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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04558125
Recruitment Status : Active, not recruiting
First Posted : September 22, 2020
Last Update Posted : October 27, 2020
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Victor Tapson, MD, Cedars-Sinai Medical Center

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
Pulmonary Embolism COVID Drug: TNKase 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 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 Acture Pulmonary Embolism: A Randomized, Double-Blind, Placebo-Controlled Trial
Actual Study Start Date : September 8, 2020
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : June 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: TNKase
TNKase infusion plus standard of care which can be heparin or lovenox
Drug: TNKase
Randomized to TNKase or placebo infusion. Both groups with have SOC which will be either heparin infusion or enoxaparin SQ injections.

Placebo Comparator: Placebo
Placebo infusion plus standard of care which can be heparin or lovenox
Drug: TNKase
Randomized to TNKase or placebo infusion. Both groups with have SOC which will be either heparin infusion or enoxaparin SQ injections.




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. [ Time Frame: 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. [ Time Frame: 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




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04558125


Locations
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United States, California
Cedars-Sinai Medical Center
Los Angeles, California, United States, 90048
Sponsors and Collaborators
Cedars-Sinai Medical Center
Genentech, Inc.
Investigators
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Principal Investigator: Victor E Tapson, MD Cedars-Sinai Medical Center
Additional Information:
Publications:
Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, de Ferranti SD, Ferguson JF, Fornage M, Gillespie C, Isasi CR, Jiménez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Lutsey PL, Mackey JS, Matchar DB, Matsushita K, Mussolino ME, Nasir K, O'Flaherty M, Palaniappan LP, Pandey A, Pandey DK, Reeves MJ, Ritchey MD, Rodriguez CJ, Roth GA, Rosamond WD, Sampson UKA, Satou GM, Shah SH, Spartano NL, Tirschwell DL, Tsao CW, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation. 2018 Mar 20;137(12):e67-e492. doi: 10.1161/CIR.0000000000000558. Epub 2018 Jan 31. Review. Erratum in: Circulation. 2018 Mar 20;137(12 ):e493.
Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, Schonewille WJ, Vos JA, Nederkoorn PJ, Wermer MJ, van Walderveen MA, Staals J, Hofmeijer J, van Oostayen JA, Lycklama à Nijeholt GJ, Boiten J, Brouwer PA, Emmer BJ, de Bruijn SF, van Dijk LC, Kappelle LJ, Lo RH, van Dijk EJ, de Vries J, de Kort PL, van Rooij WJ, van den Berg JS, van Hasselt BA, Aerden LA, Dallinga RJ, Visser MC, Bot JC, Vroomen PC, Eshghi O, Schreuder TH, Heijboer RJ, Keizer K, Tielbeek AV, den Hertog HM, Gerrits DG, van den Berg-Vos RM, Karas GB, Steyerberg EW, Flach HZ, Marquering HA, Sprengers ME, Jenniskens SF, Beenen LF, van den Berg R, Koudstaal PJ, van Zwam WH, Roos YB, van der Lugt A, van Oostenbrugge RJ, Majoie CB, Dippel DW; MR CLEAN Investigators. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015 Jan 1;372(1):11-20. doi: 10.1056/NEJMoa1411587. Epub 2014 Dec 17. Erratum in: N Engl J Med. 2015 Jan 22;372(4):394.
From the American Association of Neurological Surgeons (AANS), American Society of Neuroradiology (ASNR), Cardiovascular and Interventional Radiology Society of Europe (CIRSE), Canadian Interventional Radiology Association (CIRA), Congress of Neurological Surgeons (CNS), European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), European Stroke Organization (ESO), Society for Cardiovascular Angiography and Interventions (SCAI), Society of Interventional Radiology (SIR), Society of NeuroInterventional Surgery (SNIS), and World Stroke Organization (WSO), Sacks D, Baxter B, Campbell BCV, Carpenter JS, Cognard C, Dippel D, Eesa M, Fischer U, Hausegger K, Hirsch JA, Shazam Hussain M, Jansen O, Jayaraman MV, Khalessi AA, Kluck BW, Lavine S, Meyers PM, Ramee S, Rüfenacht DA, Schirmer CM, Vorwerk D. Multisociety Consensus Quality Improvement Revised Consensus Statement for Endovascular Therapy of Acute Ischemic Stroke. Int J Stroke. 2018 Aug;13(6):612-632. doi: 10.1177/1747493018778713. Epub 2018 May 22.

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Responsible Party: Victor Tapson, MD, Professor of Medicine, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier: NCT04558125    
Other Study ID Numbers: ML42522
First Posted: September 22, 2020    Key Record Dates
Last Update Posted: October 27, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Pulmonary Embolism
Embolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Tenecteplase
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action