Clinical trial NCT04558125: Low-Dose Tenecteplase in Covid-19 Diagnosed With Pulmonary Embolism
Official title: Low-Dose Tenecteplase in Covid-19 Patients With Acute Pulmonary Embolism: A Randomized, Double-Blind, Placebo-Controlled Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Pulmonary Embolism
COVID
Lead sponsor: Cedars-Sinai Medical Center
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2020-09-22
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Detailed description: 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.

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

Primary outcomes:
measure: Percent Improvement in Shock Index (Defined as Heart Rate Divided by Systolic Blood Pressure) 6 Hours After the TNK/Placebo Bolus.
timeFrame: 6 hours post TNK/placebo infusion
Secondary outcomes:
measure: 1. Clinical Status at 24 Hours After Administration of TNK / Placebo Based Upon 7-point Scale.
timeFrame: 24 +/- 6 hours post TNK/placebo infusion.
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
Study officials:
affiliation: Cedars-Sinai Medical Center
name: Victor E Tapson, MD
role: PRINCIPAL_INVESTIGATOR
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