Covid19
Conditions
Brief summary
A multicenter, adaptive, randomized platform trial evaluating the efficacy and safety of antithrombotic strategies in patients with COVID-19 following hospital discharge
Detailed description
This study is an adaptive, prospective, randomized platform trial designed to compare the effectiveness and safety of antithrombotic therapy with no antithrombotic therapy after hospitalization for 48 hours or longer for COVID-19. For Stage 1 of this study, participants will be randomized to either prophylactic anticoagulation or matching placebo for 30 days, and then followed for an additional 60 days after the completion of treatment (total duration of follow-up, 90 days). The primary objective is to determine the most effective and safe antithrombotic strategy to prevent the composite outcome of symptomatic deep vein thrombosis, pulmonary embolism, other venous thromboembolism, ischemic stroke, myocardial infarction, other arterial thromboembolism, and all-cause mortality by 30 days following discharge from the hospital. Biobanking of samples for future biomarker and mechanistic studies will be available for centers able to participate and collect samples from eligible participants. Samples will be collected at the time of enrollment and after the completion of 30 days of therapy
Interventions
DRUGApixaban 2.5 MG
Participants will take Apixaban 2.5 MG twice a day, once in the morning and once in the evening for 30 days. Participants will be contacted (electronic or telephone) 2 days after starting the study medication and will continue up to day 90 after starting study treatment. Followup will occur from the time of discharge through the 30 day study period with contacts at 2 days, 10 days, 20 days and 30 days after discharge. Two additional study contacts will take place 45 days and 90 days after discharge.
DRUGPlacebo
Participants will take placebo twice a day, once in the morning and once in the evening for 30 days. Participants will be contacted (electronic or telephone) 2 days after starting the study medication and will continue up to day 90 after starting study treatment. Followup will occur from the time of discharge through the 30 day study period with contacts at 2 days, 10 days, 20 days and 30 days after discharge. Two additional study contacts will take place 45 days and 90 days after discharge.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Thomas L. Ortel
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double Blind
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* • Age ≥ 18 years * PCR-positive COVID-19 infection * Hospitalized for two or more days
Exclusion criteria
* Pre-existing indication for anticoagulation (e.g., pulmonary embolism or deep vein thrombosis; atrial fibrillation; mechanical cardiac valve) * Contraindication to antithrombotic therapy (e.g., known bleeding within the last 30 days requiring emergency room presentation or hospitalization; major surgery within 14 days; ischemic stroke, intracranial bleed or neurosurgery within 3 months. * Platelet count \< 50,000/mcL * Hemoglobin \<8 gm/dL * Renal insufficiency (eGFR \< 30 mL/min/1.73 m2) * Pregnancy * Prison inmate * Life expectancy less than 90 days * Unwilling or unable to provide informed consent/unwilling or unable to complete the study protocol * Dual antiplatelet therapy that cannot be discontinued * Concomitant need for strong inducers/inhibitors of p-gp or CYP3A4
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Outcome of Symptomatic Deep Vein Thrombosis, Pulmonary Embolism, Other Venous Thromboembolism, Ischemic Stroke, Myocardial Infarction, Other Arterial Thromboembolism, and All-cause Mortality as Measured by Hospital Records. | 30 days after hospital discharge | Composite endpoint (CE) of venous and arterial thrombotic complications-including new, symptomatic proximal, or distal DVT of the upper or lower extremities, PE, and new thrombosis of other veins (including cerebral sinus and splanchnic veins), ischemic stroke, myocardial infarction, other arterial thromboembolism (e.g., mesenteric or acute limb ischemia), and all-cause mortality by day 30. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Composite Outcome of All-cause Mortality and the EQ5D Index Score. | 90 days after hospital discharge | Composite endpoint of mortality and EQ5D index at Day 90. All mortality events will be considered worse than any possible EQ5D response. Death was designated as a score of 0. Scores range from 0 (where 0 is the value of a health state equivalent to dead) to 1 (the value of full health), with higher scores indicating higher health utility. |
