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Tenecteplase in Patients With COVID-19

Primary Purpose

COVID-19, Respiratory Failure, ARDS

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Tenecteplase
Placebo
Sponsored by
Hooman Poor
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for COVID-19 focused on measuring COVID-19, ARDS, thrombolysis, tenecteplase

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

  • Patient/legally authorized representative has completed the Informed Consent Form
  • Age ≥18 years
  • Ability to comply with the study protocol, in the investigator's judgment
  • Respiratory failure secondary to COVID-19 requiring mechanical ventilation for no greater than 24 hours, or high-flow nasal cannula (HFNC),non-rebreather (NRB) mask or non-invasive positive pressure ventilation (NIPPV) for no greater than 48 hours
  • Confirmed infection with SARS-CoV-2 virus (PCR positive within 14 days)
  • Elevated D-dimer (>6 times upper limit of normal within past 72 hours)
  • For patient who are intubated >12 hours prior to randomization or with any evidence of neurologic deficit a head CT within 12 hours demonstrating no evidence of acute or subacute infarct or hemorrhage

Exclusion Criteria

  • Current participation in another investigational drug study within the prior 7 days
  • Known hypersensitivity or allergy to any ingredients of tenecteplase
  • Active internal bleeding
  • Known bleeding diathesis
  • Use of one of the new oral anticoagulants within the last 48 hours (dabigatran, rivaroxaban, apixaban, edoxaban)
  • Treatment with a thrombolytic within the last 3 months prior to randomization (exception for the use of Cathflo alteplase for occlusions of central venous catheters)
  • Baseline platelet count <80,000/L (results must be available prior to treatment)
  • Baseline blood glucose >400 mg/dL (22.20 mmol/L)
  • Baseline blood glucose <50 mg/dL needs to be normalized prior to randomization
  • Intracranial or intraspinal surgery or trauma within 2 months
  • Other, non-COVID-19 related, serious, advanced, or terminal illness (investigator judgment) or life expectancy is less than 6 months
  • History of acute ischemic stroke in the last 90 days
  • History of intracranial bleeding, including hemorrhagic stroke
  • Presumed septic embolus; suspicion of bacterial endocarditis
  • Mechanical ventilation > 24 hours, HFNC, NRB, NIPPV, or any combination, for greater than 48 hours
  • Mechanical ventilation, HFNC, NRB, or NIPVV (for reasons other than obstructive sleep apnea) within the prior 30 days (excluding 48 hours prior to randomization)
  • Moribund status suggesting imminent vascular collapse and inability to survive > 72 hours (investigator determination)
  • Uncontrolled hypertension defined as systolic BP > 180 mm Hg and/or diastolic BP > 110 mm Hgb
  • Age > 75 years
  • History of traumatic brain injury within 2 months
  • Recent head trauma with fracture or brain injury
  • History of Heparin Induced Thrombocytopenia (HIT) and/or other hereditary or acquired hemorrhagic diathesis or coagulation factor deficiency
  • INR > 2 or recent oral anticoagulant therapy with INR >1.7
  • Pregnancy or lactation within the prior 30 days; women of childbearing age (<55 years old) should have documentation of a negative pregnancy test
  • Chronic liver disease defined as > Childs-Pugh Class B
  • Atrial fibrillation, mitral stenosis, or known left heart thrombosis
  • Any other condition that, in the opinion of the investigator, precludes administration of tenecteplase or poses a significant hazard to the patient receives tenecteplase

Sites / Locations

  • Mount Sinai Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Tenecteplase

Placebo

Arm Description

First 20 patients randomized to treatment will receive tenecteplase 0.25 mg/kg (maximum 25 mg). Last 20 patients randomized to treatment will receive tenecteplase 0.50 mg/kg (maximum 40 mg).

Placebo control

Outcomes

Primary Outcome Measures

Number of Participants Free of Respiratory Failure
The number of patients free of respiratory failure defined as not requiring high flow nasal cannula, non-rebreather, noninvasive positive pressure ventilation, or mechanical ventilation at 28 days
Number of Participants With Occurrences of Bleeding
Safety as assessed by number of participants with occurrences of intracranial bleeding or major bleeding

