Factor Xa Inhibitor Versus Standard of Care Heparin in Hospitalized Patients With COVID-19 (XACT)

Study Overview
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Brief Summary
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This study is a multicenter, randomized trial to study the potential benefit of treatments with a direct FXa inhibitor (rivaroxaban) versus standard of care dose subcutaneous low molecular weight heparin (LMWH) (Lovenox) in hospitalized subjects with COVID-19.

Detailed Description
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As clinicians learn how to better care for hospitalized COVID-19 patients, the clinical picture of a hypercoagulable state with abnormal blood clotting has emerged. Fulminant heart, lung, kidney, and liver failure are hallmarks of COVID-19 non-survivors and have been associated with abnormal blood coagulation parameters, such as elevated D-Dimer levels. The current standard of care using prophylactic levels of subcutaneous heparin has not significantly mitigated the risk of patients entering a hypercoagulable state, however the dysregulated thrombotic and inflammatory events that drive poor outcomes in many COVID-19 patients may be amenable to early treatment with a factor Xa (FXa) inhibitor. The purpose of this study is to study the potential benefit of treatments with a direct FXa inhibitor (rivaroxaban) versus standard of care dose subcutaneous LMWH (Lovenox) in hospitalized subjects with COVID-19.

Official Title
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A Phase 2-3, Multi-Center, Randomized Trial to Study the Potential Benefit of Factor Xa Inhibitor (Rivaroxaban) Versus Standard of Care Low Molecular Weight Heparin (Lovenox) in Hospitalized Patients With COVID-19 (XACT)

Conditions
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Covid19

Intervention / Treatment
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* Drug: Enoxaparin
* Drug: Rivaroxaban


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients age 18-100 admitted to hospital with laboratory-confirmed SARS-CoV-2 infection Not be intubated or mechanically ventilated or imminently at risk for same or ICU admission within 24 hours of enrollment. Not be admitted for central nervous system (CNS) diagnosis Not have a current history of a condition requiring full therapeutic anticoagulation such as venous thromboembolism, atrial fibrillation. Exclusion Criteria: Medical Conditions Life expectancy of less than 6 months Active or recent gastrointestinal bleeding in the past 6 months Intracranial bleeding in the past 6 months Major trauma or head trauma in the past 2 months Major surgery in the past 2 months or planned within 2 weeks after completion of the study Recent spinal or epidural procedures in the past 2 weeks Ischemic stroke in the past 2 weeks History of intracranial neoplasm, arteriovenous malformation or aneurysm History of acquired or spontaneous impairment of hemostasis such as but not limited to hemophilia, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), von Willebrand disease Allergy to heparin or rivaroxaban or any factor Xa inhibitors, including a history of heparin-induced thrombocytopenia History of antiphospholipid syndrome End-stage renal failure requiring dialysis Valvular heart disease requiring chronic anticoagulation History of atrial fibrillation, atrial flutter or venous thromboembolic event (VTE) currently requiring anticoagulation History of solid organ transplant requiring immunosuppressant therapy Cancer requiring ongoing anticoagulation History of cirrhosis or liver failure, hepatorenal syndrome History of baseline bronchiectasis History of systemic lupus erythematosus or other autoimmune diseases requiring immunosuppressant therapy. Vital signs Uncontrolled hypertension: systolic blood pressure (SBP) > 180 mm Hg or diastolic blood pressure (DBP) > 105mm Hg. Subjects who have a transient, higher blood pressure elevation (SBP 180-200 mm Hg) may enter the study if a repeat confirmation is back in range prior to enrollment. Laboratory PT INR > 2.0. Platelet < 90 10^3/µL Total bilirubin > 3.0 mg/dL Hemoglobin < 9.0 g/dL Urine with gross hematuria (not due to menses) Estimated glomerular filtration rate (GFR) less than 30 mL/min calculated with the Cockcroft-Gault formula Medications Patients on dual anti-platelet therapy Patients taking hypoxia-inducible factor prolyl hydroxylase inhibitors (such as roxadustat.) Erythropoiesis-stimulating agents (such as epoetin alfa, darbepoetin alfa) Other COVID-19 drug studies or trials Any COVID19 vaccination trials Experimental COVID drug trial except for treatment(s) that has become accepted standard of care.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open-label Multicenter Prospective Randomized Trial in hospitalized patients with severe acute respiratory syndrome (SARS)-CoV-2 infection. Patients will be randomized 1:1 to subcutaneous enoxaparin (Lovenox) versus rivaroxaban after hospitalization, with the exact dosing is based on an adaptive strategy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Adaptive Dosing: Enoxaparin<br>Low 40mg subcutaneous (SQ) daily, or Intermediate 40mg SQ q12 hours, or Therapeutic 1mg/kg SQ q12 hours | Drug: Enoxaparin<br>* Subcutaneous enoxaparin While hospitalized only.<br>|
| Active Comparator: Adaptive Dosing: Rivaroxaban<br>Low 10mg po daily Intermediate 10mg po daily Therapeutic 20mg po daily | Drug: Rivaroxaban<br>* Oral rivaroxaban While hospitalized and through discharge for a total of 28 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death or 30-day all cause mortality |  | 30 days | 
| Mechanical ventilation, intubation |  | 30 days | 
| Transfer to an ICU setting |  | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| New requirement for hemodialysis (HD) or continuous renal replacement therapy (CRRT) or extracorporeal membrane oxygenation (ECMO) |  | 30 days | 
| New thrombotic events |  | 30 days | 
| Major bleeding event |  | 30 days | 
| Time to recovery (defined as no limitation or minor limitation in activity level or hospitalized but require no oxygen) |  | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronavirus, Enoxaparin, Rivaroxaban, Anticoagulants, Anti-inflammatory, Anti-viral, ARDS