NCT04416048.

Study name	Effect of anticoagulation therapy on clinical outcomes in moderate to severe coronavirus disease 2019 (COVID‐19)
Starting date	15 June 2020
Contact information	Ulf Landmesser Charite University, Berlin, Germany +49 30 450 513 702 | ulf.landmesser@charite.de
Methods	Multicenter, prospective, event‐driven, 2‐armed, parallel‐assignment RCT
Participants	400 participants, ≥ 18 years, female and male Inclusion criteria Participant must be willing, understanding and able to provide written informed consent Participant must be a man or a woman aged > 18 years at screening Participant must have active moderate to severe COVID‐19 confirmed by a positive SARS‐CoV‐2 PCR test in the last 14 days At least 1 of the following features should be present: D‐Dimer elevation > 1.5 ULN (age‐adjusted cut‐offs) cardiac injury reflected by an elevation in hs‐cTnT > 2.0 ULN at least one of the following conditions: known coronary artery disease; known diabetes mellitus; active smoking A woman of childbearing potential must have a negative serum or urine pregnancy test before randomisation occurs. Before randomisation, a woman must be either: postmenopausal, defined as > 45 years of age with amenorrhoea for at least 18 months, if menstruating: if heterosexually active, practicing a highly effective method of birth control, including hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double‐barrier method (e.g. condoms, diaphragm, or cervical cap, with spermicidal foam, cream, or gel), or male partner sterilisation, consistent with local regulations regarding use of birth control methods for participants in clinical studies, for the duration of their participation in the study, or surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), or not heterosexually active Exclusion criteria: Participant has a very high bleeding risk: any condition that, in the opinion of the investigator, contraindicates anticoagulant therapy or would have an unacceptable risk of bleeding, such as, but not limited to, the following: any bleeding (defined as bleeding requiring hospitalisation, transfusion, surgical intervention, invasive procedures, occurring in a critical anatomical site, or causing disability) within 1 months prior to randomisation or occurring during index hospitalisation major surgery, biopsy of a parenchymal organ, ophthalmic surgery (excluding cataract surgery), or serious trauma (including head trauma) within 4 weeks before randomisation history of haemorrhagic stroke or any intracranial bleeding at any time in the past, evidence of primary intracranial haemorrhage on CT or magnetic resonance imaging scan of the brain, or clinical presentation consistent with intracranial haemorrhage. This applies as well to participants hospitalised for ischaemic stroke upon randomisation participant has a history of or current intracranial neoplasm (benign or malignant), cerebral metastases, arteriovenous (AV) malformation, or aneurysm active gastroduodenal ulcer, defined as diagnosed within 1 month or currently symptomatic or known AV malformations of the gastrointestinal tract platelet count < 90,000/μL at screening participants with the diagnosis of bronchiectasis, that due to the investigator's judgement are at an increased bleeding risk Participant has any of the following diseases in the medical history active cancer (excluding non‐melanoma skin cancer) defined as cancer not in remission or requiring active chemotherapy or adjunctive therapies such as immunotherapy or radiotherapy. Chronic hormonal therapy (e.g. tamoxifen, anastrozole, leuprolide acetate) for cancer in remission is allowed any medical condition (e.g. atrial fibrillation) that requires use of any therapeutic parenteral or oral anticoagulant(s) (e.g. warfarin sodium or other vitamin K antagonists, Factor IIa or FXa inhibitors, fibrinolytics) concomitantly with study medication participant has known allergies, hypersensitivity, or intolerance to rivaroxaban or any of its excipients baseline estimated GFR < 30 mL/min/1.73 m2 calculated using CKD‐EPI formula known significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis), which is associated with coagulopathy or moderate or severe hepatic impairment. known HIV infection Participant has undergone any of the following procedures or received any of the following drugs received