COVID-19
Conditions
Keywords
COVID-19, Anticoagulation
Brief summary
The purpose of this study is to determine if therapeutic dose anticoagulation (experimental group) improves 30-day mortality in participants with COVID-19 compared to those patients receiving the intermediate dose prophylaxis (control group). Following screening, subjects will be randomized 1:1 to intermediate dose prophylaxis or therapeutic dose anticoagulation treatment arms.Treatment will continue for 28 days, followed by a 6 month follow-up period.
Interventions
DRUGEnoxaparin sodium
Intermediate Dose Prophylaxis Arm: 0.5 mg/kg subcutaneously every 12 hours if creatinine clearance greater than or equal to 30 ml/min --OR-- 0.5 mg/kg subcutaneously every 24 hours if creatinine clearance less than 30 ml/min Therapeutic Dose Anticoagulation Arm: 1 mg/kg subcutaneously every 12 hours
DRUGUnfractionated heparin
Intermediate Dose Prophylaxis Arm: 7,500 units subcutaneously every 8 hours Therapeutic Dose Anticoagulation Arm: Dosed to target anti-Xa level 0.3 - 0.7 IU/mL or activated partial thromboplastin time (aPTT), according to institutional protocol
DRUGFondapariniux
Intermediate Dose Prophylaxis Arm: 2.5 mg daily subcutaneously Therapeutic Dose Anticoagulation Arm: Dose by weight: * If greater than or equal to 100 kg: 10 mg daily * If less than 100 kg but greater than or equal to 50 kg: 7.5 mg daily * If less than 50 kg: 5 mg daily
DRUGArgatroban
Therapeutic Dose Anticoagulation Arm: Dosed according to institutional protocol
Sponsors
Weill Medical College of Cornell University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \>18 years old * COVID-19 positive on (RT-PCR) nasopharyngeal swab, or suspected COVID-19 infection with detectable SARS-CoV-2 IgG or IgM. * Intensive care unit (ICU) patient or non-ICU patient on invasive mechanical ventilation, BiPAP, 100% non-rebreather mask, or high flow oxygen or supplemental oxygen of at least 4 liters per minute nasal cannula. * D dimer level greater than 700 ng/mL (3 times the upper limit of normal).
Exclusion criteria
* Objectively documented deep vein thrombosis or pulmonary embolism * Patients in whom there is very high suspicion for pulmonary embolism and are on full-dose anticoagulation as per the treating physician * Platelets \<30,000 not due to disseminated intravascular coagulation (DIC), based on the International Society of Thrombosis and Haemostasis (ISTH) criteria and American Society of Hematology (ASH) Frequently Asked Questions * Active bleeding that poses a contraindication to therapeutic anticoagulation in the opinion of the investigator. * History of bleeding diathesis (e.g., hemophilia, severe von Willebrand disease, severe thrombocytopathy) * History of intracranial hemorrhage in the last 90 days * History of ischemic stroke in the past 2 weeks * Major neurosurgical procedure in the past 30 days * Cardiothoracic surgery in the past 30 days * Intra-abdominal surgery in the past 30 days * Intracranial malignancy * Patients who require therapeutic anticoagulation for other reasons like atrial fibrillation, deep venous thrombosis, pulmonary embolism, or antiphospholipid syndrome.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 30-day Mortality | 30 days | Comparison of number of COVID-19 positive patients who have died within 30 days of starting treatment on each treatment arm |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Length of Intensive Care Unit (ICU) Stay in Days | 6 months | Comparison of length of ICU stay in days between each treatment arm. |
| Number of Documented Venous Thromboembolism (VTE), Arterial Thrombosis (Stroke, Myocardial Infarction, Other) and Microthrombosis Events | 6 months | Comparison of number of documented VTE, arterial thrombosis and microthrombosis events on each treatment arm |
| Number of Major and Clinically Relevant Non-major Bleeding Events | 6 months | Comparison of major and clinically-relevant non-major bleeding events on each treatment arm, as defined by the International Society of Thrombosis and Haemostasis (ISTH) criteria. |
Countries
United States
Participant flow
Pre-assignment details
1 subject signed consent but failed screening and was not randomized.
