Recruiting
Phase 2

Anticoagulation

Sponsor:

Massachusetts General Hospital

Code:

NCT04377997

Conditions

Cardiovascular Diseases

COVID-19

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

Enoxaparin

Study Details

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.

Conditions

Cardiovascular Diseases

COVID-19

Study ID

NCT04377997

Start date

May 15, 2020

Status verified date

Feb, 2022

Completion date

Jun 1, 2022

Anticipated

Primary completion date

Jun 1, 2022

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

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

Study Design

Enrollment

300 participants

Anticipated

Allocation

Randomized

Intervention Model

Parallel Assignment

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

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.

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.

Interventions

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.

Primary outcome measure

  • 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. [ Time Frame: 12 weeks ]
  • Number of patients with a major bleeding event according to the International Society on Thrombosis and Haemostasis (ISTH) definition. [ Time Frame: 12 weeks ]

Central Contacts and Locations

Central contacts

Rahul Sakhuja, MD

617-643-2403RSAKHUJA@PARTNERS.ORG

Abdurahman Khalil

617-643-1452akhalil1@mgh.harvard.edu

Locations

Abdurahman Khalil

Recruiting

Boston, Massachusetts, United States, 02114

Contacts

Abdurahman Khalil

617-643-1452akhalil1@mgh.harvard.edu

Rahul Sakhuja, MD

617-643-2403rsakhuja@partners.org

More Information

Sponsor

Massachusetts General Hospital

Last update posted

Feb 22, 2022

Last verified

Feb, 2022

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by Massachusetts General Hospital on 2022-02-22.