E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Device-detected sub-clinical atrial fibrillation |
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E.1.1.1 | Medical condition in easily understood language |
Sub-clinical atrial fibrillation detected by pacemaker, ICD or loop recorder |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003658 |
E.1.2 | Term | Atrial fibrillation |
E.1.2 | System Organ Class | 10007541 - Cardiac 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, when compared to aspirin, will reduce the incidence of stroke and systemic embolism in patients with sub-clinical atrial fibrillation (SCAF). |
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E.2.2 | Secondary objectives of the trial |
To demonstrate the safety of apixaban compared to aspirin with respect to major bleeding in patients with device-detected sub-clinical atrial fibrillation. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Permanent pacemaker or defibrillator (with or without resynchronization) or insertable cardiac monitor capable of detecting SCAF 2. At least one episode of device-detected SCAF ≥ 6 minutes in duration (atrial rate > 175/min if an atrial lead is present), but no single episode > 24 hours in duration at any time prior to enrollment. SCAF requires electrogram confirmation (at least one episode) unless ≥ 6 hours in duration 3. Age ≥ 55 years 4. Risk Factor(s) for Stroke: Previous stroke, TIA or systemic arterial embolism OR Age at least 75 OR Age 65-74 with at least 2 other risk factors OR Age 55-64 with at least 3 other risk factors
Other risk factors are: • hypertension • CHF • diabetes • vascular disease (i.e. CAD, PAD or Aortic Plaque) • female
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E.4 | Principal exclusion criteria |
1. Clinical atrial fibrillation documented by surface ECG (12 lead ECG, Telemetry, Holter) lasting ≥ 6 minutes, with or without clinical symptoms 2. Receiving treatment with an oral anticoagulant for any reason (i.e., Mechanical valve prosthesis, deep vein thrombosis, etc.) 3. Severe heart failure, not currently receiving adequate treatment 4. Allergy to aspirin or apixaban 5. Severe renal insufficiency (serum creatinine > 2.5 mg/dL [221 µmol/L] or a calculated creatinine clearance < 25 ml/min) 6. Serious bleeding in the last 6 months or at high risk of bleeding (this includes, but is not limited to: prior intracranial hemorrhage, active peptic ulcer disease, clinically significant thrombocytopenia or anemia, recent stroke within past 10 days, documented hemorrhagic tendencies or blood dyscrasias) 7. Moderate to severe hepatic impairment 8. Ongoing need for combination therapy with aspirin and clopidogrel (or other combination of two platelet inhibitors) 9. Meets criteria for requiring lower dose of apixaban AND also has ongoing need for strong inhibitors of both CYP3A4 and P-glycoprotein (e.g., ketoconazole, itraconazole, ritonavir or clarithromycin) 10. Ongoing need for strong inducers of both CYP3A4 and P-glycoprotein (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) 11. Received an investigational drug in the past 30 days 12. Participants considered by the investigator to be unsuitable for the study for any of the following reasons: a. Not agreeable for treatment with either aspirin or apixaban or anticipated to have poor compliance on study drug treatment b. Unwilling to attend study follow-up visits c. Life expectancy less than 2 years due to concomitant disease 13. Women who are pregnant, breast-feeding or of child-bearing potential without an acceptable form of contraception in place (sexual abstinence for duration of study treatment*, combined (estrogen & progestogen) or progestogen-only hormonal contraception , intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner or other method with less than 1% failure rate)
*defined as refraining from heterosexual intercourse during the entire duration of study treatment. This must be evaluated in relationship to the expected duration of study treatment for each patient.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy outcome is a composite of stroke and systemic embolism.
The primary safety outcome will be the occurrence of clinically overt major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria: 1. Fatal bleeding 2. Symptomatic bleeding in a critical area or organ such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial or intramuscular with compartment syndrome, and/or 3. Bleeding causing a fall in hemoglobin level of 2 g/dL or more, or leading to transfusion of two or more units of whole blood or red cells. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time to first event during the study follow-up period. The study will be event driven and will continue until 248 primary efficacy events have occurred, which is anticipated with average patient follow-up of 36 months. |
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E.5.2 | Secondary end point(s) |
Secondary endpoints include: 1. Ischemic stroke 2. Myocardial infarction 3. Vascular death 4. Total death (vascular and non-vascular) 5. Composite of stroke, myocardial infarction, systemic embolism and total death 6. Composite of stroke, myocardial infarction, systemic embolism, total death and major bleeding |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints of evaluation will every six months for the duration of study (estimated to be an average 36 months of follow-up). |
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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 | 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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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.8.2.4 | 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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 70 |
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 |
Austria |
Belgium |
Canada |
Czech Republic |
Denmark |
France |
Germany |
Hungary |
Italy |
Netherlands |
Norway |
Spain |
Sweden |
Switzerland |
United Kingdom |
United States |
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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 | 7 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 31 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 25 |