Endothelial injury as a consequence of SARS-CoV-2 infection leads to a dysregulated host inflammatory response and activation of coagulation pathways. Macro- and micro-vascular thrombosis may contribute to morbidity, organ failure, and death. Therapeutic anticoagulation with heparin may improve clinical outcomes in patients with COVID-19 through anti-thrombotic, anti-inflammatory, and anti-viral activities of heparins. This pragmatic, Bayesian adaptive randomized controlled trial will determine whether therapeutic anticoagulation with heparin (subcutaneous low molecular weight heparin or intravenous unfractionated heparin) versus usual care reduces the need for intubation or death in hospitalized patients with COVID-19. The trial uses an adaptive design which was chosen to overcome limitations in available data to inform a priori estimation of event rates and possible effect sizes. The adaptive design also includes response-adaptive randomization based on baseline D-dimer level, probing for differential efficacy across subgroups defined based on initial D-dimer level. This Bayesian adaptive randomized trial will stop at a conclusion 1) when the posterior probability that the proportional odds ratio is greater than 1.0 reaches 99% (definition of benefit); 2) when the posterior probability that the proportional odds ratio is greater than 1.2 is less than 10% (definition of futility) or; 3) when the posterior probability that the proportional odds ratio is less than 1.0 is greater than 90% (definition of harm). The trial will enroll a maximum of 3,000 patients, although in many simulations the trial may require fewer patients. The trial is strategically aligned with the international REMAP-CAP/COVID platform trial to accelerate evidence generation.
This is a prospective, open-label, multicentre, Bayesian adaptive randomized clinical trial to establish whether therapeutic-dose parenteral anticoagulation improves outcomes for patients hospitalized with COVID-19 (e.g., reduces intubation or mortality). Participants will be randomized either to the investigational arm (therapeutic anticoagulation with heparin for 14 days or until "recovery" \[defined as hospital discharge or liberation from supplemental oxygen if initially required\], whichever comes first), or to the control arm (usual care, including thromboprophylactic dose anticoagulation according to local practice).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1,200
Low molecular weight heparin (LMWH) Preferred therapeutic anticoagulant is enoxaparin. Generally regimens: 1.5 mg/kg subcutaneous once daily or 1 mg/kg subcutaneous twice daily. Alternatively, other subcutaneous LMWH used, including tinzaparin (175 anti-Xa IU/kg subcutaneous once daily) or dalteparin (200 IU/kg subcutaneous once daily or 100 IU/kg subcutaneous twice a day). Unfractionated heparin (UFH) Commenced, administered, and monitored according to local hospital policy, and guidelines that are used for the treatment of venous thromboembolism (i.e. not for acute coronary syndrome). Intravenous infusion of UFH is according to total body weight and pragmatically adjusted according to local institutional policy to achieve an activated partial thromboplastin time (aPTT) of 1.5-2.5x the reference value. If UFH is used, the availability of a local hospital policy that has specifies an aPTT target in this range or an anti-Xa value is a requirement.
Emory University Hospital Midtown
Atlanta, Georgia, United States
University of Chicago
Chicago, Illinois, United States
Ochsner Clinic
Jefferson, Louisiana, United States
Maine Medical Center
Portland, Maine, United States
Henry Ford University
Dearborn, Michigan, United States
Beaumont Hospital
Mortality and days free of organ support
The primary endpoint in the trial is days alive and free of organ support at day 21. This endpoint is defined as the number of days that a patient is alive and free of organ support through the first 21 days after trial entry. Organ support is defined as receipt of invasive or non-invasive mechanical ventilation, high flow nasal oxygen (\>30 L/min), vasopressor therapy, or ECMO support. Death at any time (including beyond 21 days) during the index hospital stay is assigned the worst possible score of -1.
Time frame: 21 days
Arterial and venous thrombotic conditions
A composite endpoint of death, deep vein thrombosis, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke collected during hospitalization or at 28 days and 90 days after enrollment (whichever is earlier).
Time frame: 28 days and 90 days
Intubation and mortality
Ordered categorical endpoint with three possible outcomes based on the worst status of each patient through day 30 following randomization: no invasive mechanical ventilation, invasive mechanical ventilation, or death.
Time frame: 30 days
All-cause mortality
Time frame: 28 days and 90 days
Intubation
Invasive mechanical ventilation.
Time frame: 30 days
Hospital-free days
Days alive outside of the hospital through 28 days following randomization.
Time frame: 28 days
Ventilator-free days
Days alive not on a ventilator assessed at 28 days following randomization.
Time frame: 28 days
Myocardial infarction
Time frame: 28 days and 90 days
Ischaemic stroke
Time frame: 28 days and 90 days
Venous thromboembolism
Symptomatic proximal venous thromboembolism (DVT or PE).
Time frame: 28 days and 90 days
Vasopressor-free days
Days alive not on a vasopressor assessed at 28 days following randomization.
Time frame: 28 days
Renal replacement free days
Days alive not on renal replacement assessed at 28 days following randomization.
Time frame: 28 days
Hospital re-admission
Hospital re-admission within 28 days.
Time frame: 28 days
Acute kidney injury
As defined by KDIGO criteria.
Time frame: Duration of study
Systemic arterial thrombosis or embolism
Time frame: 28 days and 90 days
ECMO support
Use of extracorporeal membrane oxygenation (ECMO) support.
Time frame: Duration of study
Mechanical circuit thrombosis
Dialysis or ECMO.
Time frame: Duration of study
WHO ordinal scale
Peak scale over 28 days, scale at 14 days, and proportion with improvement by at least 2 categories compared to enrollment, at 28 days.
Time frame: 28 days
Major bleeding
As defined by the International Society on Thrombosis and Haemostasis (ISTH).
Time frame: Intervention period (maximum 14 days)
Heparin-induced thrombocytopenia (HIT)
Laboratory-confirmed.
Time frame: Intervention period (maximum 14 days)
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Royal Oak, Michigan, United States
Mayo Clinic
Rochester, Minnesota, United States
Saint Louis University School of Medicine/Saint Louis Veterans Affairs Medical Center
St Louis, Missouri, United States
Cooper University Health Care
Camden, New Jersey, United States
Hackensack University Medical Center
Hackensack, New Jersey, United States
...and 50 more locations