Secondary Outcome Measures

Number of Participants With In-hospital Deaths at 14 Days
Number of patients who expired in the hospital within the first 14 days of their participation in the study
Number of Participants With Death at 28 Days
Number of participants who expired by 28 days/end of study
Number of Ventilator-free Days
Number of ventilator-free days in 28 days period
Number of Respiratory Failure-free Days
Respiratory failure-free defined as not requiring high flow nasal cannula, non-rebreather, noninvasive positive pressure ventilation, or mechanical ventilation. Number of respiratory failure-free days in 28 days period.
Number of Vasopressor-free Days
Number of vasopressor-free days over 28 days period
Number of Vasopressor Doses at 24 Hours
P/F Ratio
The P/F ratio equals the arterial pO2 ("P") from the ABG divided by the FIO2 ("F") - the fraction (percent) of inspired oxygen that the patient is receiving expressed as a decimal (40% oxygen = FIO2 of 0.40). Ratio of arterial pO2 over fraction of inspired oxygen that the person is receiving. Normal P/F Ratio is ≥ 400. 300 to 200 is considered mild ARDS 200 to 100 is considered moderate ARDS Anything below 100 is considered severe ARDS.
Number of ICU-free Days
Number of days the patient spent outside the ICU
Hospital Length of Stay
Length of time the patient spent in the hospital, including ICU
Number of Participants With New-onset Renal Failure
Number of patients who experienced renal failure during the course of the study
Number of Participants With Need for Renal Replacement Therapy
Number of patients who underwent renal replacement treatment for their renal failure

Full Information

First Posted
August 6, 2020
Last Updated
April 4, 2023
Sponsor
Hooman Poor
Collaborators
Genentech, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT04505592
Brief Title
Tenecteplase in Patients With COVID-19
Official Title
Tenecteplase With Concomitant Anticoagulation for Severe Acute Respiratory Failure in Patients With COVID-19
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Completed
Study Start Date
September 25, 2020 (Actual)
Primary Completion Date
March 10, 2022 (Actual)
Study Completion Date
March 10, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Hooman Poor
Collaborators
Genentech, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a placebo-controlled, double blind, randomized, Phase II dose escalation study intended to evaluate the potential safety and efficacy of tenecteplase for the treatment of COVID-19 associated respiratory failure. The hypothesis is that administration of the drug, in conjunction with heparin anticoagulation, will improve patients' clinical outcomes.
Detailed Description
Patients with COVID-19 who suffer from acute hypoxemic respiratory failure have a poor prognosis. COVID-19 has been associated with a hyperinflammatory and hypercoagulable state, leading to a range of thromboembolic complications from pulmonary embolism to ischemic stroke. Furthermore, emerging data suggest that the associated acute respiratory failure is, at least in part, due to pulmonary vascular disease caused by micro- and/or macro-emboli, creating pulmonary vascular shunting and dead-space ventilation. In this placebo-controlled, double blind, randomized, Phase II dose escalation study, we plan to evaluate the clinical efficacy and safety of low-dose IV bolus tenecteplase together with anticoagulation compared with control patients on therapeutic anticoagulation alone in hospitalized adults diagnosed with COVID-19 respiratory failure with elevated D-dimer. We believe these patients can be successfully treated without significantly increasing the risk of major bleeding while improving recovery rates, shorten hospitalization time, and perhaps ultimately prove to improve survival.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19, Respiratory Failure, ARDS
Keywords
COVID-19, ARDS, thrombolysis, tenecteplase

