Safety and Efficacy of Therapeutic Anticoagulation on Clinical Outcomes in Hospitalized Patients With COVID-19

Sponsor

Massachusetts General Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT04377997

Collaborator

Bristol-Myers Squibb (Industry)

300

Enrollment

Location

Arms

24.5

Anticipated Duration (Months)

12.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The coronavirus disease 2019 (COVID-19) global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused considerable morbidity and mortality in over 170 countries. Increasing age and burden of cardiovascular comorbidities are associated with a worse prognosis among patients with COVID-19. In addition, serologic markers of more severe disease including coagulation abnormalities and thrombocytopenia, are not uncommon among patients hospitalized with severe COVID-19 infection and are more common in patients who died in-hospital. As the COVID-19 pandemic continues to grow, there is a pressing need to identify safe, effective, and widely available therapies that can be scaled and rapidly incorporated into clinical practice. Understanding the putative mechanism of increased mortality risk associated with abnormal coagulation function and cardiac injury is critical to guide studies of promising therapeutic interventions. Published and anecdotal reports indicate that endothelial dysfunction and thrombosis are common in critically ill patients with COVID-19, including reports of diffuse microvascular thrombosis in the lungs, heart, liver, and kidneys. Patients with cardiovascular disease (CVD) and CVD risk factors are known to have endothelial dysfunction and a heightened risk of thrombosis. A recent study of COVID-19 inpatients from Wuhan, China observed that an elevated D-dimer level greater than 1 ug/mL was associated with an 18 times higher risk of in-hospital death, underscoring the importance of increased coagulation activity as a potential modifiable risk marker that may drive end-organ injury. Given the established link between endothelial dysfunction and thrombosis in patients with cardiovascular disease, and the association between coagulopathy and adverse outcomes in patients with sepsis, the association between increased coagulation activity, end-organ injury, and mortality risk may represent a modifiable risk factor among COVID-19 patients with critical illness. Therefore, we propose to conduct a randomized, open-label trial of therapeutic anticoagulation in COVID-19 patients with an elevated D-dimer to evaluate the efficacy and safety.

Condition or Disease	Intervention/Treatment	Phase
Cardiovascular Diseases COVID-19	Drug: Enoxaparin	Phase 2

Detailed Description

For research purposes, 20mL of blood will be drawn and stored for biobanking at the following timepoints: at baseline (i.e., after enrollment and before randomization), 5-7 days post-randomization, and on the day of discharge.

After enrollment and blood collection, patients will then be randomized to therapeutic anticoagulation (LMWH for most subjects but UFH for those with morbid obesity or moderate to severe renal dysfunction as noted below) or standard of care.

Based on the MGH COVID-19 Treatment Guidance document, the risk stratification recommends daily complete blood count (CBC), comprehensive metabolic panel (CMP), creatine kinase (CPK), ferritin, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). In addition, PT, PTT, fibrinogen, and D-dimer are recommended to be checked every other day if in the ICU or daily if elevated. Given that by virtue of the inclusion criteria of our study (i.e., a D-dimer >1ug/mL), all of our patients will be within Category 3 and all of the above markers will be obtained for clinical purposes and thus will also be documented for research purposes. For clinical risk stratification, LDH is to be checked daily if elevated and troponin to be checked q2-3d if elevated. If clinically indicated, procalcitonin will be measured and IL-6 obtained in patients in Category 2 or 3 disease severity. If measured for clinical purposes, LDH, troponin, procalcitonin, and IL-6 will be recorded for research purposes.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

300 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

randomized 1:1randomized 1:1

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized, Open-Label Trial of Therapeutic Anticoagulation in COVID-19 Patients With an Elevated D-Dimer

Actual Study Start Date :

May 15, 2020

Anticipated Primary Completion Date :

Jun 1, 2022

Anticipated Study Completion Date :

Jun 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Therapeutic Anticoagulation Group Patients identified as eligible through discussions with the primary care team and review of the electronic medical record will be approached and consented as described above in "Subject Enrollment" and "Procedures for obtaining consent". For research purposes, 20ml of blood will be drawn and stored for biobanking at the following timepoints: at baseline (i.e., after enrollment and before randomization), 5-7 days post-randomization, and on the day of discharge. The blood sample taken at baseline will also be used to conduct a pregnancy test for women of childbearing age. After enrollment and blood collection, patients will then be randomized to therapeutic anticoagulation (LMWH for most subjects but UFH for those with morbid obesity or moderate to severe renal dysfunction as noted below) or standard of care anticoagulation. Those assigned to the therapeutic anticoagulation group will receive a higher dose of heparin.	Drug: Enoxaparin Given the established link between endothelial dysfunction and thrombosis in patients with cardiovascular disease9, 10 and the association between coagulopathy and adverse outcomes in patients with sepsis11, the association between increased coagulation activity, end-organ injury, and mortality risk may represent a modifiable risk factor among COVID-19 patients with critical illness. Therefore, we propose to conduct a randomized, open-label trial of therapeutic anticoagulation in COVID-19 patients with an elevated D-dimer to evaluate the efficacy. Most patients will receive low molecular weight heparin however, unfractionated heparin (UFH) will be administered for those with morbid obesity or moderate to severe renal dysfunction. Other Names: Heparin Low molecular weight heparin
Active Comparator: Standard of Care Anticoagulation Group Patients identified as eligible through discussions with the primary care team and review of the electronic medical record will be approached and consented as described above in "Subject Enrollment" and "Procedures for obtaining consent". For research purposes, 20ml of blood will be drawn and stored for biobanking at the following timepoints: at baseline (i.e., after enrollment and before randomization), 5-7 days post-randomization, and on the day of discharge. The blood sample taken at baseline will also be used to conduct a pregnancy test for women of childbearing age. After enrollment and blood collection, patients will then be randomized to therapeutic anticoagulation or standard of care anticoagulation. Those assigned to the standard of care anticoagulation group will receive the normal dose of heparin as per the Mass General guidelines.	Drug: Enoxaparin Given the established link between endothelial dysfunction and thrombosis in patients with cardiovascular disease9, 10 and the association between coagulopathy and adverse outcomes in patients with sepsis11, the association between increased coagulation activity, end-organ injury, and mortality risk may represent a modifiable risk factor among COVID-19 patients with critical illness. Therefore, we propose to conduct a randomized, open-label trial of therapeutic anticoagulation in COVID-19 patients with an elevated D-dimer to evaluate the efficacy. Most patients will receive low molecular weight heparin however, unfractionated heparin (UFH) will be administered for those with morbid obesity or moderate to severe renal dysfunction. Other Names: Heparin Low molecular weight heparin

Arm

Intervention/Treatment

Experimental: Therapeutic Anticoagulation Group

Patients identified as eligible through discussions with the primary care team and review of the electronic medical record will be approached and consented as described above in "Subject Enrollment" and "Procedures for obtaining consent". For research purposes, 20ml of blood will be drawn and stored for biobanking at the following timepoints: at baseline (i.e., after enrollment and before randomization), 5-7 days post-randomization, and on the day of discharge. The blood sample taken at baseline will also be used to conduct a pregnancy test for women of childbearing age. After enrollment and blood collection, patients will then be randomized to therapeutic anticoagulation (LMWH for most subjects but UFH for those with morbid obesity or moderate to severe renal dysfunction as noted below) or standard of care anticoagulation. Those assigned to the therapeutic anticoagulation group will receive a higher dose of heparin.

Drug: Enoxaparin

Given the established link between endothelial dysfunction and thrombosis in patients with cardiovascular disease9, 10 and the association between coagulopathy and adverse outcomes in patients with sepsis11, the association between increased coagulation activity, end-organ injury, and mortality risk may represent a modifiable risk factor among COVID-19 patients with critical illness. Therefore, we propose to conduct a randomized, open-label trial of therapeutic anticoagulation in COVID-19 patients with an elevated D-dimer to evaluate the efficacy. Most patients will receive low molecular weight heparin however, unfractionated heparin (UFH) will be administered for those with morbid obesity or moderate to severe renal dysfunction.

Other Names:

Heparin

Low molecular weight heparin

Active Comparator: Standard of Care Anticoagulation Group

Patients identified as eligible through discussions with the primary care team and review of the electronic medical record will be approached and consented as described above in "Subject Enrollment" and "Procedures for obtaining consent". For research purposes, 20ml of blood will be drawn and stored for biobanking at the following timepoints: at baseline (i.e., after enrollment and before randomization), 5-7 days post-randomization, and on the day of discharge. The blood sample taken at baseline will also be used to conduct a pregnancy test for women of childbearing age. After enrollment and blood collection, patients will then be randomized to therapeutic anticoagulation or standard of care anticoagulation. Those assigned to the standard of care anticoagulation group will receive the normal dose of heparin as per the Mass General guidelines.

Drug: Enoxaparin

Other Names:

Heparin

Low molecular weight heparin

Outcome Measures

Primary Outcome Measures

Number of patients with the composite efficacy endpoint of death, cardiac arrest, symptomatic deep venous thrombosis, pulmonary embolism, arterial thromboembolism, myocardial infarction, or hemodynamic shock. [12 weeks]
Aim 1 - Risk of death, cardiac arrest, symptomatic deep venous thrombosis, pulmonary embolism, arterial thromboembolism, myocardial infarction, or hemodynamic shock.
Number of patients with a major bleeding event according to the International Society on Thrombosis and Haemostasis (ISTH) definition. [12 weeks]
Aim 2 - Risk of major bleeding event according to the International Society on Thrombosis and Haemostasis (ISTH) definition.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion:

COVID-19 positive on admission or during hospitalization (having been tested within the past 5 days) with symptoms consistent with COVID-19 including fever (≥ 38C, 100.4F), pneumonia, symptoms of lower respiratory illness (e.g., cough, difficulty breathing), loss of smell or taste, myalgias, pharyngitis, or diarrhea
Admitted to the regular medical floor or intensive care unit (ICU) without severe ARDS (P/F ratio<100)
Elevated D-dimer (>1.5g/mL)
Age>18 years and not older than 90
Fibrinogen >100
Platelets >50,000
No prior intracranial hemorrhage or recent ischemic stroke or TIA within 6 months
D-dimer > 1500 ng/ml
No other clinical indication for therapeutic anticoagulation (e.g., deep vein thrombosis [DVT], pulmonary embolism [PE], atrial fibrillation, acute coronary syndromes, or extracorporeal membrane oxygenation)

Exclusion:

Disseminated intravascular coagulation (DIC) according to the International Society on Thrombosis and Hemostasis overt DIC definition
Hemoglobin (Hgb) <8 g/dl
Hypersensitivity to heparin or heparin formulation including heparin-induced thrombocytopenia
Thrombocytopenia: platelets<50,000 platelets/ul
Uncontrolled or active/recent bleeding including intracranial hemorrhage, signs of active bleeding (e.g., blood transfusion within 30 days), any GI bleed within the past 6 months, or internal bleeding within the past 1 month
High bleeding risk: significant closed-head or facial trauma within 3 months, traumatic or prolonged CPR (>10min), or use of dual anti-platelet therapy
Known or suspected pregnancy
Recent (<48 hours) or planned spinal or epidural anesthesia or puncture
If the patient is on other anticoagulants, antihistamines, nonsteroidal anti-inflammatory drugs (i.e. aspirin) or hydroxychloroquine
Uncontrolled hypertension