E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention |
|
E.1.1.1 | Medical condition in easily understood language |
atrial fibrillation and heart attacks with a coronary stent placement (PCI = percutaneous coronary intervention) OR after having elective PCI for chest pain. |
|
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 |
|
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 | 10051592 |
E.1.2 | Term | Acute coronary syndrome |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
|
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 | 10065608 |
E.1.2 | Term | Percutaneous coronary intervention |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
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 is noninferior to VKA (INR target range 2.0-3.0) on the combined endpoint of ISTH major and clinically relevant non-major bleeding in patients with NVAF who develop ACS or undergo PCI with planned concomitant P2Y12 inhibitor therapy.
- To determine if anticoagulant plus single antiplatelet therapy with a P2Y12 inhibitor is superior to anticoagulant plus dual antiplatelet therapy with a P2Y12 inhibitor and aspirin on the combined outcome of ISTH major and
clinically relevant non-major bleeding in patients with NVAF who develop ACS or undergo PCI with planned concomitant P2Y12 inhibitor therapy. |
|
E.2.2 | Secondary objectives of the trial |
To compare apixaban and VKA (with concomitant P2Y12 inhibitor therapy), in patients with NVAF who develop ACS or undergo PCI, with respect to:
- Superiority on ISTH major or clinically relevant non-major (CRNM) bleeding
- The composite of all-cause death and all-cause re-hospitalization
- Death, stroke, myocardial infarction, stent thrombosis, or urgent coronary revascularization
To compare aspirin and aspirin placebo (with concomitant P2Y12 inhibitor therapy), in patients with NVAF who develop ACS or undergo PCI with respect to:
-The composite of all-cause death and all-cause re-hospitalization
- Death, stroke, myocardial infarction, stent thrombosis, or urgent coronary revascularization
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed Written Informed Consent
a) Subjects will be required to provide a written informed consent.
2. Target Population
a) Males and females 18 years of age (or age of majority) or older with either active or a
history of non-valvular atrial fibrillation or flutter with the planned or existing use of an
oral anticoagulant for prophylaxis of thromboembolism for at least 6 months AND.
b) An acute coronary syndrome (ST-elevation myocardial infarction [STEMI], non-ST-elevation myocardial infarction [NSTEMI], or unstable angina), within the prior 14 days with planned use of an approved P2Y12 inhibitor for at least 6 months
AND/OR
c)PCI (with or without stents) within the prior 14 days with planned use of an approved P2Y12 inhibitor for at least 6 months.
(If both an ACS event and an elective PCI occur within the same 14 day period, the investigator has the option to define the index event for the randomization to the interactive voice/web response system. It is recommended to choose the most recent event as the index event.
However, for the electronic case report form, if a patient has both an ACS and PCI within 14 days, both events can be selected.)
3. Subject Re-enrollment:
a) This study does permit the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (screen failure).
4. Age and Reproductive Status
a) Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within
24 hours prior to the start of study drug.
b) Women must not be breastfeeding
c) WOCBP must agree to use effective contraception for the duration of treatment with study drugs plus
i. 33 days for patients on apixaban
ii. 40 days for patients on warfarin
d) Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. |
|
E.4 | Principal exclusion criteria |
- Conditions other than atrial fibrillation that require chronic anticoagulation (eg, prosthetic mechanical heart valve)
- Severe renal insufficiency (serum creatinine > 2.5 mg/dL [133 micromol/L] or a calculated creatinine clearance < 30 mL/min
- Patients with any history of intracranial hemorrhage
- Any contraindications to warfarin, apixaban, to intended P2Y12 inhibitors or to aspirin
- Patients who have or will undergo coronary arterial bypass graft (CABG) for their index
ACS event
- Patients with known ongoing bleeding
- Patients with known coagulopathies |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoints (safety):
The primary endpoint for apixaban versus VKA is
- ISTH major or CRNM bleeding
The primary endpoint for aspirin versus aspirin placebo is
- ISTH major or CRNM bleeding |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
A blinded assessment of the primary endpoint event rate will be performed after 50% of subjects have completed the study (please refer to Protocol section 8.1). |
|
E.5.2 | Secondary end point(s) |
The secondary endpoint for apixaban versus VKA includes
- Superiority on ISTH major or CRNM bleeding
- The composite of all-cause death and all cause re-hospitalization
- The composite endpoints of death, stroke, myocardial infarction, stent thrombosis, urgent coronary revascularization
The secondary endpoint for aspirin versus aspirin placebo includes
- The composite of all-cause death and all-cause re-hospitalization
- The composite endpoints of death, stroke, myocardial infarction, stent thrombosis, urgent coronary revascularization |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to Protocol section 8.1 |
|
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 | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 253 |
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 |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
Chile |
Colombia |
Croatia |
Czech Republic |
Denmark |
Germany |
Hungary |
India |
Israel |
Italy |
Korea, Republic of |
Mexico |
Netherlands |
Norway |
Peru |
Portugal |
Romania |
Russian Federation |
Serbia |
Slovakia |
Spain |
Sweden |
Switzerland |
Ukraine |
United Kingdom |
|
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 | 1 |
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 | 1 |