| The Composite Outcome of Symptomatic Deep Vein Thrombosis, Pulmonary Embolism, Other Venous Thromboembolism, Ischemic Stroke, Myocardial Infarction, Other Arterial Thromboembolism, and All-cause Mortality as Measured by Hospital Records. | 45 days after hospital discharge | — |
| New, Symptomatic VTE (Inclusive of DVT, PE, or Other Venous Thrombosis) for up to 30 Days After Randomization as Measured by Hospital Records. | 30 days after randomization (which occurred at time of hospital discharge) | — |
| New, Symptomatic ATE (Inclusive of Ischemic Stroke, MI, or Peripheral Arterial Thromboembolism) for up to 30 Days After Randomization as Measured by Hospital Records. | 30 days after randomization (which occurred at time of hospital discharge) | — |
| The Composite Outcome of All-cause Mortality and the EuroQoL Group 5-Dimension (EQ5D) Index Score. | 30 days after hospital discharge | Composite endpoint of mortality and EQ5D index at Day 30. All mortality events will be considered worse than any possible EQ5D response \[QOL&M30\]. Death was designated as a score of 0. Scores range from 0 (where 0 is the value of a health state equivalent to dead) to 1 (the value of full health), with higher scores indicating higher health utility. |
Other
| Measure | Time frame |
|---|---|
| The Individual Domains of EQ5D and the EQ5D Visual Analog Scale for 30 and 90 Days After Randomization | 30 and 90 days following discharge from hospital |
| The Incidence of All-cause Rehospitalization for up to 90 Days After Randomization | 90 days following discharge from hospital |
| Percentage of Participants With All-cause Mortality | 30 days following discharge from hospital |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Drug: Placebo Participants will be given study medication at the time of discharge from the hospital. Participants will take the Placebo twice a day, once in the morning and once in the evening, for 30 days. Participants will be contacted (electronic or telephone) 2 days after starting the study medication and contact will continue up to day 90 after starting study treatment. Follow up will be through electronic and/or telephone contact depending on the participant's preference, compliance, and medication adherence. Participants will be queried for any clinically relevant endpoints, especially major bleeding or a need to seek healthcare attention for any reason. Follow-up will occur from the time of discharge and through the 30 day study period, with contacts 2 days, 10 days, 20 days, and 30 days after discharge. Two additional study contacts will take place 45 days and 90 days after discharge.
Placebo: Participants will take placebo twice a day, once in the morning and once in the evening for 30 days. Participants will be contacted (electronic or telephone) 2 days after starting the study medication and will continue up to day 90 after starting study treatment. Followup will occur from the time of discharge through the 30 day study period with contacts at 2 days, 10 days, 20 days and 30 days after discharge. Two additional study contacts will take place 45 days and 90 days after discharge. | 607 |
| Apixaban Drug: Apixaban 2.5 MG Participants will be given study medication at the time of discharge from the hospital. Participants will take Apixaban 2.5 MG twice a day, once in the morning and once in the evening, for 30 days. Participants will be contacted (electronic or telephone) 2 days after starting the study medication and contact will continue up to day 90 after starting study treatment. Follow up will be through electronic and/or telephone contact depending on the participant's preference, compliance, and medication adherence. Participants will be queried for any clinically relevant endpoints, especially major bleeding or a need to seek healthcare attention for any reason. Follow-up will occur from the time of discharge and through the 30 day study period, with contacts 2 days, 10 days, 20 days, and 30 days after discharge. Two additional study contacts will take place 45 days and 90 days after discharge.
Apixaban 2.5 MG: Participants will take Apixaban 2.5 MG twice a day, once in the morning and once in the evening for 30 days. Participants will be contacted (electronic or telephone) 2 days after starting the study medication and will continue up to day 90 after starting study treatment. Followup will occur from the time of discharge through the 30 day study period with contacts at 2 days, 10 days, 20 days and 30 days after discharge. Two additional study contacts will take place 45 days and 90 days after discharge. | 610 |
| Total | 1,217 |
Baseline characteristics
| Characteristic | Placebo | Apixaban | Total |
|---|---|---|---|
| Age, Continuous | 54.1 years | 54.1 years | 54.1 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 103 Participants | 100 Participants | 203 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 484 Participants | 487 Participants | 971 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 20 Participants | 23 Participants | 43 Participants |
| Medical history of Deep Vein Thrombosis (DVT) | 7 Participants | 6 Participants | 13 Participants |
| Medical History of Pulmonary Embolism (PE) | 3 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized Aboriginal or First Nations | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 4 Participants | 6 Participants | 10 Participants |
| Race/Ethnicity, Customized Asian | 12 Participants | 10 Participants | 22 Participants |
| Race/Ethnicity, Customized Black or African American | 154 Participants | 168 Participants | 322 Participants |
| Race/Ethnicity, Customized Middle Eastern or North African | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized More than one race | 3 Participants | 5 Participants | 8 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 5 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized Other Race | 20 Participants | 23 Participants | 43 Participants |
| Race/Ethnicity, Customized Unknown | 46 Participants | 45 Participants | 91 Participants |
| Race/Ethnicity, Customized White | 363 Participants | 350 Participants | 713 Participants |
| Region of Enrollment United States | 607 participants | 610 participants | 1217 participants |
| Sex: Female, Male Female | 303 Participants | 311 Participants | 614 Participants |
| Sex: Female, Male Male | 304 Participants | 299 Participants | 603 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 12 / 610 | 9 / 607 |
| other Total, other adverse events | 80 / 610 | 90 / 607 |
| serious Total, serious adverse events | 71 / 610 | 66 / 607 |
Outcome results
Primary
Composite Outcome of Symptomatic Deep Vein Thrombosis, Pulmonary Embolism, Other Venous Thromboembolism, Ischemic Stroke, Myocardial Infarction, Other Arterial Thromboembolism, and All-cause Mortality as Measured by Hospital Records.
Composite endpoint (CE) of venous and arterial thrombotic complications-including new, symptomatic proximal, or distal DVT of the upper or lower extremities, PE, and new thrombosis of other veins (including cerebral sinus and splanchnic veins), ischemic stroke, myocardial infarction, other arterial thromboembolism (e.g., mesenteric or acute limb ischemia), and all-cause mortality by day 30.
Time frame: 30 days after hospital discharge
Population: intention-to-treat (ITT) population, including all participants randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Composite Outcome of Symptomatic Deep Vein Thrombosis, Pulmonary Embolism, Other Venous Thromboembolism, Ischemic Stroke, Myocardial Infarction, Other Arterial Thromboembolism, and All-cause Mortality as Measured by Hospital Records. | 2.31 percentage of participants |
| Apixaban | Composite Outcome of Symptomatic Deep Vein Thrombosis, Pulmonary Embolism, Other Venous Thromboembolism, Ischemic Stroke, Myocardial Infarction, Other Arterial Thromboembolism, and All-cause Mortality as Measured by Hospital Records. | 2.13 percentage of participants |
95% CI: [0.44, 1.95]
Secondary
New, Symptomatic ATE (Inclusive of Ischemic Stroke, MI, or Peripheral Arterial Thromboembolism) for up to 30 Days After Randomization as Measured by Hospital Records.
Time frame: 30 days after randomization (which occurred at time of hospital discharge)
Population: intention-to-treat (ITT) population, including all participants randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | New, Symptomatic ATE (Inclusive of Ischemic Stroke, MI, or Peripheral Arterial Thromboembolism) for up to 30 Days After Randomization as Measured by Hospital Records. | 0.49 percentage of participants |
| Apixaban | New, Symptomatic ATE (Inclusive of Ischemic Stroke, MI, or Peripheral Arterial Thromboembolism) for up to 30 Days After Randomization as Measured by Hospital Records. | 0.16 percentage of participants |
95% CI: [0.03, 3.18]
Secondary
New, Symptomatic VTE (Inclusive of DVT, PE, or Other Venous Thrombosis) for up to 30 Days After Randomization as Measured by Hospital Records.
Time frame: 30 days after randomization (which occurred at time of hospital discharge)
Population: intention-to-treat (ITT) population, including all participants randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | New, Symptomatic VTE (Inclusive of DVT, PE, or Other Venous Thrombosis) for up to 30 Days After Randomization as Measured by Hospital Records. | 0.82 percentage of participants |
| Apixaban | New, Symptomatic VTE (Inclusive of DVT, PE, or Other Venous Thrombosis) for up to 30 Days After Randomization as Measured by Hospital Records. | 0.82 percentage of participants |
95% CI: [0.29, 3.42]
Secondary
The Composite Outcome of All-cause Mortality and the EQ5D Index Score.
