Clinical trial NCT04505592: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19
Respiratory Failure
ARDS
Keywords: COVID-19
ARDS
thrombolysis
tenecteplase
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2020-08-10
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of Participants Free of Respiratory Failure
timeFrame: 28 Days
measure: Number of Participants With Occurrences of Bleeding
timeFrame: 28 days
Secondary outcomes:
measure: Number of Participants With In-hospital Deaths at 14 Days
timeFrame: 14 days
measure: Number of Participants With Death at 28 Days
timeFrame: 28 days
measure: Number of Ventilator-free Days
timeFrame: 28 days
measure: Number of Respiratory Failure-free Days
timeFrame: 28 days
measure: Number of Vasopressor-free Days
timeFrame: 28 days
measure: Number of Vasopressor Doses at 24 Hours
timeFrame: 24 hours and 72 hours
measure: P/F Ratio
timeFrame: 24 hours and 72 hours
measure: Number of ICU-free Days
timeFrame: 28 days
measure: Hospital Length of Stay
timeFrame: up to 29 days
measure: Number of Participants With New-onset Renal Failure
timeFrame: 28 days
measure: Number of Participants With Need for Renal Replacement Therapy
timeFrame: 28 days
Other outcomes:
Locations:
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: Hooman Poor, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Icahn School of Medicine at Mount Sinai
name: J Mocco, MD
role: STUDY_DIRECTOR
References: