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

Sponsor
Cedars-Sinai Medical Center (Other)
Overall Status
Terminated
CT.gov ID
NCT04558125
Collaborator
Genentech, Inc. (Industry)
2
Enrollment
1
Location
2
Arms
11
Actual Duration (Months)
0.2
Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease Intervention/Treatment Phase
Phase 4

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 Design

Study Type:
Interventional
Actual Enrollment :
2 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Low-Dose Tenecteplase in Covid-19 Patients With Acute Pulmonary Embolism: A Randomized, Double-Blind, Placebo-Controlled Trial
Actual Study Start Date :
Sep 8, 2020
Actual Primary Completion Date :
Jul 10, 2021
Actual Study Completion Date :
Aug 8, 2021

Arms and Interventions

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:
  • Tenecteplase
  • TNK

    • Drug: Enoxaparin
    All participants must also receive standard of care anticoagulation therapy.
    Other Names:
  • Low molecular weight heparin
  • Lovenox
  • Enoxaparin sodium
  • Heparin
  • Heparin sodium

    		•
    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: Placebo
    Placebo to match supplied by Genentech, Inc. as a sterile, lyophilized powder, diluted with 10mL sterile water.

    Drug: Enoxaparin
    All participants must also receive standard of care anticoagulation therapy.
    Other Names:
  • Low molecular weight heparin
  • Lovenox
  • Enoxaparin sodium
  • Heparin
  • Heparin sodium

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Percent Improvement in Shock Index (Defined as Heart Rate Divided by Systolic Blood Pressure) 6 Hours After the TNK/Placebo Bolus. [6 hours post TNK/placebo infusion]

      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.

    Secondary Outcome Measures

    1. 1. Clinical Status at 24 Hours After Administration of TNK / Placebo Based Upon 7-point Scale. [24 +/- 6 hours post TNK/placebo infusion.]

      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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    1. Subject (or legally authorized representative) provides written informed consent prior to the performance of any study procedures.

    2. 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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Cedars-Sinai Medical Center Los Angeles California United States 90048

    Sponsors and Collaborators

    • Cedars-Sinai Medical Center
    • Genentech, Inc.

    Investigators

    • Principal Investigator: Victor E Tapson, MD, Cedars-Sinai Medical Center

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Victor Tapson, MD, Professor of Medicine, Cedars-Sinai Medical Center
    ClinicalTrials.gov Identifier:
    NCT04558125
    Other Study ID Numbers:
    • ML42522
    First Posted:
    Sep 22, 2020
    Last Update Posted:
    Oct 26, 2021
    Last Verified:
    Oct 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    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
    Additional relevant MeSH terms:
    Pulmonary Embolism
    Embolism
    Heparin
    Calcium heparin
    Enoxaparin
    Heparin, Low-Molecular-Weight
    Tinzaparin
    Dalteparin
    Tenecteplase
    Enoxaparin sodium

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail The study was terminated early and never unblinded. With only 2 subjects, statistical significance could never be demonstrated. Therefore, Arm/Group randomization information is not available.
    Arm/Group Title All Study Participants
    Arm/Group Description TNKase (0.25 mg/kg) bolus as a sterile, lyophilized powder, diluted with 10mL sterile water, and administered as a 5-second bolus; AND standard of care anticoagulation therapy (enoxaparin or heparin). OR Placebo-to-match-TNKase bolus as a sterile, lyophilized powder, diluted with 10mL sterile water, and administered as a 5-second bolus; AND standard of care anticoagulation therapy (enoxaparin or heparin).
    Period Title: Overall Study
    STARTED 2
    COMPLETED 1
    NOT COMPLETED 1

    Baseline Characteristics

    Arm/Group Title All Study Participants
    Arm/Group Description TNKase (0.25 mg/kg) bolus as a sterile, lyophilized powder, diluted with 10mL sterile water, and administered as a 5-second bolus; AND standard of care anticoagulation therapy (enoxaparin or heparin). OR Placebo-to-match-TNKase bolus as a sterile, lyophilized powder, diluted with 10mL sterile water, and administered as a 5-second bolus; AND standard of care anticoagulation therapy (enoxaparin or heparin).
    Overall Participants 2
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    2
    100%
    >=65 years
    0
    0%
    Sex: Female, Male (Count of Participants)
    Female
    1
    50%
    Male
    1
    50%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    1
    50%
    Not Hispanic or Latino
    1
    50%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    0
    0%
    White
    2
    100%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    2
    100%