fibrinolysis during index hospitalisation use of antiplatelet therapy with prasugrel or ticagrelor up to 7 days prior to randomisation. Other P2Y12 antagonists can be given. However, the use of concomitant antiplatelet therapy should be carefully considered. ASS > 100 mg/d and continuous NSAIDs should be avoided use of dual antiplatelet therapy, such as aspirin plus clopidogrel during the study Participant is a woman who is pregnant or breast‐feeding Known intolerance or history of hypersensitivity to the active substance or to any of the excipients of the Investigational Medicinal Product (IMP) Participants who are legally detained in an official institution Participants who may be dependent on the sponsor, the investigator or the trial sites, are not eligible to enter the trial
Interventions	Experimental: rivaroxaban Treatment with rivaroxaban 20 mg (15 mg for participants with an estimated GFR ≥ 30 mL/min/1.73 m2 and < 50 mL/min/1.73 m2) once daily for at least 7 days. In case of hospitalisation for > 7 days, the therapeutic treatment with rivaroxaban will be continued for the duration of the hospital stay until discharge. After at least 7 days of therapeutic treatment with rivaroxaban or after hospital discharge, the study dose of rivaroxaban will be adjusted as follows: participants randomised to the rivaroxaban study arm will reduce daily dosage to 10 mg once daily, provided that they were not diagnosed with a condition requiring continued therapeutic anticoagulation thromboprophylaxis therapy will be given for 28 days up to day 35 post‐randomisation or even longer if the participant cannot be discharged from the hospital prior to day 35 post‐randomisation, the thromboprophylaxis phase will also start upon hospital discharge, but is then shorter than 28 days, because the study ends at day 60 post‐randomisation. Other Name: XARELTO Comparator: standard care Participants will receive standard care treatment including prophylactic LMWH or UFH, when considered appropriate according to the judgment of the treating physician.
Outcomes	Primary Composite endpoint of VTE (DVT and/or fatal or non‐fatal PE), arterial thromboembolism, new myocardial infarction, non‐hemorrhagic stroke, all‐cause mortality or progression to intubation and invasive ventilation (time frame: 35 days post‐randomisation) Secondary Development of disseminated intravascular coagulation according to the ISTH criteria (time frame: 35 days post randomisation) Number of days requiring invasive ventilation (time frame: 35 days post‐randomisation) Number of days requiring non‐invasive ventilation (time frame: 35 days post‐randomisation) Improvement on a 7‐category ordinal scale recommended by the WHO as clinical improvement scale for participants with respiratory infections (time frame: 35 days post‐randomisation) scale range from 1‐7; improvement means a reduction in the scale number of at least 1 point
Notes	NCT04416048 | 2020‐002282‐33 | No data provided

APTT: activated partial thromboplastin time; ACS: acute coronary syndrome; AKI: acute kidney injury; ARDS: acute respiratory distress syndrome; BARC: Bleeding Academic Research Consortium; BMI: body mass index; BP: blood pressure; CKI‐EPI: Chronic Kidney Disease Epidemiology Collaboration; CPAP: continuous positive airway pressure; CPR: cardiopulmonary resuscitation; CT: computed tomography;DBP: diastolic blood pressure; DIC: disseminated intravascular coagulation; DVT: deep vein thrombosis; ECMO: extracorporeal membrane oxygenation; ELISA: enzyme‐linked immunosorbent assay; GFR: glomerular filtration rate; GI: gastrointestinal; HFOV: High‐frequency oscillatory ventilation; HIT: heparin‐induced thrombocytopenia ICU: intensive care unit; INR: international normalised ratio; ISTH: International Society on Thrombosis and Haemostasis; IV: intravenous(ly); LMWH: low molecular weight heparin; NIV: non‐invasive ventilation; PCR: polymerase chain reaction; PE: pulmonary embolism; PRCB: packed red blood cell; RCT: randomised controlled trial; RT‐PCR: reverse transcription polymerase chain reaction; SARS: severe acute respiratory syndrome; SBP: systolic blood pressure; SC: subcutaneous(ly);SIC: sepsis‐induced coagulopathy;SOFA: sequential organ failure assessment; TIA: transient ischaemic attack; UFH: unfractionated heparin; ULN: upper limit of normal; WHO: World Health Organization