Composite endpoint of mortality and EQ5D index at Day 90. All mortality events will be considered worse than any possible EQ5D response. Death was designated as a score of 0. Scores range from 0 (where 0 is the value of a health state equivalent to dead) to 1 (the value of full health), with higher scores indicating higher health utility.
Time frame: 90 days after hospital discharge
Population: intention-to-treat (ITT) population, including all participants randomized
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | The Composite Outcome of All-cause Mortality and the EQ5D Index Score. | 0.94 score on a scale |
| Apixaban | The Composite Outcome of All-cause Mortality and the EQ5D Index Score. | 0.94 score on a scale |
95% CI: [0.78, 1.24]
Secondary
The Composite Outcome of All-cause Mortality and the EuroQoL Group 5-Dimension (EQ5D) Index Score.
Composite endpoint of mortality and EQ5D index at Day 30. All mortality events will be considered worse than any possible EQ5D response \[QOL&M30\]. Death was designated as a score of 0. Scores range from 0 (where 0 is the value of a health state equivalent to dead) to 1 (the value of full health), with higher scores indicating higher health utility.
Time frame: 30 days after hospital discharge
Population: intention-to-treat (ITT) population, including all participants randomized
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | The Composite Outcome of All-cause Mortality and the EuroQoL Group 5-Dimension (EQ5D) Index Score. | 0.93 score on a scale |
| Apixaban | The Composite Outcome of All-cause Mortality and the EuroQoL Group 5-Dimension (EQ5D) Index Score. | 0.93 score on a scale |
95% CI: [0.83, 1.31]
Secondary
The Composite Outcome of Symptomatic Deep Vein Thrombosis, Pulmonary Embolism, Other Venous Thromboembolism, Ischemic Stroke, Myocardial Infarction, Other Arterial Thromboembolism, and All-cause Mortality as Measured by Hospital Records.
Time frame: 90 days after hospital discharge
Population: intention-to-treat (ITT) population, including all participants randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Composite Outcome of Symptomatic Deep Vein Thrombosis, Pulmonary Embolism, Other Venous Thromboembolism, Ischemic Stroke, Myocardial Infarction, Other Arterial Thromboembolism, and All-cause Mortality as Measured by Hospital Records. | 2.80 percentage of participants |
| Apixaban | The Composite Outcome of Symptomatic Deep Vein Thrombosis, Pulmonary Embolism, Other Venous Thromboembolism, Ischemic Stroke, Myocardial Infarction, Other Arterial Thromboembolism, and All-cause Mortality as Measured by Hospital Records. | 3.11 percentage of participants |
95% CI: [0.58, 2.12]
Secondary
The Composite Outcome of Symptomatic Deep Vein Thrombosis, Pulmonary Embolism, Other Venous Thromboembolism, Ischemic Stroke, Myocardial Infarction, Other Arterial Thromboembolism, and All-cause Mortality as Measured by Hospital Records.
Time frame: 45 days after hospital discharge
Population: intention-to-treat (ITT) population, including all participants randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Composite Outcome of Symptomatic Deep Vein Thrombosis, Pulmonary Embolism, Other Venous Thromboembolism, Ischemic Stroke, Myocardial Infarction, Other Arterial Thromboembolism, and All-cause Mortality as Measured by Hospital Records. | 2.80 percentage of participants |
| Apixaban | The Composite Outcome of Symptomatic Deep Vein Thrombosis, Pulmonary Embolism, Other Venous Thromboembolism, Ischemic Stroke, Myocardial Infarction, Other Arterial Thromboembolism, and All-cause Mortality as Measured by Hospital Records. | 2.46 percentage of participants |
95% CI: [0.44, 1.74]
Other Pre-specified
Percentage of Participants With All-cause Mortality
Time frame: 30 days following discharge from hospital
Population: intention-to-treat (ITT) population, including all participants randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With All-cause Mortality | 1.48 percentage of participants |
| Apixaban | Percentage of Participants With All-cause Mortality | 1.31 percentage of participants |
95% CI: [0.34, 2.28]
Other Pre-specified
The Incidence of All-cause Rehospitalization for up to 90 Days After Randomization
Time frame: 90 days following discharge from hospital
Other Pre-specified
The Individual Domains of EQ5D and the EQ5D Visual Analog Scale for 30 and 90 Days After Randomization
Time frame: 30 and 90 days following discharge from hospital