    Outcome Measures

    1. Primary Outcome
    Title Percent Improvement in Shock Index (Defined as Heart Rate Divided by Systolic Blood Pressure) 6 Hours After the TNK/Placebo Bolus.
    Description 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.
    Time Frame 6 hours post TNK/placebo infusion

    Outcome Measure Data

    Analysis Population Description
    The study was terminated early and never unblinded. With only 2 subjects, statistical significance could never be demonstrated. Therefore, Arm/Group randomization information is not available.
    Arm/Group Title All Study Participants
    Arm/Group Description TNKase (0.25 mg/kg) bolus as a sterile, lyophilized powder, diluted with 10mL sterile water, and administered as a 5-second bolus; AND standard of care anticoagulation therapy (enoxaparin or heparin). OR Placebo-to-match-TNKase bolus as a sterile, lyophilized powder, diluted with 10mL sterile water, and administered as a 5-second bolus; AND standard of care anticoagulation therapy (enoxaparin or heparin).
    Measure Participants 0
    2. Secondary Outcome
    Title 1. Clinical Status at 24 Hours After Administration of TNK / Placebo Based Upon 7-point Scale.
    Description 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
    Time Frame 24 +/- 6 hours post TNK/placebo infusion.

    Outcome Measure Data

    Analysis Population Description
    The study was terminated early and never unblinded. With only 2 subjects, statistical significance could never be demonstrated. Therefore, Arm/Group randomization information is not available.
    Arm/Group Title All Study Participants
    Arm/Group Description TNKase (0.25 mg/kg) bolus as a sterile, lyophilized powder, diluted with 10mL sterile water, and administered as a 5-second bolus; AND standard of care anticoagulation therapy (enoxaparin or heparin). OR Placebo-to-match-TNKase bolus as a sterile, lyophilized powder, diluted with 10mL sterile water, and administered as a 5-second bolus; AND standard of care anticoagulation therapy (enoxaparin or heparin).
    Measure Participants 0

    Adverse Events

    Time Frame 30 days
    Adverse Event Reporting Description The study not unblinded. All data was entered in treatment fields.
    Arm/Group Title All Study Participants
    Arm/Group Description TNKase (0.25 mg/kg) bolus as a sterile, lyophilized powder, diluted with 10mL sterile water, and administered as a 5-second bolus; AND standard of care anticoagulation therapy (enoxaparin or heparin). OR Placebo-to-match-TNKase bolus as a sterile, lyophilized powder, diluted with 10mL sterile water, and administered as a 5-second bolus; AND standard of care anticoagulation therapy (enoxaparin or heparin).
    All Cause Mortality
    All Study Participants
    Affected / at Risk (%) # Events
    Total 1/2 (50%)
    Serious Adverse Events
    All Study Participants
    Affected / at Risk (%) # Events
    Total 1/2 (50%)
    Gastrointestinal disorders
    Gastrointestinal Bleeding 1/2 (50%) 1
    Respiratory, thoracic and mediastinal disorders
    Respiratory Failure 1/2 (50%) 1
    Other (Not Including Serious) Adverse Events
    All Study Participants
    Affected / at Risk (%) # Events
    Total 1/2 (50%)
    Cardiac disorders
    Hypotension 1/2 (50%) 1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis 1/2 (50%) 1
    Productive cough 1/2 (50%) 1

    Limitations/Caveats

    The study was terminated early due to enrollment being slower than anticipated, with study enrollment highly dependent upon COVID-19 surge patterns. We were otherwise hopeful to enroll and complete all assessments for this study.

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Victor Tapson, MD
    Organization Cedars-Sinai Medical Center
    Phone 919-971-6441
    Email Victor.Tapson@cshs.org
    Responsible Party:
    Victor Tapson, MD, Professor of Medicine, Cedars-Sinai Medical Center
    ClinicalTrials.gov Identifier:
    NCT04558125
    Other Study ID Numbers:
    • ML42522
    First Posted:
    Sep 22, 2020
    Last Update Posted:
    Oct 26, 2021
    Last Verified:
    Oct 1, 2021