Patients with moderate to severe COVID-19 disease which may cause acute cardiac injury
Conditions
Interventions
Trade Name: Xarelto
Product Name: Xarelto
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: RIVAROXABAN
CAS Number: 366789-02-8
Concentration unit: mg milligram(s)
Concentration type: equa
Sponsors
Charité - Universitaetsmedizin Berlin
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Subject must be willing, understanding and able to provide written informed consent 2. Subject must be a man or a woman with age > 18 years at screening 3. Subject must have an active moderate to severe COVID-19 confirmed by a. A positive SARS-CoV-2 PCR test in the last 14 days 4. At least one of the following features should be present a. D-Dimer elevation > 1.5 ULN (age adjusted cut-offs) AND/OR b. Cardiac injury reflected by an elevation in hs-cTnT > 2.0 ULN AND at least one of the following conditions: i. Known CAD ii. Known diabetes mellitus iii. Active smoking 5. A woman of childbearing potential must have a negative serum or urine pregnancy test before randomization occurs. Before randomization, a woman must be either: a. Postmenopausal, defined as >45 years of age with amenorrhea for at least 18 months, b. If menstruating: i. If heterosexually active, practicing a highly effective method of birth control with a failure rate less than 1% per year, including hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch or intrauterine device, or male partner sterilization, consistent with local regulations regarding use of birth control methods for subjects participating in clinical studies, for the duration of their participation in the study, or ii. Surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), or iii. Not heterosexually active Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 130 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 270
Exclusion criteria
Exclusion criteria: Any potential subject who meets any of the following criteria will be excluded from participating in the study. 1. Subject 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: a. Any bleeding (defined as bleeding requiring hospitalization, transfusion, surgical intervention, invasive procedures, occurring in a critical anatomical site, or causing disability) within 1 months prior to randomization or occurring during index hospitalization. b. Major surgery, biopsy of a parenchymal organ, ophthalmic surgery (excluding cataract surgery), or serious trauma (including head trauma) within 4 weeks before randomization. c. A history of hemorrhagic stroke or any intracranial bleeding at any time in the past, evidence of primary intracranial hemorrhage on CT or magnetic resonance imaging scan of the brain, or clinical presentation consistent with intracranial hemorrhage. This applies as well to subjects hospitalized for ischemic stroke upon randomization. d. Subject has a history of or current intracranial neoplasm (benign or malignant), cerebral metastases, arteriovenous (AV) malformation, or aneurysm. e. Active gastroduodenal ulcer, defined as diagnosed within 1 months or currently symptomatic or known AV malformations of the gastrointestinal tract. f. Platelet count 100 mg/d and continuous NSAIDs should be avoided. c. Use of dual antiplatelet therapy, such as aspirin plus clopidogrel during the study. 4. Subjects with acute critical illness that leads to an altered mental status affecting the ability to consent (i.e. hemodynamically unstable, pa
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to assess the effect of rivaroxaban compared with standard of care (SOC) with the use of prophylactic low molecular weight heparin (LMWH) or unfractionated heparin (UFH) (see Attachment 1) on D-dimer as a clinical marker for the clinical outcome at day 7 post randomization adjusted for baseline measurement in patients with moderate to severe COVID-19. The co-primary objective is to evaluate the impact of rivaroxaban compared with standard of care (SOC) with the use of prophylactic low molecular weight heparin (LMWH) or unfractionated heparin (UFH) on a seven-category (Attachment 2) ordinal scale recommended by the WHO (23-25) as a measure of clinical benefit at day 7 post randomization adjusted for baseline score in patients with moderate to severe COVID-19. ;Secondary Objective: Secondary objectives: The secondary objective is to assess the efficacy and safety of rivaroxaban compared with standard of care (SOC) (if appropriate including the use of prophylactic low molecular weight heparin (LMWH) or unfractionated heparin (UFH) (see Attachment 1)) in the prevention of the composite endpoint described below up to day 35 in patients with moderate to severe COVID-19. Safety objectives: The safety objectives are to compare rivaroxaban with SOC with prophylactic LMWH or UFH in bleeding outcomes up to day 35 in patients with moderate to severe COVID-19. ;Primary end point(s): Primary Endpoint • D-dimer at day 7 post randomization Co-primary Endpoint • Seven-category ordinal scale recommended by the WHO at day 7 post randomization ;Timepoint(s) of evaluation of this end point: up to day 35 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Venous thromboembolism (VTE) (deep venous thrombosis (DVT) and/or fatal or non-fatal • pulmonary embolism (PE)) • Arterial thromboembolism • New myocardial infarction (MI) • Non-hemorrhagic stroke • All-cause mortality (ACM) • Progression to intubation and invasive ventilation Secondary combined Endpoint Time to first event of either of • Venous thromboembolism (VTE) (deep venous thrombosis (DVT) and/or fatal or non-fatal pulmonary embolism (PE)) • Arterial thromboembolism • New myocardial infarction (MI) • Non-hemorrhagic stroke • All-cause death • Progression to intubation and invasive ventilation In addition, all single components of the primary composite as well as the secondary endpoints will be additionally evaluated separately. Primary Safety Endpoints: - Fatal and non-fatal major bleeding using the International Society on Thrombosis and Haemostasis (ISTH) bleeding criteria Secondary Safety Endpoints: - Clinically relevant non-major bleeding - Non-major bleeding that lead to study-drug interruption for more than 7 days Other endpoints of interest: • Length of hospital stay • Time to intubation • Re-hospitalization due to heart failure • Re-hospitalization due to any other reason • Effects on coagulation parameters for thrombosis (TAT, PAI-1, PF-4, TF, TF-activity) • Effects on inflammatory and fibrotic parameters (interleukines, interferons, growth factors) • Change of N-terminal prohormone brain natriuretic peptide (NT-pro-BNP) • Unscheduled outpatient visits ;Timepoint(s) of evaluation of this end point: up to day 60 | — |
Countries
Germany
Contacts
Public ContactMedizinische Klinik für Kardiolog
Charité - Universitätsmedizin Berlin
Outcome results
None listed