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Model Description
Subjects will be randomized in a 2:1 ratio to treatment or control in blocks of 15, performed twice per dose (low and high) with randomization stratified by site.
Masking
ParticipantCare ProviderInvestigator
Masking Description
Patients and study investigators will be blinded to subject treatment.
Allocation
Randomized
Enrollment
13 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tenecteplase
Arm Type
Experimental
Arm Description
First 20 patients randomized to treatment will receive tenecteplase 0.25 mg/kg (maximum 25 mg). Last 20 patients randomized to treatment will receive tenecteplase 0.50 mg/kg (maximum 40 mg).
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo control
Intervention Type
Drug
Intervention Name(s)
Tenecteplase
Intervention Description
First 20 patients randomized to treatment arm will receive 0.25 mg/kg of tenecteplase. Next 20 patients randomized to treatment arm will receive 0.50 mg/kg of tenecteplase. Both will receive concomitant heparin to maintain activated partial thromboplastin time between 2.0 and 2.5 upper limit of normal.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Patients will receive placebo with concomitant heparin to maintain activated partial thromboplastin time between 2.0 and 2.5 upper limit of normal.
Primary Outcome Measure Information:
Title
Number of Participants Free of Respiratory Failure
Description
The number of patients free of respiratory failure defined as not requiring high flow nasal cannula, non-rebreather, noninvasive positive pressure ventilation, or mechanical ventilation at 28 days
Time Frame
28 Days
Title
Number of Participants With Occurrences of Bleeding
Description
Safety as assessed by number of participants with occurrences of intracranial bleeding or major bleeding
Time Frame
28 days
Secondary Outcome Measure Information:
Title
Number of Participants With In-hospital Deaths at 14 Days
Description
Number of patients who expired in the hospital within the first 14 days of their participation in the study
Time Frame
14 days
Title
Number of Participants With Death at 28 Days
Description
Number of participants who expired by 28 days/end of study
Time Frame
28 days
Title
Number of Ventilator-free Days
Description
Number of ventilator-free days in 28 days period
Time Frame
28 days
Title
Number of Respiratory Failure-free Days
Description
Respiratory failure-free defined as not requiring high flow nasal cannula, non-rebreather, noninvasive positive pressure ventilation, or mechanical ventilation. Number of respiratory failure-free days in 28 days period.
Time Frame
28 days
Title
Number of Vasopressor-free Days
Description
Number of vasopressor-free days over 28 days period
Time Frame
28 days
Title
Number of Vasopressor Doses at 24 Hours
Time Frame
24 hours and 72 hours
Title
P/F Ratio
Description
The P/F ratio equals the arterial pO2 ("P") from the ABG divided by the FIO2 ("F") - the fraction (percent) of inspired oxygen that the patient is receiving expressed as a decimal (40% oxygen = FIO2 of 0.40). Ratio of arterial pO2 over fraction of inspired oxygen that the person is receiving. Normal P/F Ratio is ≥ 400. 300 to 200 is considered mild ARDS 200 to 100 is considered moderate ARDS Anything below 100 is considered severe ARDS.
Time Frame
24 hours and 72 hours
Title
Number of ICU-free Days
Description
Number of days the patient spent outside the ICU
Time Frame
28 days
Title
Hospital Length of Stay
Description
Length of time the patient spent in the hospital, including ICU
Time Frame
up to 29 days
Title
Number of Participants With New-onset Renal Failure
Description
Number of patients who experienced renal failure during the course of the study
Time Frame
28 days
Title
Number of Participants With Need for Renal Replacement Therapy
Description
Number of patients who underwent renal replacement treatment for their renal failure
Time Frame
28 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Patient/legally authorized representative has completed the Informed Consent Form Age ≥18 years Ability to comply with the study protocol, in the investigator's judgment Respiratory failure secondary to COVID-19 requiring mechanical ventilation for no greater than 24 hours, or high-flow nasal cannula (HFNC),non-rebreather (NRB) mask or non-invasive positive pressure ventilation (NIPPV) for no greater than 48 hours Confirmed infection with SARS-CoV-2 virus (PCR positive within 14 days) Elevated D-dimer (>6 times upper limit of normal within past 72 hours) For patient who are intubated >12 hours prior to randomization or with any evidence of neurologic deficit a head CT within 12 hours demonstrating no evidence of acute or subacute infarct or hemorrhage Exclusion Criteria Current participation in another investigational drug study within the prior 7 days Known hypersensitivity or allergy to any ingredients of tenecteplase Active internal bleeding Known bleeding diathesis Use of one of the new oral anticoagulants within the last 48 hours (dabigatran, rivaroxaban, apixaban, edoxaban) Treatment with a thrombolytic within the last 3 months prior to randomization (exception for the use of Cathflo alteplase for occlusions of central venous catheters) Baseline platelet count <80,000/L (results must be available prior to treatment) Baseline blood glucose >400 mg/dL (22.20 mmol/L) Baseline blood glucose <50 mg/dL needs to be normalized prior to randomization Intracranial or intraspinal surgery or trauma within 2 months Other, non-COVID-19 related, serious, advanced, or terminal illness (investigator judgment) or life expectancy is less than 6 months History of acute ischemic stroke in the last 90 days History of intracranial bleeding, including hemorrhagic stroke Presumed septic embolus; suspicion of bacterial endocarditis Mechanical ventilation > 24 hours, HFNC, NRB, NIPPV, or any combination, for greater than 48 hours Mechanical ventilation, HFNC, NRB, or NIPVV (for reasons other than obstructive sleep apnea) within the prior 30 days (excluding 48 hours prior to randomization) Moribund status suggesting imminent vascular collapse and inability to survive > 72 hours (investigator determination) Uncontrolled hypertension defined as systolic BP > 180 mm Hg and/or diastolic BP > 110 mm Hgb Age > 75 years History of traumatic brain injury within 2 months Recent head trauma with fracture or brain injury History of Heparin Induced Thrombocytopenia (HIT) and/or other hereditary or acquired hemorrhagic diathesis or coagulation factor deficiency INR > 2 or recent oral anticoagulant therapy with INR >1.7 Pregnancy or lactation within the prior 30 days; women of childbearing age (<55 years old) should have documentation of a negative pregnancy test Chronic liver disease defined as > Childs-Pugh Class B Atrial fibrillation, mitral stenosis, or known left heart thrombosis Any other condition that, in the opinion of the investigator, precludes administration of tenecteplase or poses a significant hazard to the patient receives tenecteplase
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hooman Poor, MD
Organizational Affiliation
Icahn School of Medicine at Mount Sinai
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
J Mocco, MD
Organizational Affiliation
Icahn School of Medicine at Mount Sinai
Official's Role
Study Director
Facility Information:
Facility Name
Mount Sinai Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Tenecteplase in Patients With COVID-19

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