| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prevention of Stroke and Non-CNS Systemic Embolism in Non-Valvular Atrial Fibrillation |
|
| 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 | 10003658 |
| E.1.2 | Term | Atrial fibrillation |
|
| 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 of this study is to demonstrate that the efficacy of rivaroxaban, a direct FXa inhibitor, is non-inferior to that of dose-adjusted warfarin for the prevention of thromboembolic events in subjects with non-valvular atrial fibrillation as measured by the composite of stroke and non-central nervous system (non-CNS) systemic embolism.
The principal safety objective of this study is to demonstrate that rivaroxaban is superior to dose adjusted warfarin as assessed by the composite of major and non-major clinically relevant bleeding events. |
|
| E.2.2 | Secondary objectives of the trial |
The major secondary efficacy objectives are to compare the effects of rivaroxaban and warfarin with respect to the composite of stroke, non-CNS systemic embolism, and vascular death and the composite of stroke, non-CNS systemic embolism, myocardial infarction, and vascular death.
Other secondary efficacy objectives are to compare the effects of rivaroxaban and warfarin with respect to the individual components of the composite primary and major secondary endpoints, disabling stroke (modified Rankin Scale score of 3 to 5 inclusive), and all-cause mortality.
Other safety objectives are to compare rivaroxaban and warfarin with respect to the individual bleeding event categories, adverse events, and clinical laboratory evaluations (including liver function tests [LFTs]). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must satisfy the following criteria to be enrolled in the study:
-Men or women aged ≥18 years with non-valvular atrial fibrillation
- Atrial fibrillation must be documented by ECG evidence (e.g., 12-lead ECG, rhythm strip, Holter, pacemaker interrogation) within 30 days before randomization. In addition, subjects must have medical evidence of atrial fibrillation within 1 year before and at least one day before the qualifying ECG evidence. This could be obtained from a notation in the subject's record (e.g., medical chart, hospital discharge summary).
Subjects with newly diagnosed atrial fibrillation are eligible provided that:
– there is evidence that the atrial fibrillation is non-valvular
– cardioversion is not planned
– there is ECG evidence on 2 occasions 24 hours apart demonstrating atrial fibrillation
- History of prior ischemic stroke, TIA or non-CNS systemic embolism believed to be cardioembolic in origin or has 2 or more of the following risk factors:
- Heart failure and/or left ventricular ejection fraction ≤ 35%
- Hypertension (defined as use of antihypertensive medications within
6 months before the screening visit or persistent systolic blood pressure
above 140 mmHg or diastolic blood pressure above 90 mmHg)
- Age ≥75 years
- Diabetes mellitus (defined as a history of type 1 or type 2 diabetes
mellitus or use of antidiabetic medications within 6 months before
screening visit)
- Female subjects must be postmenopausal (for at least 2 years), surgically sterile, abstinent, or, if sexually active, be practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilization) before entry and throughout the study; and, for those of childbearing potential, have a negative serum β-hCG pregnancy test at screening.
- Subjects must have signed an informed consent document
- In order to participate in the optional pharmacogenomic component, subjects must have signed the informed consent for DNA research document indicating willingness to participate in the pharmacogenomic component of the study (where local regulations permit) |
|
| E.4 | Principal exclusion criteria |
Potential subjects who meet any of the following criteria will be excluded from participating in the study:
Cardiac-Related Conditions
- Hemodynamically significant mitral valve stenosis
- Prosthetic heart valve (annuloplasty with or without prosthetic ring, commissurotomy and/or valvuloplasty are permitted)
- Planned cardioversion (electrical or pharmacological)
- Transient atrial fibrillation caused by a reversible disorder (e.g., thyrotoxicosis, PE, recent surgery, MI)
- Known presence of atrial myxoma or left ventricular thrombus
- Active endocarditis
Hemorrhage Risk-Related Criteria
- Active internal bleeding
- History of or condition associated with increased bleeding risk including, but not limited to:
- Major surgical procedure or trauma within 30 days before the
randomization visit
- Clinically significant gastrointestinal bleeding within 6 months before the
randomization visit
- History of intracranial, intraocular, spinal, or atraumatic intra-articular
bleeding
- Chronic hemorrhagic disorder
- Known intracranial neoplasm, arteriovenous malformation, or aneurysm
- Planned invasive procedure with potential for uncontrolled bleeding, including major surgery
- Platelet count <90,000/µL at the screening visit
- Sustained uncontrolled hypertension: systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥100 mmHg
Concomitant Conditions and Therapies
- Severe, disabling stroke (modified Rankin score of 4 to 5, inclusive) within 3 months or any stroke within 14 days before the randomization visit
- Transient ischemic attack within 3 days before the randomization visit
- Indication for anticoagulant therapy for a condition other than atrial fibrillation (e.g., VTE)
- Treatment with:
– Aspirin >100 mg daily
– Aspirin in combination with thienopyridines within 5 days before randomization
– Intravenous antiplatelets within 5 days before randomization
– Fibrinolytics within 10 days before randomization
– Note: Aspirin £100 mg monotherapy is allowed and thienopyridine monotherapy
is allowed.
- Anticipated need for chronic treatment with a non steroidal anti inflammatory drug
- Systemic treatment with a strong inhibitor of cytochrome P450 3A4, such as ketoconazole or protease inhibitors, within 4 days before randomization, or planned treatment during the time period of the study
- Treatment with a strong inducer of cytochrome P450 3A4, such as rifampin/rifampicin, within 4 days before randomization, or planned treatment during the time period of the study
- Anemia (hemoglobin <10 g/dL) at the screening visit
- Pregnancy or breast feeding
- Any other contraindication to warfarin
- Known HIV infection at time of screening
- Calculated CLCR <30 mL/min at the screening visit
- Known significant liver disease (e.g., acute clinical hepatitis, chronic active hepatitis, cirrhosis), or ALT >3 x the ULN
Study Participation and Follow-up-Related Criteria
- Serious concomitant illness associated with a life expectancy of less than 2 years
- Drug addiction or alcohol abuse within 3 years before the randomization visit
- Have received an experimental drug or used an experimental medical device within 30 days before the planned start of treatment
- Previous randomization in the present study or other study of rivaroxaban
- Known allergy or hypersensitivity to any component of rivaroxaban, warfarin or placebo excipients (includes lactose, microcrystalline cellulose, magnesium stearate, hypromellose, macrogol, croscarmellose sodium, sodium lauryl sulfate, titanium oxide/ferric oxide red, titanium dioxide/ferric oxide red, anhydrous lactose, pregelatinized starch, FD&C Red #6 barium lake, FD&C Yellow #10 aluminum lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, cornstarch, lactose monohydrate)
- Inability or unwillingness to comply with study-related procedures
- 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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy outcome is the composite of stroke and non CNS systemic embolism.
The principal safety endpoint is the composite of major and non-major clinically relevant bleeding events. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| 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) | 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.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 500 |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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