E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with atrial fibrillation and at least one additional risk factor for stroke who have failed or are unsuitable for vitamin K antagonist therapy. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10042244 |
E.1.2 | Term | Stroke |
E.1.2 | System Organ Class | 10029205 - Nervous system 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 |
To determine if apixaban 5 mg BID (2.5 mg BID in selected patients) is superior to ASA (81 to 324 mg QD) for preventing the composite outcome of stroke or systemic embolism in patients with atrial fibrillation and at least one additional risk factor for stroke who have failed or are unsuitable for vitamin K antagonist therapy. |
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E.2.2 | Secondary objectives of the trial |
To determine if , in the same patients, apixaban is superior to ASA for the prevention of the composite outcome of: *Stroke, systemic embolism, myocardial infarction or vascular death (major vascular events) |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Effectiveness of Apixaban for Prevention of Embolic Stroke MRI Assessment (Amendment Number 02 - Site Specific dated 22-Jun-07)
Primary Objective: to determine whether apixaban reduces the risk of ‘embolic’ ischemic stroke (symptomatic and asymptomatic) compared to ASA in high-risk patients with atrial fibrillation.
Secondary Objectives: 1) To determine the cross-sectional and longitudinal relationship between white matter ischemia/hyperintensity on MRI, and cognitive function. 2) To explore MRI-based predictors of intracerebral bleeding. |
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E.3 | Principal inclusion criteria |
1) a) Signed written informed consent form
2) Target Population b) Permanent, paroxysmal or persistent atrial fibrillation documented by 12 lead ECG on the day of screening OR If not in atrial fibrillation at screening, atrial fibrillation must be documented in the 6 months prior to enrollment by 12 lead ECG, or as an episode at least 5 minutes in duration on a rhythm strip or Holter recording. Pacemaker or ICD electrogram recordings may be used to document AF but the duration of atrial fibrillation must be at least 30 minutes if this is the only documentation of AF. c) Presence of at least one of the following risk factors for stroke: • Prior stroke or TIA • Age ≥ 75 years • Arterial hypertension on treatment • Diabetes mellitus • Heart failure. NYHA Class 2 or greater at time of enrollment • Left ventricular ejection fraction 35% or less, documented within 6 months of enrollment • Documented peripheral arterial disease (previous arterial revascularization, limb or foot amputation, or current intermittent claudication with ankle-arm systolic blood pressure ratio < 0.9) d) The patient is not currently receiving vitamin K antagonist therapy for one of the following reasons: − Previous vitamin K antagonist therapy has been demonstrated to be unsuitable and its use has been discontinued (e.g., poor anticoagulant control, adverse events, need for other treatments that may interact with VKA, patient unable or unwilling to adhere to dose or INR monitoring instructions) − Vitamin K antagonist therapy has not been previously used but would be expected to be unsuitable (e.g., unlikely to comply with dosing or monitoring requirement, need for other treatments which may interact with VKA, unlikely to adhere to restrictions on alcohol, diet or nonprescription medications, risk of VKA therapy considered to outweigh the risk of stroke or systemic embolism, patient is unwilling to take VKA). 3) Age and Sex e) Men and women ≥ 50 years of age
LONG TERM OPEN LABEL EXTENSION
1) Signed Written Informed a) All subjects must provide signed written informed consent to participate in the Long-Term Open-Label Extension 2) Target Population a) All subjects must be receiving double-blind study medication (i.e., not having permanently or temporarily [for >30 days] discontinued study medication) at the time they present for their last double-blind study visit (Month 36/EOT).
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E.4 | Principal exclusion criteria |
1) Sex and reproductive status a) Women who are pregnant or breast feeding b) Women of child bearing potential (WOCBP) who are unwilling to meet the study requirements for pregnancy testing (see section 7.6.1 Requirements for Pregnancy Testing) or are unwilling or unable to use an acceptable method to avoid pregnancy. WOCBP includes any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or> 12 consecutive months; or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35 m IU/ml]. Even women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered of child bearing potential. 2) Target Disease Exceptions c) Atrial fibrillation due to reversible causes (e.g. thyrotoxicosis, pericarditis) d) Valvular disease requiring surgery e) Planned atrial fibrillation ablation procedure to be performed within 3 months. 3) Medical History and Concurrent Disease f) Conditions other than atrial fibrillation that require chronic anticoagulation (e.g., prosthetic mechanical heart valve, venous thromboembolism; also see section 5.5 Concomitant Treatments). g) Patient with serious bleeding in the last 6 months or at high risk of bleeding. This includes, but is not limited to: • Active peptic ulcer disease • Platelet count < 100,000/mm3 or hemoglobin < 10g/dL • Recent stroke (within 10 days) • Documented hemorrhagic tendencies or blood dyscrasias h) Current alcohol or drug abuse, or psychosocial reasons that make study participation impractical i) Severe co-morbid condition with life expectancy <1 year 4) Physical and Laboratory Test Findings j) Severe renal insufficiency (creatinine clearance must be calculated in all patients; any patient with either a serum creatinine > 2.5 mg/dL [221 umol/L] or a calculated creatinine clearance < 25 ml/min is excluded) k) ALT or AST > 2 times upper limit of normal or a total bilirubin > 1.5 times upper limit of normal (unless an alternative causative factor [e.g., Gilbert’s syndrome] is identified) 5) Allergies and Adverse Drug Reactions None. Allergy or adverse reaction to ASA. 6) Prohibited Treatments and/or Therapies l) See section 5.5.1 (Prohibited and/or Restricted Treatments) for therapies which are prohibited at study entry m) Required treatment with a thienopyridine (clopidogrel or ticlopidine; see also section 5.5.2.1 Acetylsalicylic acid (ASA) and Thienopyridines). 7) Other Exclusion Criteria n) Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) o) Use of an investigational drug or device within the past 30 days or prior randomization into an apixaban clinical study p) Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness Eligibility criteria for this study have been carefully considered to ensure the safety of study subjects and to ensure that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria.
EXCLUSION
LONG TERM OPEN LABEL EXTENSION .a) No exclusion criterion for the double-blind trial (see Section 4.2.2) can be present at the timing of entry into the Long-Term Open-Label Extension with the exception of laboratory criteria. Patients entering the Long-Term Open-Label Extension who do not initially meet laboratory criteria but have qualifying values at the time of the Month LTOLE 1 visit may continue to participate in the LTOLE.
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E.5 End points |
E.5.1 | Primary end point(s) |
The following outcomes will be examined: - Primary efficacy outcome: time to the composite of stroke or systemic embolism - Primary safety outcome: time to major bleeding - Secondary Efficacy Outcome: time to stroke, systemic embolism, myocardial infarction or vascular death (major vascular events)
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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 | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 |
Open label for the long term part of the study |
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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.8.4.1 | Number of sites anticipated in Member State concerned | 18 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 195 |
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 | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |