Anticoagulation in Critically Ill Patients With COVID-19 (The IMPACT Trial)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine if therapeutic dose anticoagulation (experimental group) improves 30-day mortality in participants with COVID-19 compared to those patients receiving the intermediate dose prophylaxis (control group). Following screening, subjects will be randomized 1:1 to intermediate dose prophylaxis or therapeutic dose anticoagulation treatment arms.Treatment will continue for 28 days, followed by a 6 month follow-up period.

Official Title
-----------------
InterMediate ProphylACtic Versus Therapeutic Dose Anticoagulation in Critically Ill Patients With COVID-19: A Prospective Randomized Study (The IMPACT Trial)

Conditions
-----------------
COVID-19

Intervention / Treatment
-----------------
* Drug: Enoxaparin sodium
* Drug: Unfractionated heparin
* Drug: Fondapariniux
* Drug: Argatroban


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age >18 years old COVID-19 positive on (RT-PCR) nasopharyngeal swab, or suspected COVID-19 infection with detectable SARS-CoV-2 IgG or IgM. Intensive care unit (ICU) patient or non-ICU patient on invasive mechanical ventilation, BiPAP, 100% non-rebreather mask, or high flow oxygen or supplemental oxygen of at least 4 liters per minute nasal cannula. D dimer level greater than 700 ng/mL (3 times the upper limit of normal). Exclusion Criteria: Objectively documented deep vein thrombosis or pulmonary embolism Patients in whom there is very high suspicion for pulmonary embolism and are on full-dose anticoagulation as per the treating physician Platelets <30,000 not due to disseminated intravascular coagulation (DIC), based on the International Society of Thrombosis and Haemostasis (ISTH) criteria and American Society of Hematology (ASH) Frequently Asked Questions Active bleeding that poses a contraindication to therapeutic anticoagulation in the opinion of the investigator. History of bleeding diathesis (e.g., hemophilia, severe von Willebrand disease, severe thrombocytopathy) History of intracranial hemorrhage in the last 90 days History of ischemic stroke in the past 2 weeks Major neurosurgical procedure in the past 30 days Cardiothoracic surgery in the past 30 days Intra-abdominal surgery in the past 30 days Intracranial malignancy Patients who require therapeutic anticoagulation for other reasons like atrial fibrillation, deep venous thrombosis, pulmonary embolism, or antiphospholipid syndrome.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intermediate Dose Prophylaxis<br>Subjects will receive one of the following interventions, at their physician's discretion: Enoxaparin 0.5 mg/kg subcutaneously every 12 hours if creatinine clearance greater than or equal to 30 ml/min Enoxaparin 0.5 mg/kg subcutaneously every 24 hours if creatinine clearance less than 30 mL/min If patient develops acute kidney injury: unfractionated heparin 7,500 units subcutaneously every 8 hours. Fondaparinux (if history of heparin-inducted thrombocytopenia [HIT]) 2.5 mg daily subcutaneously | Drug: Enoxaparin sodium<br>* Intermediate Dose Prophylaxis Arm: 0.5 mg/kg subcutaneously every 12 hours if creatinine clearance greater than or equal to 30 ml/min --OR-- 0.5 mg/kg subcutaneously every 24 hours if creatinine clearance less than 30 ml/min Therapeutic Dose Anticoagulation Arm: 1 mg/kg subcutaneously every 12 hours<br>* Other names: Lovenox;Drug: Unfractionated heparin<br>* Intermediate Dose Prophylaxis Arm: 7,500 units subcutaneously every 8 hours Therapeutic Dose Anticoagulation Arm: Dosed to target anti-Xa level 0.3 - 0.7 IU/mL or activated partial thromboplastin time (aPTT), according to institutional protocol<br>* Other names: Sodium heparin;Drug: Fondapariniux<br>* Intermediate Dose Prophylaxis Arm: 2.5 mg daily subcutaneously Therapeutic Dose Anticoagulation Arm: Dose by weight: If greater than or equal to 100 kg: 10 mg daily If less than 100 kg but greater than or equal to 50 kg: 7.5 mg daily If less than 50 kg: 5 mg daily<br>* Other names: Arixtra;|
| Experimental: Therapeutic Dose Anticoagulation<br>Subjects will receive one of the following interventions, at their physician's discretion: Unfractionated heparin (UFH) to target anti-Xa level 0.3 -0.7 IU/mL or activated partial thromboplastin time (aPTT) (according to institutional protocol). Enoxaparin 1 mg/kg subcutaneously every 12 hours Argatroban (if heparin-induced thrombocytopenia [HIT]), dosed according to institutional protocol. Fondaparinux (if HIT and creatinine clearance greater than or equal to 50 ml/min) dosed by weight: ≥100 kg: 10 mg daily <100 kg but ≥50 kg: 7.5 mg daily <50 kg: 5 mg daily | Drug: Enoxaparin sodium<br>* Intermediate Dose Prophylaxis Arm: 0.5 mg/kg subcutaneously every 12 hours if creatinine clearance greater than or equal to 30 ml/min --OR-- 0.5 mg/kg subcutaneously every 24 hours if creatinine clearance less than 30 ml/min Therapeutic Dose Anticoagulation Arm: 1 mg/kg subcutaneously every 12 hours<br>* Other names: Lovenox;Drug: Unfractionated heparin<br>* Intermediate Dose Prophylaxis Arm: 7,500 units subcutaneously every 8 hours Therapeutic Dose Anticoagulation Arm: Dosed to target anti-Xa level 0.3 - 0.7 IU/mL or activated partial thromboplastin time (aPTT), according to institutional protocol<br>* Other names: Sodium heparin;Drug: Fondapariniux<br>* Intermediate Dose Prophylaxis Arm: 2.5 mg daily subcutaneously Therapeutic Dose Anticoagulation Arm: Dose by weight: If greater than or equal to 100 kg: 10 mg daily If less than 100 kg but greater than or equal to 50 kg: 7.5 mg daily If less than 50 kg: 5 mg daily<br>* Other names: Arixtra;Drug: Argatroban<br>* Therapeutic Dose Anticoagulation Arm: Dosed according to institutional protocol<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 30-day Mortality | Comparison of number of COVID-19 positive patients who have died within 30 days of starting treatment on each treatment arm | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of Intensive Care Unit (ICU) Stay in Days | Comparison of length of ICU stay in days between each treatment arm. | 6 months | 
| Number of Documented Venous Thromboembolism (VTE), Arterial Thrombosis (Stroke, Myocardial Infarction, Other) and Microthrombosis Events | Comparison of number of documented VTE, arterial thrombosis and microthrombosis events on each treatment arm | 6 months | 
| Number of Major and Clinically Relevant Non-major Bleeding Events | Comparison of major and clinically-relevant non-major bleeding events on each treatment arm, as defined by the International Society of Thrombosis and Haemostasis (ISTH) criteria. | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID-19, Anticoagulation