| 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. |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 15.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10042244 |
| E.1.2 | Term | Stroke |
| E.1.2 | System Organ Class | 100000004852 |
|
| 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. |
|
| 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) |
|
| 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. |
|
| 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).
|
|
| 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.
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.
If the value of serum creatinine at Month 1 is > 221umol/L or > 2.5
mg/dL you should do the following:
Patient should be instructed to temporarily discontinue open-label
apixaban until renal function recovers
Repeat serum creatinine tests should be performed (locally or centrally
via unscheduled lab request) to confirm recovery of renal function before
considering restarting apixaban
If repeat test results show that value is < 221 umol/L or 2.5 mg/dL,
open-label apixaban may be resumed as long as the patient has not
temporarily discontinued study drug for > 60 days. If patient has
temporarily discontinued study drug for > 60 days, they are no
longer eligible to participate in the LTOLE phase of the trial. Study drug
must permanently discontinued and the Final LTOLE Visit must occur
|
|
| 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)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy outcome will be the time (days) from first dose of study drug to first occurrence of unrefuted Ischemic stroke, hemorrhagic
stroke, systemic embolism, myocardial infarction, or vascular death |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 |
|
| 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 |
|
| 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 | 3 |
| 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 | 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Hong Kong |
| India |
| Indonesia |
| Israel |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Philippines |
| Russian Federation |
| Singapore |
| Taiwan |
| Turkey |
| Ukraine |
| United States |
|
| 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 | 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 |
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