Participants by arm
| Arm | Count |
|---|---|
| Intermediate Dose Prophylaxis Subjects will receive one of the following interventions, at their physician's discretion:
* Enoxaparin 0.5 mg/kg subcutaneously every 12 hours if creatinine clearance greater than or equal to 30 ml/min
* Enoxaparin 0.5 mg/kg subcutaneously every 24 hours if creatinine clearance less than 30 mL/min
* If patient develops acute kidney injury: unfractionated heparin 7,500 units subcutaneously every 8 hours.
* Fondaparinux (if history of heparin-inducted thrombocytopenia \[HIT\]) 2.5 mg daily subcutaneously
Enoxaparin sodium: Intermediate Dose Prophylaxis Arm:
0.5 mg/kg subcutaneously every 12 hours if creatinine clearance greater than or equal to 30 ml/min --OR-- 0.5 mg/kg subcutaneously every 24 hours if creatinine clearance less than 30 ml/min
Therapeutic Dose Anticoagulation Arm:
1 mg/kg subcutaneously every 12 hours
Unfractionated heparin: Intermediate Dose Prophylaxis Arm:
7,500 units subcutaneously every 8 hours
Therapeutic Dose Anticoagulation Arm:
Dosed to target anti-Xa level 0.3 - 0.7 IU/mL or activated partial thromboplastin time (aPTT), according to institutional protocol
Fondapariniux: Intermediate Dose Prophylaxis Arm:
2.5 mg daily subcutaneously
Therapeutic Dose Anticoagulation Arm:
Dose by weight:
* If greater than or equal to 100 kg: 10 mg daily
* If less than 100 kg but greater than or equal to 50 kg: 7.5 mg daily
* If less than 50 kg: 5 mg daily | 4 |
| Therapeutic Dose Anticoagulation Subjects will receive one of the following interventions, at their physician's discretion:
* Unfractionated heparin (UFH) to target anti-Xa level 0.3 -0.7 IU/mL or activated partial thromboplastin time (aPTT) (according to institutional protocol).
* Enoxaparin 1 mg/kg subcutaneously every 12 hours
* Argatroban (if heparin-induced thrombocytopenia \[HIT\]), dosed according to institutional protocol.
* Fondaparinux (if HIT and creatinine clearance greater than or equal to 50 ml/min) dosed by weight:
* 100kg: 10 mg daily \<100kg but ≥50 kg: 7.5 mg daily \<50kg: 5 mg daily
Enoxaparin sodium: Intermediate Dose Prophylaxis Arm:
0.5 mg/kg subcutaneously every 12 hours if creatinine clearance greater than or equal to 30 ml/min, OR 0.5 mg/kg subcutaneously every 24 hours if creatinine clearance less than 30 ml/min
Therapeutic Dose Anticoagulation Arm:
1 mg/kg subcutaneously every 12 hours
Unfractionated heparin: Intermediate Dose Prophylaxis Arm:
7,500 units subcutaneously every 8 hours
Therapeutic Dose Anticoagulation Arm:
Dosed to target anti-Xa level 0.3 - 0.7 IU/mL or activated partial thromboplastin time (aPTT), according to institutional protocol
Fondapariniux: Intermediate Dose Prophylaxis Arm:
2.5mg daily subcutaneously
Therapeutic Dose Anticoagulation Arm:
Dose by weight:
≥100kg: 10 mg daily \<100kg but ≥50 kg: 7.5 mg daily \<50kg: 5 mg daily
Argatroban: Therapeutic Dose Anticoagulation Arm:
Dosed according to institutional protocol | 10 |
| Total | 14 |
Baseline characteristics
| Characteristic | Intermediate Dose Prophylaxis | Total | Therapeutic Dose Anticoagulation |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 8 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 6 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 8 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 2 Participants |
| 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 | 2 Participants | 2 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 | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) White | 3 Participants | 8 Participants | 5 Participants |
| Region of Enrollment United States | 4 participants | 14 participants | 10 participants |
| Respiratory Support at Time of Randomization High Flow Nasal Cannula or Non-Invasive Ventilation (>15 L/min) | 1 Participants | 7 Participants | 6 Participants |
| Respiratory Support at Time of Randomization Invasive Mechanical Ventilation or ECMO | 1 Participants | 3 Participants | 2 Participants |
| Respiratory Support at Time of Randomization Supplemental Oxygen (<15L/min) | 2 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 8 Participants | 6 Participants |
| Subject Location at Time of Randomization Intensive Care Unit | 2 Participants | 8 Participants | 6 Participants |
| Subject Location at Time of Randomization Ward | 2 Participants | 6 Participants | 4 Participants |
| Vasopressor Support at Time of Randomization Subjects not on Vasopressor Support | 4 Participants | 12 Participants | 8 Participants |
| Vasopressor Support at Time of Randomization Subjects on Vasopressor Support | 0 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 4 / 10 |
| other Total, other adverse events | 1 / 4 | 5 / 10 |
| serious Total, serious adverse events | 1 / 4 | 4 / 10 |
Outcome results
Primary
30-day Mortality
Comparison of number of COVID-19 positive patients who have died within 30 days of starting treatment on each treatment arm
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intermediate Dose Prophylaxis | 30-day Mortality | 0 Participants |
| Therapeutic Dose Anticoagulation | 30-day Mortality | 2 Participants |
Secondary
Length of Intensive Care Unit (ICU) Stay in Days
Comparison of length of ICU stay in days between each treatment arm.
