ARDS, COVID-19, Respiratory Failure
Conditions
Keywords
COVID-19, ARDS, thrombolysis, tenecteplase
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.
Interventions
DRUGTenecteplase
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.
DRUGPlacebo
Patients will receive placebo with concomitant heparin to maintain activated partial thromboplastin time between 2.0 and 2.5 upper limit of normal.
Sponsors
Genentech, Inc.
Hooman Poor
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Patients and study investigators will be blinded to subject treatment.
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Free of Respiratory Failure | 28 Days | 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 | 28 days | Safety as assessed by number of participants with occurrences of intracranial bleeding or major bleeding |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Ventilator-free Days | 28 days | Number of ventilator-free days in 28 days period |
| Number of Respiratory Failure-free Days | 28 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 | 28 days | Number of vasopressor-free days over 28 days period |
| Number of Vasopressor Doses at 24 Hours | 24 hours and 72 hours | — |
| Number of Participants With In-hospital Deaths at 14 Days | 14 days | Number of patients who expired in the hospital within the first 14 days of their participation in the study |
| Number of ICU-free Days | 28 days | Number of days the patient spent outside the ICU |
| Hospital Length of Stay | up to 29 days | Length of time the patient spent in the hospital, including ICU |
| Number of Participants With New-onset Renal Failure | 28 days | Number of patients who experienced renal failure during the course of the study |
| Number of Participants With Need for Renal Replacement Therapy | 28 days | Number of patients who underwent renal replacement treatment for their renal failure |
| P/F Ratio | 24 hours and 72 hours | 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 Participants With Death at 28 Days | 28 days | Number of participants who expired by 28 days/end of study |
Countries
United States
Participant flow
Recruitment details
Patients were recruited in a tertiary academic hospital in New York City.
Participants by arm
| Arm | Count |
|---|---|
| Tenecteplase Tenecteplase 0.25 mg/kg (maximum dose of 25 mg) And received concomitant heparin to maintain activated partial thromboplastin time between 2.0 and 2.5 upper limit of normal. | 8 |
| Placebo Patients received placebo with concomitant heparin to maintain activated partial thromboplastin time between 2.0 and 2.5 upper limit of normal. | 5 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 1 |
Baseline characteristics
| Characteristic | Total | Tenecteplase | Placebo |
|---|---|---|---|
| Age, Continuous | 69 years | 67.5 years | 71 years |
| Body Mass Index (BMI) | 31 kg/m^2 | 35 kg/m^2 | 26 kg/m^2 |
| Coronary Artery Disease (CAD) | 3 Participants | 3 Participants | 0 Participants |
| Diabetes | 3 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 8 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Hypertension | 9 Participants | 6 Participants | 3 Participants |
| Obstructive Sleep Apnea | 1 Participants | 1 Participants | 0 Participants |
| P/F Ratio | 83 Ratio | 80 Ratio | 87 Ratio |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 9 Participants | 6 Participants | 3 Participants |
| Remdesivir | 9 Participants | 7 Participants | 2 Participants |
| Respiratory Support high-flow nasal cannula (HFNC) | 7 Participants | 4 Participants | 3 Participants |
| Respiratory Support Mechanical ventilation | 1 Participants | 1 Participants | 0 Participants |
| Respiratory Support non-invasive positive pressure ventilation (NIPPV) | 5 Participants | 2 Participants | 3 Participants |
| Respiratory Support non-rebreather (NRB) | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 9 Participants | 7 Participants | 2 Participants |
| Steroids | 13 Participants | 8 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 8 | 1 / 5 |
| other Total, other adverse events | 3 / 8 | 2 / 5 |
| serious Total, serious adverse events | 4 / 8 | 4 / 5 |
Outcome results
Primary
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
Time frame: 28 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tenecteplase | Number of Participants Free of Respiratory Failure | 5 Participants |
| Placebo | Number of Participants Free of Respiratory Failure | 2 Participants |
Primary
Number of Participants With Occurrences of Bleeding
Safety as assessed by number of participants with occurrences of intracranial bleeding or major bleeding
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tenecteplase | Number of Participants With Occurrences of Bleeding | 2 Participants |
| Placebo | Number of Participants With Occurrences of Bleeding | 1 Participants |
Secondary
Hospital Length of Stay
Length of time the patient spent in the hospital, including ICU
Time frame: up to 29 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tenecteplase | Hospital Length of Stay | 11 days |
| Placebo | Hospital Length of Stay | 13 days |
Secondary
Number of ICU-free Days
Number of days the patient spent outside the ICU
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tenecteplase | Number of ICU-free Days | 1 days |
| Placebo | Number of ICU-free Days | 1 days |
Secondary
Number of Participants With Death at 28 Days
Number of participants who expired by 28 days/end of study
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tenecteplase | Number of Participants With Death at 28 Days | 2 Participants |
| Placebo | Number of Participants With Death at 28 Days | 1 Participants |
Secondary
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
Time frame: 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tenecteplase | Number of Participants With In-hospital Deaths at 14 Days | 2 Participants |
| Placebo | Number of Participants With In-hospital Deaths at 14 Days | 1 Participants |
Secondary
Number of Participants With Need for Renal Replacement Therapy
Number of patients who underwent renal replacement treatment for their renal failure
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tenecteplase | Number of Participants With Need for Renal Replacement Therapy | 0 Participants |
| Placebo | Number of Participants With Need for Renal Replacement Therapy | 2 Participants |
Secondary
Number of Participants With New-onset Renal Failure
Number of patients who experienced renal failure during the course of the study
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tenecteplase | Number of Participants With New-onset Renal Failure | 0 Participants |
| Placebo | Number of Participants With New-onset Renal Failure | 3 Participants |
Secondary
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.
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tenecteplase | Number of Respiratory Failure-free Days | 0.5 days |
| Placebo | Number of Respiratory Failure-free Days | 3 days |
Secondary
Number of Vasopressor Doses at 24 Hours
Time frame: 24 hours and 72 hours
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tenecteplase | Number of Vasopressor Doses at 24 Hours | 24 hours | 0 doses |
| Tenecteplase | Number of Vasopressor Doses at 24 Hours | 72 hours | 0 doses |
| Placebo | Number of Vasopressor Doses at 24 Hours | 72 hours | 0 doses |
| Placebo | Number of Vasopressor Doses at 24 Hours | 24 hours | 0 doses |
Secondary
Number of Vasopressor-free Days
Number of vasopressor-free days over 28 days period
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tenecteplase | Number of Vasopressor-free Days | 9 days |
| Placebo | Number of Vasopressor-free Days | 9 days |
Secondary
Number of Ventilator-free Days
Number of ventilator-free days in 28 days period
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tenecteplase | Number of Ventilator-free Days | 18 days |
| Placebo | Number of Ventilator-free Days | 19 days |
Secondary
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.
Time frame: 24 hours and 72 hours
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tenecteplase | P/F Ratio | 24 hours | 89 Ratio |
| Tenecteplase | P/F Ratio | 72 hours | 89 Ratio |
| Placebo | P/F Ratio | 24 hours | 97 Ratio |
| Placebo | P/F Ratio | 72 hours | 78 Ratio |