| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with moderate to severe COVID-19 disease which may cause acute cardiac injury |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with moderate to severe COVID-19 disease which may cause acute cardiac injury |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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.
|
|
| E.2.2 | Secondary objectives of the trial |
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.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
|
|
| E.4 | Principal 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 <90,000/μl at screening.
g. Patients with the diagnosis of bronchiectasis, that due to the investigator judgement are at an increased bleeding risk.
2. Subject has any of the following diseases in the medical history:
a. 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.
b. 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. In case of “off label” use of a NOAC, the patient can be included in the study if the NOAC was stopped for 24 hours or more.
c. Subject has known allergies, hypersensitivity, or intolerance to rivaroxaban or any of its excipients.
d. Baseline eGFR <30 mL/min/1.73m2 calculated using CKD-EPI formula provided in attachment 3
e. Known significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) which is associated with coagulopathy or moderate or severe hepatic impairment.
f. Known HIV infection.
3. Subject has undergone any of the following procedures or received any of the following drugs:
a. Received fibrinolysis during index hospitalization.
b. Use of antiplatelet therapy with prasugrel or ticagrelor up to 7 days prior to randomization. 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.
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, patients with immediate indication for ICU admission)
5. Subject is a woman who is pregnant or breast-feeding.
6. Known intolerance or history of hypersensitivity to the active substance or to any of the excipients of the Investigational Medicinal Product (IMP)
7. Other contraindications for the use of the IMPs according to the SmPCs
8. Subjects who are legally detained in an official institution.
9. Subjects who may be dependent on the sponsor, the investigator or the trial sites, are not eligible to enter the trial.
10. Subjects participating in another clinical trial of an investigational medicinal product |
|
| E.5 End points |
| E.5.1 | 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
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Standard of Care with prophylactic LMWG or UFH |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 25 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
LVLS
individual trial duration: 60 days |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
Print
