E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Long-term prevention of recurrent symptomatic venous thromboembolism in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism |
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E.1.1.1 | Medical condition in easily understood language |
Prevention of blood clots from reccuring in the veins of your legs or blood vessels of your lungs |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10051055 |
E.1.2 | Term | Deep vein thrombosis |
E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10037439 |
E.1.2 | Term | Pulmonary thrombotic and embolic conditions |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10034572 |
E.1.2 | Term | Peripheral embolism and thrombosis |
E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10037377 |
E.1.2 | Term | Pulmonary embolism |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 primary efficacy objective is to evaluate whether rivaroxaban, in doses of 10 mg or 20 mg, is superior to acetylsalicylic acid (ASA) 100 mg in the prevention of the primary efficacy outcome (i.e. fatal or non-fatal symptomatic recurrent venous thromboembolism).
The principal safety objective is to document the incidence of the principal safety outcome (i.e. major bleeding).
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E.2.2 | Secondary objectives of the trial |
The secondary efficacy objective is to evaluate whether rivaroxaban 10 mg and rivaroxaban 20 mg are superior to ASA 100 mg in the prevention of the secondary efficacy outcome (i.e. fatal or non-fatal symptomatic recurrent venous thromboembolism, myocardial infarction, ischemic stroke, systemic non-central nervous system [CNS] embolism).
The secondary safety objective is to document the incidence of the secondary safety outcome (i.e. clinically relevant non-major bleeding).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients with confirmed symptomatic PE and/or DVT who have been treated for 6 to 12 months and did not interrupt anticoagulation for longer than 1 week.
2. Written informed consent
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E.4 | Principal exclusion criteria |
1. Legal lower age limitations (country specific)
2. Indication for therapeutic-dosed anticoagulants
3. Hypersensitivity to investigational or comparator treatment
4. Any other contraindication listed in the local labeling for investigational or comparator treatment
5. Indication for antiplatelet therapy or a conventional non-steroid anti-inflammatory drug (NSAID)
6. Hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk
7. Calculated creatinine clearance < 30 mL/min
8. Active bleeding or high risk for bleeding contraindicating anticoagulant therapy
9. Life expectancy <6 months
10. Concomitant use of strong inhibitors of both cytochrome P450 isoenzyme 3A4 (CYP3A4) and P-glycoprotein (P-gp), i.e. all human immunodeficiency virus protease inhibitors and the following azole-antimycotics agents: ketoconazole, itraconazole, voriconazole, posaconazole, if used systemically
11. Childbearing potential without proper contraceptive measures, pregnancy or breast feeding
12. Participation in a study with an investigational drug or medical device within 30 days prior to randomization
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E.5 End points |
E.5.1 | Primary end point(s) |
Fatal or non-fatal symptomatic recurrent venous thromboembolism
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Composite efficacy outcomes will be analyzed based on time to first event in the intended 12-month treatment period, using a stratified (for index DVT only and index PE± DVT) Cox proportional hazard model in the full analysis set (FAS). Adjudication results will be the basis for the final analyses.
The primary efficacy analysis will use a hierarchical (fixed sequence) testing procedure for testing superiority of the individual rivaroxaban doses vs. ASA. |
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E.5.2 | Secondary end point(s) |
fatal or non-fatal symptomatic recurrent venous thromboembolism,
myocardial infarction, ischemic stroke, systemic non-central nervous system [CNS] embolism |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary composite outcome will be analyzed with Cox regression and with log rank test as described for the primary efficacy analysis. |
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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 | 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) | 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 | No |
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.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 117 |
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 | No |
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 |
Australia |
Austria |
Belgium |
Brazil |
Canada |
China |
Czech Republic |
Denmark |
France |
Germany |
Hungary |
Israel |
Italy |
Korea, Republic of |
Mexico |
Netherlands |
New Zealand |
Norway |
Philippines |
Poland |
Russian Federation |
South Africa |
Spain |
Sweden |
Switzerland |
Taiwan |
Thailand |
Turkey |
United Kingdom |
United States |
Vietnam |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 2 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 10 |