E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prevention of venous thromboembolism in patients who have been hospitalized for a medical illness |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012108 |
E.1.2 | Term | Deep venous thrombosis prophylaxis |
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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 objective of this study is to demonstrate the superior efficacy of VTE prophylaxis with oral rivaroxaban 10 mg once daily administered for 35 +/- 4 days to SC enoxaparin 40 mg once daily (OD) administered for 10 +/- 4 days in men and women aged 40 years or above who have been hospitalized for a medical illness. The safety of rivaroxaban and enoxaparin will be compared as well. |
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E.2.2 | Secondary objectives of the trial | |
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female patients aged 40 years or more 2. Patients at risk of venous thromboembolic events being hospitalized for acute medical conditions such as: • Heart failure, NYHA class III or IV • Active cancer (eg, admitted for chemotherapy or for treatment of a complication of the active cancer) • Acute ischemic stroke (documented) with leg paresis or paralysis and inability to walk without assistance • Acute infection • Acute respiratory insufficiency • Acute rheumatic disorders • Acute inflammatory bowel disease • Diabetes mellitus (eg, diabetic ketoacidosis, hyperosmolar coma), pancreatitis (surgical management not planned), cholecystitis (surgical management not planned) • Other 3. Anticipated complete immobilization during the first day of hospitalization and anticipated decreased level of mobility (bed rest) and hospital stay duration of at least 4 days 4. Hospitalized less than 48 hours before randomization 5. Patients’ written informed consent for participation after receiving detailed written and oral information prior to any study specific procedures |
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E.4 | Principal exclusion criteria |
1. Conditions that contraindicate the use of antithrombotic therapy with the LMWH enoxaparin 2. Conditions that may increase the risk of bleeding, including intracranial hemorrhage, such as: • Clinically significant bleeding, within 30 days of randomization • Platelet count < 100 x 10^9/L • Major surgery, biopsy of a parenchymal organ, ophthalmic surgery, or serious trauma within 6 weeks before randomization • A presenting diagnosis for which surgery is intended during hospitalization (eg, cholecystitis and planned cholecystectomy) • Have a known coagulopathy or bleeding diathesis (eg, disseminated intravascular coagulation) or an international normalized ratio (INR) known to be > 1.5 at the time of screening unrelated to VKA therapy • History of hemorrhagic stroke at any time in the past, evidence of primary intracranial hemorrhage on CT or MRI scan of the brain, or clinical presentation consistent with intracranial hemorrhage (eg, severe headache or new neurologic deficit after fibrinolytic therapy) • Recent severe head trauma within 30 days of randomization which includes concussion, skull fracture, or hospitalization for head injury • Known intracranial neoplasm, cerebral metastases, arteriovenous malformation, or aneurysm 3. Required drugs or procedures, such as: • More than 2 days of prophylactic use of anticoagulants. Up to 2 doses of LMWH or up to 6 doses of unfractionated heparin pre-randomization are allowed. • Systemic treatment with more than 2 doses of strong inhibitors of cytochrome P450 3A4 (CYP 3A4), such as ketoconazole or protease inhibitors, within 4 days before randomization or planned treatment during the time period of the study drug administration • Indication for fibrinolysis or need for continued treatment with anticoagulant agents • Treatment with or use of mechanical thromboprophylaxis (eg, pneumatic compression devices, foot pumps) for VTE prevention 4. Concomitant conditions or diseases, such as: • Known allergy to rivaroxaban or any of its excipients • Renal dysfunction (ie, calculated creatinine clearance <30 mL/min, Cockcroft-Gault formula) • Known significant liver disease (eg, acute hepatitis, chronic active hepatitis, cirrhosis), or LFT abnormalities (confirmed with repeat testing) which would require study medication discontinuation, ie, ALT > 5 x ULN or ALT > 3 x ULN plus total bilirubin > 2 x ULN and the ratio of direct to total bilirubin ≥ 50% • Known human immunodeficiency virus (HIV) infection at screening • Sustained uncontrolled systolic blood pressure of ≥ 180 mmHg or diastolic pressure of ≥ 100 mmHg at time of screening despite treatment • Anemia (ie, hemoglobin < 10 g/dL) at the time of screening • History of ongoing drug or alcohol abuse • Cardiogenic or septic shock with the need for vasopressor(s), such as noradrenaline, and/or inotropes, such as dobutamine or milrinone • Any severe condition that would limit life expectancy to less than 6 months, ie, advanced malignancy, etc 5. General: • 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 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 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). • Previous participation in this study or any other study of rivaroxaban • Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is defined as a composite endpoint of the following components: • Asymptomatic proximal lower extremity DVT detected by mandatory bilateral lower extremity venous ultrasonography at Day 35 +/- 4 days • Symptomatic lower extremity DVT (proximal or distal) up to Day 35 + 4 days • Symptomatic non fatal PE up to Day 35 + 4 days • VTE related death up to Day 35 + 4 days
The analysis of the primary efficacy endpoint will be solely based on the assessments made by the UAC and the CEAC.
The major secondary endpoint is defined as the composite of the primary efficacy endpoint (as above), with the addition of all-cause mortality, up to Day 35 + 4 days.
Further secondary endpoints are given by: • Incidence of symptomatic VTE (DVT or PE) up to Day 35 + 4 days • Incidence of each of the components of the primary efficacy endpoint • Incidence of symptomatic VTE up to Day 90 + 7 days • Incidence of all-cause mortality up to Day 90 + 7 days • Incidence of the composite of cardiovascular death, acute myocardial infarction or acute ischemic stroke up to Day 35 + 4 days • Incidence of the composite of cardiovascular death, acute myocardial infarction or acute ischemic stroke up to Day 90 + 7 days. • ‘Net clinical benefit’ as assessed by the composite endpoint comprising the primary efficacy endpoint and treatment-emergent major bleeding or non-major clinically relevant bleeding
The analysis of the secondary efficacy endpoint will be solely based on the assessments made by the UAC and the CEAC. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 225 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 4 |