Low-Dose Tenecteplase in Covid-19 Diagnosed With Pulmonary Embolism

Low-Dose Tenecteplase in Covid-19 Patients With Acute Pulmonary Embolism: A Randomized, Double-Blind, Placebo-Controlled Trial

• 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

Study Overview

• Status: Terminated
• Conditions: COVID; Pulmonary Embolism
• Intervention / Treatment: Drug: TNKase; Drug: Enoxaparin; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Low-dose TNKase and Standard of Care Anticoagulation; TNKase (0.25 mg/kg) bolus Other names: Tenecteplase, TNK; Standard of care anticoagulation (heparin or enoxaparin)	Drug: TNKase; Tenecteplase (0.25 mg/kg) supplied by Genentech, Inc. as a sterile, lyophilized powder, diluted with 10mL sterile water.; Other Names: TNK; Tenecteplase; Drug: Enoxaparin; All participants must also receive standard of care anticoagulation therapy.; Other Names: Lovenox; Heparin; Enoxaparin sodium; Heparin sodium; Low molecular weight heparin
ACTIVE_COMPARATOR: Placebo and and Standard of Care Anticoagulation; Placebo bolus (intravenous syringe identical to that of TNK ); Standard of care anticoagulation (heparin or enoxaparin)	Drug: Enoxaparin; All participants must also receive standard of care anticoagulation therapy.; Other Names: Lovenox; Heparin; Enoxaparin sodium; Heparin sodium; Low molecular weight heparin; Drug: Placebo; Placebo to match supplied by Genentech, Inc. as a sterile, lyophilized powder, diluted with 10mL sterile water.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Improvement in Shock Index (Defined as Heart Rate Divided by Systolic Blood Pressure) 6 Hours After the TNK/Placebo Bolus.	For example, a patient may start with a heart rate of 100 beats/min and systolic blood pressure of 100 mm Hg (shock index = 1) and after therapy there may be an improvement where the heart rate is 90 beats/min, with systolic blood pressure of 110 mm Hg (shock index of 0.81), an improvement of 19%. A normal shock index is between 0.5 and 0.7 in healthy patients.	6 hours post TNK/placebo infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1. Clinical Status at 24 Hours After Administration of TNK / Placebo Based Upon 7-point Scale.	Assessment of patient status using an ordinal scale will be recorded at baseline and once daily in the morning while hospitalized. Level 1: Discharged (or "ready for discharge" on ambient air or < 2L suppl O2) Level 2: Non-ICU hospital ward (or "ready for hospital ward") not requiring suppl O2 Level 3: Non-ICU hospital ward (or "ready for hospital ward") requiring suppl O2 Level 4. ICU or non-ICU, requiring non-invasive ventilation or high-flow O2 Level 5. ICU, requiring intubation and mechanical ventilation Level 6: ICU, requiring ECMO or mechanical ventilation and additional organ support (e.g. vasopressors, renal replacement therapy) Level 7: Death	24 +/- 6 hours post TNK/placebo infusion.

Collaborators and Investigators

• Sponsor: Cedars-Sinai Medical Center
• Collaborators: Genentech, Inc.
• Investigators: Principal Investigator: Victor E Tapson, MD, Cedars-Sinai Medical Center

Publications and helpful links

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Helpful Links

• CDC Stroke Facts
• Stroke Early Management Guidelines
• Practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with COVID-19
• TEG max clot strength is consistently elevated and may be predictive of COVID-19 status at the time of ICU admission
• A randomized trial of anticoagulation strategies in COVID-19
• Preventing COVID-19 complications with low- and high-dose anticoagulation (COVID-HEP)
• Trial evaluating efficacy and safety of anticoagulation in patients with COVID-19 infection, nested in the Corimmuno-19 Cohort (CORIMMUNO-COAG)
• Generalized odds ratios for ordinal data

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 8, 2020
• Primary Completion (ACTUAL): July 10, 2021
• Study Completion (ACTUAL): August 8, 2021

Study Registration Dates

• First Submitted: September 19, 2020
• First Submitted That Met QC Criteria: September 21, 2020
• First Posted (ACTUAL): September 22, 2020

Study Record Updates

• Last Update Posted (ACTUAL): October 26, 2021
• Last Update Submitted That Met QC Criteria: October 20, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Pulmonary Embolism; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin; Enoxaparin; Calcium heparin; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin; Enoxaparin sodium; Tenecteplase
• Other Study ID Numbers: ML42522

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes