| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003658 |
| E.1.2 | Term | Atrial fibrillation |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10057613 |
| E.1.2 | Term | Thromboembolic stroke |
|
| 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 warfarin (INR target range 2.0-3.0) in the
combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism, in
subjects with AF and at least one additional risk factor for stroke. |
|
| E.2.2 | Secondary objectives of the trial |
• Determine in subjects with AF & at least 1 additional risk factor for stroke,
whether apixaban is superior to warfarin in combined endpoints of:
- ischemic stroke, hemorrhagic stroke & systemic embolism
− ischemic stroke, hemorrhagic stroke, systemic embolism & major bleeding, in warfarin naïve subjects
− ischemic stroke, hemorrhagic stroke, systemic embolism and major bleeding
• To compare, in subjects with AF & at least 1 additional risk factor for stroke,
apixaban and warfarin with respect to the composite endpoint of:
- ischemic stroke, hemorrhagic stroke, systemic embolism & all cause death
− ischemic stroke, hemorrhagic stroke, systemic embolism, major bleeding & all cause death
− ischemic stroke, hemorrhagic stroke, systemic embolism, myocardial infarction & all cause death
− incidence of major bleeding
• To assess safety of apixaban in subjects with AF & at least 1 additional risk
factor for stroke.
|
|
| 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 |
| Pharmacogenetics Blood Sample Amendment Number 1 - Site Specific, version 3.0, dated 04-Nov-2006 |
|
| E.3 | Principal inclusion criteria |
For entry into the study, the following criteria MUST be met.
1) Age >= 18 years
2) Permanent or persistent atrial fibrillation or atrial flutter documented by ECG at the
time of enrollment.
OR
If not in atrial fibrillation/flutter at the time of enrollment, must have atrial
fibrillation/flutter documented on two separate occasions at least 2 weeks apart in the 6
months prior to enrollment. Atrial fibrillation/flutter may be documented by ECG, or as
an episode at least one minute in duration on a rhythm strip or Holter recording.
3) One or more of the following risk factor(s) for stroke:
a) Age 75 years or older
b) Prior stroke, TIA or systemic embolus
c) Either symptomatic congestive heart failure within 3 months or left ventricular
dysfunction with an LV ejection fraction (LVEF) =< 40% by echocardiography,
radionuclide study or contrast angiography
d) Diabetes mellitus
e) Hypertension requiring pharmacological treatment
4) Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the treatment period of the study or for
2 weeks after the last dose of study medication, whichever is longer, in such a manner that the risk of pregnancy is minimized.
WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >= 12 consecutive months; or women on hormone replacement therapy [HRT] with documented serum follicle stimulating hormone [FSH] level > 35 mIU/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 arepracticing abstinence or where their partner is sterile (eg, vasectomy) should be
considered to be of childbearing potential.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25
IU/L or equivalent units of HCG) within 48 hours prior to the start of investigational
product.
5) All subjects must provide signed written informed consent. |
|
| E.4 | Principal exclusion criteria |
1) Atrial fibrillation or flutter due to reversible causes (e.g. thyrotoxicosis, pericarditis)
2) Clinically significant (moderate or severe) mitral stenosis
3) Increased bleeding risk that is believed to be a contraindication to oral anticoagulation
(e.g. documented peptic ulcer disease within 6 months, previous intracranial
hemorrhage)
4) Conditions other than atrial fibrillation that require chronic anticoagulation (e.g.
prosthetic mechanical heart valve)
5) Persistent, uncontrolled hypertension (systolic BP > 180 mm Hg, or diastolic BP
> 100 mm Hg)
6) Active infective endocarditis
7) Planned major surgery
8) Planned atrial fibrillation or flutter ablation procedure
9) Use of an unapproved, investigational drug or device within the past 30 days
10) Required treatment with aspirin > 165 mg/day
11) Simultaneous treatment with both aspirin and a thienopyridine (e.g., clopidogrel,
ticlopidine)
12) Severe comorbid condition with life expectancy of =< 1 year
13) Active alcohol or drug abuse, or psychosocial reasons that make study participation
impractical
14) Recent stroke (within 30 days)
15) Severe renal insufficiency (serum creatinine > 2.5 mg/dL or a calculated creatinine
clearance < 25 mL/min)
16) ALT or AST > 2X ULN or a Total Bilirubin >= 1.5X ULN (unless an alternative
causative factor [e.g., Gilbert’s syndrome] is identified)
17) Platelet count =< 100,000/ mm3
18) Hemoglobin < 10 g/dL
19) Inability to comply with INR monitoring
20) Prior randomization into an apixaban clinical study
21) Prisoners or subjects who are involuntarily incarcerated
22) Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (e.g., infectious disease) illness
23) Women of child bearing potential (WOCBP) unwilling or unable to use an acceptable
method to avoid pregnancy:
a) WOCBP using a prohibited contraceptive method
b) WOCBP include any female who has experienced menarche and who has not
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation,
or bilateral oophorectomy) or is not postmenopausal [defined as amenorrhea >= 12
consecutive months; or women on hormone replacement therapy (HRT) with
documented serum follicle stimulating hormone (FSH) level > 35 mIU/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 to be of child bearing
potential
c) Women who are pregnant or breastfeeding
d) Women with a positive pregnancy test on enrollment or prior to administration of
investigational product.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and the integrity of the study data. It is imperative that subjects fully meet all eligibility criteria.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint
The primary efficacy endpoint will be the time to first occurrence of confirmed ischemic stroke, hemorrhagic or systemic embolism.
The secondary efficacy endpoints will be time to first occurrence of confirmed:
• ischemic stroke
• hemorrhagic stroke
• systemic embolism
• all cause death
• composite of ischemic stroke, hemorrhagic stroke, systemic embolism, major bleeding
• composite of ischemic stroke, hemorrhagic stroke, systemic embolism, all cause death
• composite of ischemic stroke, hemorrhagic stroke, systemic embolism, major bleeding, all cause death
• composite of ischemic stroke, hemorrhagic stroke, systemic embolism, myocardial infarction, all cause death
Primary safety endpoint
The primary safety endpoint is the time to first occurrence of confirmed major bleeding.
Secondary safety endpoints
The secondary safety outcome for this trial is a composite of confirmed major bleeding and confirmed clinically significant non-major bleeding. Other safety outcome measures will also be assessed, and will include minor bleeds, fractures and other AEs as well as abnormal standard clinical laboratory test results.
All major bleeding and clinically relevant non-major bleeding outcomes will be adjudicated by CEC.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 165 |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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