CorONa Virus edoxabaN ColchicinE (CONVINCE) COVID-19

Study Overview
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Brief Summary
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There is emerging evidence that patients with SARS-CoV-2 are affected by increased coagulopathy, including in the most advanced forms, a fully blown disseminated intravascular coagulation, leading to multi organ failure (MOF). Post-Morten observations from patients who died because of SARS-CoV-2 infection in Bergamo, Italy and other places have revealed the presence of diffuse venous, arterial and microcirculatorythrombosis, not only restricted to the lung but also involving the kidneys, heart and gut. Thrombin plays a central role in mediating clot forming as well as in mediating inflammation. A direct factor X inhibitor, namely edoxaban can act as prophylactic measure to mitigate the risk of venous and arterial thrombotic complications. Colchicine is an inexpensive (generic drug), orally administered, and a potent anti-inflammatory medication. It might accelerate SARS-CoV-2 clearance. The aim of the CONVINCE study is therefore to assess the safety and efficacy of edoxaban and/or colchicine administration in SARS-CoV-2 infected patients who are managed outside the hospital with respect to the occurrence of fatalities, hospitalisation, major vascular thrombotic events or the SARS-CoV-2 clearance rate under RT PCR.

Official Title
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Efficacy and Safety of Edoxaban and or Colchicine for Patients With SARS-CoV-2 Infection Managed in the Out of Hospital Setting

Conditions
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SARS-CoV Infection, COVID-19

Intervention / Treatment
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* Drug: Edoxaban Tablets
* Drug: Colchicine Tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with laboratory confirmed SARS-CoV-2 infection (under RT PCR) who are managed at home or in another out-of-hospital setting. Exclusion Criteria: Hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including Child-Pugh C cirrhosis with portal hypertension. Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Uncontrolled severe hypertension. Ongoing or planned treatment with parenteral or oral anticoagulants Unilateral or bilateral above knee lower extremity amputation. Inability to take oral medication or otherwise unable or unwilling to undergo/perform study-specified procedures Have received or will receive an experimental drug or used an experimental medical device within 30 days before the planned start of treatment Pregnancy or breast-feeding or any plan to become pregnant during the study. Women (and men, for Colchicine group only) with child-bearing potential not using adequate birth control method (note: as adequate method of birth control oral contraception is recommended. If oral contraception is not feasible, both partners should use adequate barrier birth control). Need for dual anti-platelet therapy consisting of aspirin and an oral P2Y12 inhibitor Inflammatory bowel disease or chronic diarrhea or neuromuscular disease Creatinine clearance (CrCl) <15 ml/min Anticipated use of Hydroxychloroquine Participation in any other clinical trial Inability to understand the requirements of the study and to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 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: Factorial Assignment
Interventional Model Description: 2x2 factorial design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Edoxaban<br>Edoxaban 60 mg q.d., or 30 mg q.d. in patients with CrCl = or <50 ml/min or body weight equal or less than 60 kg from randomization to end of study visit at day 25 (+/-3). | Drug: Edoxaban Tablets<br>* Treatment<br>|
| Active Comparator: Colchicine<br>Colchicine at 0.5 mg per os (PO) twice daily for the first 3 days and then once daily from randomization to day 14 (+/-3) days. Treatment could be continued to day 25 (+3/-3 days). | Drug: Colchicine Tablets<br>* Treatment<br>|
| No Intervention: No Edoxaban and No Colchicine<br>No intervention | |
| Active Comparator: Edoxaban and Colchicine<br>Edoxaban 60 mg q.d., or 30 mg q.d. in patients with CrCl = or <50 ml/min or body weight equal or less than 60 kg from randomization to end of study visit at day 25 (+/-3). Colchicine at 0.5 mg per os (PO) twice daily for the first 3 days and then once daily from randomization to day 14 (+/-3) days. Treatment could be continued to day 25 (+3/-3 days). | Drug: Edoxaban Tablets<br>* Treatment<br>Drug: Colchicine Tablets<br>* Treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Edoxaban vs. no active treatment | To assess the effect of edoxaban versus no active treatment on the composite endpoint of asymptomatic proximal deep-vein thrombosis, symptomatic proximal or distal deep-vein thrombosis, symptomatic pulmonary embolism or thrombosis, myocardial infarction, ischemic stroke, non-CNS systemic embolism or death at day 25 (+/-3) after randomization. | Baseline to day 25 | 
| Colchicine vs no active treatment | To assess the effect of colchicine versus no active treatment on the SARS-CoV-2 clearance rates under RT PCR or freedom from death or hospitalisation at day 14 (+/-3) after randomization. | Baseline to day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with asymptomatic proximal deep-vein thrombosis | An intraluminal filling defect on CT scan or MR venography in the IVC or iliac veins. | Baseline to day 25 | 
| Number of patients with symptomatic proximal or distal deep-vein thrombosis | Typical symptoms of DVT associated with non-compressible vein segment on ultrasonography or an intra-luminal filling defect on venography, CT venography or MRI venography,located in the inferior vena cava (IVC), the iliac vein, the common femoral vein, the femoral or the popliteal vein. | Baseline to day 25 | 
| Number of patient with symptomatic pulmonary embolism or thrombosis | Typical symptoms of PE associated with an intra-luminal filling defect in (sub) segmental or more proximal branches on spiral computed tomography scan (CT) or computerized tomographic pulmonary angiography (CTPA). a considerable perfusion defect (  75% of a segment) with a local normal ventilation result (high probability) during perfusion-ventilation lung scan (PLS, VLS or V/Q scan). an intraluminal filling defect or a sudden cut-off of vessels ( more than 2.5 mm in diameter) on a catheter guided pulmonary angiogram. In case of an inconclusive CTPA, inconclusive V/Q scan or inconclusive angiography demonstration of DVT in the lower extremities e.g. by compression ultrasound or venography will be required | Baseline to day 25 | 
| Number of patients with myocardial infarction | For the primary analysis, MI endpoint will be defined based on the third universal definition of myocardial infarction with the exception of periprocedural MI after PCI, which will be defined according to the SCAI definition. | Baseline to day 25 | 
| Number of patients with ischemic stroke |  | Baseline to day 25 | 
| Number of patients with non-CNS systemic embolism | Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal dysfunction caused by CNS infarction | Baseline to day 25 | 
| Number of deaths | Death will be classified in 5 categories with respect to cause. Thromboembolism, cardiovascular, bleeding, Pulmonary other known cause. In general, all deaths will be assumed to be due to thromboembolism or pulmonary in nature unless another cause is obvious | Baseline to day 25 | 
| Ventilation need | Need for non-invasive or invasive ventilation | Baseline to day 25 |