safety issue arises, it will be considered and discussed among the
 investigators. The planned sample size is 45 patients (30 treatment and 15 control). Subjects
 will be assessed daily while hospitalized. Subjects discharged from the hospital will be
 asked to attend study visits at Days 14 and 30 (telephone / telemedicine, clinic or inpatient
 ward).

 The overall objective of the study is to evaluate the clinical efficacy and safety of IV
 bolus tenecteplase (TNK) and therapeutic anticoagulation compared with placebo and
 therapeutic anticoagulation in hospitalized adults diagnosed with COVID-19 infection and
 acute intermediate-risk PE.

 Written informed consent for participation in the study must be obtained before performing
 any study-related procedures (including screening evaluations). Informed Consent Forms for
 enrolled patients and for patients who are not subsequently enrolled will be maintained at
 the study site.

 After informed consent is obtained, screening assessment will be completed to confirm a
 patient's eligibility for participation in the study. The screening visit will include
 medical history, physical exam and vital signs. Standard of care (SOC). labs will be
 reviewed. These may include INR, aPTT, PT (if patient is currently taking an anticoagulant),
 CBC with diff, comprehensive chemistry panel, D-dimer and Ferritin. The results of the
 SARS-CoV-2 will be documented. If subject is in child-bearing age and a pregnancy test was
 not done for SOC, a urine pregnancy test will be performed. Electrocadiogram and CTA will be
 reviewed.

 If the patient is determined to be eligible, the study site will obtain the patient's medical
 record number/unique patient identification number, and treatment assignment to either
 interventional (TNK) or placebo will be randomly determined. Patients will be allocated to
 the interventional versus placebo arms in a 2:1 manner as per a computer-generated
 randomization schedule using permuted blocks of random sizes. The block sizes will not be
 disclosed to ensure concealment. A total of 30 TNK subjects versus 15 placebo controls will
 be enrolled.

 Before the study drug/placebo is administered, the following labs will be drawn CBC with
 diff, comprehensive metabolic panel, CRP, Ferritin, IL-6, Fibrinogen, D-dimer, PT/PTT, LDH,
 lactate, troponin, creatinine kinase, and Thromboelastography (TEG). Vital signs and
 echocardiogram will be obtained. Shock Index will be calculated, then the infusion will
 begin.

 Within 10 minutes (+ 5min) of infusion, a second TEG will be collected. At 6 hours after the
 infusion, a second Shock Index will be calculated. At 24+/- 6 hours after the bolus, a
 physical exam will be performed, vital signs will be collected, an echocardiogram will be
 performed and D-dimer, CRP, IL-6, and Ferritin will be done. TEG will be an optional addition
 to the 24-hour labs. Daily safety labs will include CBC and chemistry panel. SOC lab results
 will be collected from the chart.

 Patients will have follow-up visits on Day 14 +/- 2 days and Day 30 +/- 4 days. These visits
 may take place via televisit or in person. Data will be collected on adverse events, vital
 signs and new concomitant medications. Safety labs will be obtained if visit occurs in
 person.
Inclusion Criteria:

 1. Male or non-pregnant female adult ≥18 years of age, but < 75 years of age at time of
 enrollment.

 2. Has laboratory-confirmed SARS-CoV-2 infection as determined by PCR, or other
 commercial or public health assay in any specimen < 14 days prior to randomization.

 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 AND

 -  Abnormal right ventricular (RV) function by echocardiography, AND

 -  Elevated troponin-I or troponin-T as defined by local lab reference ranges.

 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