Time frame: 6 months
Population: This outcome measure is only assessing participants that had an ICU stay while participating in the study. Participants that never had an ICU stay are excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intermediate Dose Prophylaxis | Length of Intensive Care Unit (ICU) Stay in Days | 25.5 Days |
| Therapeutic Dose Anticoagulation | Length of Intensive Care Unit (ICU) Stay in Days | 25 Days |
Secondary
Number of Documented Venous Thromboembolism (VTE), Arterial Thrombosis (Stroke, Myocardial Infarction, Other) and Microthrombosis Events
Comparison of number of documented VTE, arterial thrombosis and microthrombosis events on each treatment arm
Time frame: 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intermediate Dose Prophylaxis | Number of Documented Venous Thromboembolism (VTE), Arterial Thrombosis (Stroke, Myocardial Infarction, Other) and Microthrombosis Events | Venous Thromboembolism Events | 1 Count of Events |
| Intermediate Dose Prophylaxis | Number of Documented Venous Thromboembolism (VTE), Arterial Thrombosis (Stroke, Myocardial Infarction, Other) and Microthrombosis Events | Arterial Thrombosis Events | 1 Count of Events |
| Intermediate Dose Prophylaxis | Number of Documented Venous Thromboembolism (VTE), Arterial Thrombosis (Stroke, Myocardial Infarction, Other) and Microthrombosis Events | Microthrombosis Events | 0 Count of Events |
| Therapeutic Dose Anticoagulation | Number of Documented Venous Thromboembolism (VTE), Arterial Thrombosis (Stroke, Myocardial Infarction, Other) and Microthrombosis Events | Venous Thromboembolism Events | 0 Count of Events |
| Therapeutic Dose Anticoagulation | Number of Documented Venous Thromboembolism (VTE), Arterial Thrombosis (Stroke, Myocardial Infarction, Other) and Microthrombosis Events | Arterial Thrombosis Events | 0 Count of Events |
| Therapeutic Dose Anticoagulation | Number of Documented Venous Thromboembolism (VTE), Arterial Thrombosis (Stroke, Myocardial Infarction, Other) and Microthrombosis Events | Microthrombosis Events | 1 Count of Events |
Secondary
Number of Major and Clinically Relevant Non-major Bleeding Events
Comparison of major and clinically-relevant non-major bleeding events on each treatment arm, as defined by the International Society of Thrombosis and Haemostasis (ISTH) criteria.
Time frame: 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intermediate Dose Prophylaxis | Number of Major and Clinically Relevant Non-major Bleeding Events | Major Bleeding Events | 1 Count of Events |
| Intermediate Dose Prophylaxis | Number of Major and Clinically Relevant Non-major Bleeding Events | Clinically Relevant Non-Major Bleeding Events | 1 Count of Events |
| Therapeutic Dose Anticoagulation | Number of Major and Clinically Relevant Non-major Bleeding Events | Major Bleeding Events | 1 Count of Events |
| Therapeutic Dose Anticoagulation | Number of Major and Clinically Relevant Non-major Bleeding Events | Clinically Relevant Non-Major Bleeding Events | 2 Count of Events |